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Sample records for 15q24 deleted patients

  1. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region

    PubMed Central

    2010-01-01

    Background The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. Methods We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. Results Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. Conclusions From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in

  2. Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome.

    PubMed

    Van Esch, Hilde; Backx, Liesbeth; Pijkels, Elly; Fryns, Jean-Pierre

    2009-01-01

    The recurrent microdeletion 15q24 syndrome is rare with only 5 cases reported thus far. Here we describe an additional patient with this deletion, presenting with many features common to this syndrome, including developmental delay, loose connective tissue, digital and genital anomalies and a distinct facial gestalt. Interestingly, in addition, this patient has a large congenital diaphragmatic hernia, as was described in one other patient with a 15q24 microdeletion, indicating that this feature might be part of the syndrome. Chromosome 15q24 has a highly polymorphic architecture that is prone to genomic rearrangements underlying this novel microdeletion syndrome.

  3. An inferential study of the phenotype for the chromosome 15q24 microdeletion syndrome: a bootstrap analysis

    PubMed Central

    Ramírez-Prado, Dolores; Cortés, Ernesto; Aguilar-Segura, María Soledad; Gil-Guillén, Vicente Francisco

    2016-01-01

    In January 2012, a review of the cases of chromosome 15q24 microdeletion syndrome was published. However, this study did not include inferential statistics. The aims of the present study were to update the literature search and calculate confidence intervals for the prevalence of each phenotype using bootstrap methodology. Published case reports of patients with the syndrome that included detailed information about breakpoints and phenotype were sought and 36 were included. Deletions in megabase (Mb) pairs were determined to calculate the size of the interstitial deletion of the phenotypes studied in 2012. To determine confidence intervals for the prevalence of the phenotype and the interstitial loss, we used bootstrap methodology. Using the bootstrap percentiles method, we found wide variability in the prevalence of the different phenotypes (3–100%). The mean interstitial deletion size was 2.72 Mb (95% CI [2.35–3.10 Mb]). In comparison with our work, which expanded the literature search by 45 months, there were differences in the prevalence of 17% of the phenotypes, indicating that more studies are needed to analyze this rare disease. PMID:26925314

  4. An inferential study of the phenotype for the chromosome 15q24 microdeletion syndrome: a bootstrap analysis.

    PubMed

    Palazón-Bru, Antonio; Ramírez-Prado, Dolores; Cortés, Ernesto; Aguilar-Segura, María Soledad; Gil-Guillén, Vicente Francisco

    2016-01-01

    In January 2012, a review of the cases of chromosome 15q24 microdeletion syndrome was published. However, this study did not include inferential statistics. The aims of the present study were to update the literature search and calculate confidence intervals for the prevalence of each phenotype using bootstrap methodology. Published case reports of patients with the syndrome that included detailed information about breakpoints and phenotype were sought and 36 were included. Deletions in megabase (Mb) pairs were determined to calculate the size of the interstitial deletion of the phenotypes studied in 2012. To determine confidence intervals for the prevalence of the phenotype and the interstitial loss, we used bootstrap methodology. Using the bootstrap percentiles method, we found wide variability in the prevalence of the different phenotypes (3-100%). The mean interstitial deletion size was 2.72 Mb (95% CI [2.35-3.10 Mb]). In comparison with our work, which expanded the literature search by 45 months, there were differences in the prevalence of 17% of the phenotypes, indicating that more studies are needed to analyze this rare disease.

  5. Neocentromeres in 15q24-26 Map to Duplicons Which Flanked an Ancestral Centromere in 15q25

    PubMed Central

    Ventura, Mario; Mudge, Jonathan M.; Palumbo, Valeria; Burn, Sally; Blennow, Elisabeth; Pierluigi, Mauro; Giorda, Roberto; Zuffardi, Orsetta; Archidiacono, Nicoletta; Jackson, Michael S.; Rocchi, Mariano

    2003-01-01

    The existence of latent centromeres has been proposed as a possible explanation for the ectopic emergence of neocentromeres in humans. This hypothesis predicts an association between the position of neocentromeres and the position of ancient centromeres inactivated during karyotypic evolution. Human chromosomal region 15q24-26 is one of several hotspots where multiple cases of neocentromere emergence have been reported, and it harbors a high density of chromosome-specific duplicons, rearrangements of which have been implicated as a susceptibility factor for panic and phobic disorders with joint laxity. We investigated the evolutionary history of this region in primates and found that it contains the site of an ancestral centromere which became inactivated about 25 million years ago, after great apes/Old World monkeys diverged. This inactivation has followed a noncentromeric chromosomal fission of an ancestral chromosome which gave rise to phylogenetic chromosomes XIV and XV in human and great apes. Detailed mapping of the ancient centromere and two neocentromeres in 15q24-26 has established that the neocentromere domains map approximately 8 Mb proximal and 1.5 Mb distal of the ancestral centromeric region, but that all three map within 500 kb of duplicons, copies of which flank the centromere in Old World Monkey species. This suggests that the association between neocentromere and ancestral centromere position on this chromosome may be due to the persistence of recombinogenic duplications accrued within the ancient pericentromere, rather than the retention of “centromere-competent” sequences per se. The high frequency of neocentromere emergence in the 15q24-26 region and the high density of clinically important duplicons are, therefore, understandable in the light of the evolutionary history of this region. PMID:12915487

  6. Complex chromosomal rearrangement in a girl with psychomotor-retardation and a de novo inversion: inv(2)(p15;q24.2).

    PubMed

    Granot-Hershkovitz, Einat; Raas-Rothschild, Annick; Frumkin, Ayala; Granot, David; Silverstein, Shira; Abeliovich, Dvorah

    2011-08-01

    Cytogenetic analysis of DNA from a girl with severe psychomotor retardation revealed a de novo pericentric inversion of chromosome 2: 46,XX,inv(2)(p15q24.2). In order to elucidate the possible role of the inversion in the girl's abnormal phenotype, we analyzed the inversion breakpoints. FISH analysis revealed BAC clones spanning the breakpoints at 2p and 2q of the inversion. Southern blot hybridization with DNA probes from the BAC regions was used to refine the localization of the breakpoints, followed by inverse-PCR which enabled us to sequence the inversion breakpoints. We found a complex chromosomal rearrangement, including five breakpoints, four at 2q and one at 2p joined with minor insertions/deletions of a few bases. The breakpoint at 2p was within the NRXN1 gene that has previously been associated with autism, intellectual disabilities, and psychiatric disorders. In 2q, the breakpoints disrupted two genes, TANC1 and RBMS1; the phenotypic effect of these genes is not currently known.

  7. Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population.

    PubMed

    Matsuda, Koichi; Takahashi, Atsushi; Middlebrooks, Candace D; Obara, Wataru; Nasu, Yasutomo; Inoue, Keiji; Tamura, Kenji; Yamasaki, Ichiro; Naya, Yoshio; Tanikawa, Chizu; Cui, Ri; Figueroa, Jonine D; Silverman, Debra T; Rothman, Nathaniel; Namiki, Mikio; Tomita, Yoshihiko; Nishiyama, Hiroyuki; Kohri, Kenjiro; Deguchi, Takashi; Nakagawa, Masayuki; Yokoyama, Masayoshi; Miki, Tsuneharu; Kumon, Hiromi; Fujioka, Tomoaki; Prokunina-Olsson, Ludmila; Kubo, Michiaki; Nakamura, Yusuke; Shuin, Taro

    2015-02-15

    Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.

  8. Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population

    PubMed Central

    Matsuda, Koichi; Takahashi, Atsushi; Middlebrooks, Candace D.; Obara, Wataru; Nasu, Yasutomo; Inoue, Keiji; Tamura, Kenji; Yamasaki, Ichiro; Naya, Yoshio; Tanikawa, Chizu; Cui, Ri; Figueroa, Jonine D.; Silverman, Debra T.; Rothman, Nathaniel; Namiki, Mikio; Tomita, Yoshihiko; Nishiyama, Hiroyuki; Kohri, Kenjiro; Deguchi, Takashi; Nakagawa, Masayuki; Yokoyama, Masayoshi; Miki, Tsuneharu; Kumon, Hiromi; Fujioka, Tomoaki; Prokunina-Olsson, Ludmila; Kubo, Michiaki; Nakamura, Yusuke; Shuin, Taro

    2015-01-01

    Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10−9. Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r2 = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer. PMID:25281661

  9. Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence

    PubMed Central

    Cáceres, Alejandro; Esko, Tõnu; Pappa, Irene; Gutiérrez, Armand; Lopez-Espinosa, Maria-Jose; Llop, Sabrina; Bustamante, Mariona; Tiemeier, Henning; Metspalu, Andres; Wilsonx, James F.; Reina-Castillón, Judith; Shin, Jean; Pausova, Zdenka; Paus, Tomáš; Sunyer, Jordi; Pérez-Jurado, Luis A.; González, Juan R.

    2016-01-01

    The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas. PMID:27355585

  10. Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence.

    PubMed

    Cáceres, Alejandro; Esko, Tõnu; Pappa, Irene; Gutiérrez, Armand; Lopez-Espinosa, Maria-Jose; Llop, Sabrina; Bustamante, Mariona; Tiemeier, Henning; Metspalu, Andres; Joshi, Peter K; Wilsonx, James F; Reina-Castillón, Judith; Shin, Jean; Pausova, Zdenka; Paus, Tomáš; Sunyer, Jordi; Pérez-Jurado, Luis A; González, Juan R

    2016-01-01

    The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas. PMID:27355585

  11. A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

    PubMed

    Delague, Valérie; Bareil, Corinne; Bouvagnet, Patrice; Salem, Nabiha; Chouery, Eliane; Loiselet, Jacques; Mégarbané, André; Claustres, Mireille

    2002-03-01

    Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

  12. Growth patterns of patients with 1p36 deletion syndrome.

    PubMed

    Sangu, Noriko; Shimojima, Keiko; Shimada, Shino; Ando, Tomohiro; Yamamoto, Toshiyuki

    2014-05-01

    1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes. Obesity is frequently observed in patients with this syndrome. Thus, it is important to evaluate the growth status of an individual patient. For this purpose, we accumulated recorded growth data from 44 patients with this syndrome and investigated the growth patterns of patients. Most of the patients showed weight parameters within normal limits, whereas a few of these patients showed intrauterine growth delay and microcephaly. The length of the patients after birth was under the 50th centile in most patients. Many patients showed poor weight gain after birth, and only two female patients were overweight. These findings indicate two different phenotypes of the 1p36 deletion syndrome. The overweight patients with 1p36 deletion started excessive weight gain after two years of life. This characteristic of the patients with 1p36 deletion syndrome is similar to Prader-Willi syndrome.

  13. Mitochondrial DNA deletions in patients with chronic suppurative otitis media.

    PubMed

    Tatar, Arzu; Tasdemir, Sener; Sahin, Ibrahim; Bozoglu, Ceyda; Erdem, Haktan Bagis; Yoruk, Ozgur; Tatar, Abdulgani

    2016-09-01

    The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p < 0.01). Long time chronic suppurative otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media.

  14. Molecular cytogenetic detection of chromosome 15 deletions in patients with Prader-Willi and Angelman syndromes

    SciTech Connect

    Chadwick, D.E.; Weksberg, R.; Shuman, C.

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct genetic disorders involving alterations of chromosome 15q11-q13. Approximately 75% of individuals with PWS and AS have deletions within 15q11-q13 by molecular analysis. We have evaluated fluorescence in situ hybridization (FISH) for the clinical laboratory detection of del(15)(q11q13) using the cosmid probes D15S11 and GABRB3 (ONCOR, Gaithersburg, NY). 4/4 PWS and 1/1 AS patients previously identified as having cytogenetic deletions were deleted for both probes. In a prospectively ascertained series of 54 patient samples referred to rule out either PWS or AS, 8 were deleted for D15S11 and GABRB3. In addition, an atypical deletion patient with PWS was also identified who was found to be deleted for GABRB3 but not D15S11. The SNRPN locus was also deleted in this patient. Only 4 of the 9 patient samples having molecular cytogenetic deletions were clearly deleted by high resolution banding (HRB) analysis. The microscopic and submicroscopic deletions have been confirmed by dinucleotide (CA) repeat analysis. Microsatellite polymorphism analysis was also used to demonstrate that five non-deletion patients in this series had biparental inheritance of chromosome 15, including region q11-q13. Deletions were not detected by either HRB, FISH or microsatellite polymorphism analysis in samples obtained from parents of the deletion patients. Methylation studies of chromosome 15q11-q13 are in progress for this series of PWS and AS families. FISH analysis of chromosome 15q11-q13 in patients with PWS and AS is a rapid, sensitive and reliable method for deletion detection.

  15. Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy

    SciTech Connect

    Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. ); Shokeir, M. )

    1992-09-01

    In a previous study the authors identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. They have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases they detected slightly lower-molecular-weight dystrophin in 12%-15% abundance relative to the normal. By sequencing amplified mRNA they have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternate splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame. 34 refs., 5 figs. 1 tab.

  16. Cognitive and structural neuroimaging characteristics of schizophrenia patients with large, rare copy number deletions.

    PubMed

    Kenneth Martin, Andrew; Robinson, Gail; Reutens, David; Mowry, Bryan

    2014-12-30

    Large (>500 Kb), rare (frequency <1%) deletions are associated with risk for schizophrenia. The aim of the study was to characterise patients with these deletions using measures of cognition, grey-matter volume and white-matter integrity. Patients with schizophrenia and large, rare deletions (SZ-del) (n=17) were assessed on a test of intelligence, the Wechsler Abbreviated Scale of Intelligence (WASI), and compared with age- and sex-matched schizophrenia patients without large, rare deletions (SZ-nodel) (n=65), and healthy controls (HCs) (n=50). Regional grey-matter differences were investigated using voxel-based morphometry (SZ-del=9; SZ-nodel=26; HC=19). White-matter integrity was assessed using fractional anisotropy (SZ-del=9; SZ-nodel=24; HC=15). Compared with schizophrenia patients without large, rare deletions, those with large, rare deletions had lower IQ; greater grey-matter volume in clusters with peaks in the left and right cerebellum, left hippocampus, and right rectal gyrus; and increased white-matter anisotropy in the body and genu of the corpus callosum. Compared with healthy controls, patients with large, rare deletions had reduced grey matter volume in the right calcarine gyrus. In sum, patients with large, rare deletions had structural profiles intermediate to those observed in healthy controls and schizophrenia patients without large, rare deletions, but had greater impairment in intelligence. PMID:25453991

  17. Molecular analysis of three patients with interstitial deletions of chromosome band 14q31.

    PubMed Central

    Byth, B C; Costa, M T; Teshima, I E; Wilson, W G; Carter, N P; Cox, D W

    1995-01-01

    Two patients and one three generation family with interstitial deletions of distal chromosome band 14q31 are described. The deletions were initially identified by chromosome analysis; we have used highly informative simple sequence repeat polymorphisms to define the deletions at the molecular level. This analysis also establishes the parental origin of the deleted chromosome. One of the patients was initially described as having a terminal deletion of chromosome 14 from 14q31 to 14qter; we show here that this child has instead an interstitial deletion of band 14q31. The smallest deletion involves a single anonymous DNA marker and is associated with an almost normal phenotype. The two patients with larger deletions have phenotypes similar to those seen in previously described cases of interstitial deletions of chromosome 14, including minor dysmorphic features and developmental delay. Delineation of these deletions allows the ordering of markers within the 14q31 region, in which the gene for the degenerative neurological disorder Machado-Joseph disease is localised. Images PMID:7562974

  18. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy

    SciTech Connect

    Cobben, J.M.; Steege, G. van der; Grootscholten, P.

    1995-10-01

    DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type 1. SMN deletions have not yet been described to occur in healthy subjects. In this study, however, four unaffected sibs from two SMA families showed homozygosity for SMN deletions. Homozygosity for an SMN deletion in unaffected persons seems to be very rare. Therefore, demonstration of a homozygous SMN deletion in a clinically presumed SMA patient should be considered as a confirmation of the diagnosis, whether or not SMN is in fact the causal gene for SMA. 19 refs., 2 figs.

  19. Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients.

    PubMed Central

    Kayes, L. M.; Burke, W.; Riccardi, V. M.; Bennett, R.; Ehrlich, P.; Rubenstein, A.; Stephens, K.

    1994-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by marked variation in clinical severity. To investigate the contribution to variability by genes either contiguous to or contained within the NF1 gene, we screened six NF1 patients with mild facial dysmorphology, mental retardation, and/or learning disabilities, for DNA rearrangement of the NF1 region. Five of the six patients had NF1 gene deletions on the basis of quantitative densitometry, locus hemizygosity, and analysis of somatic cell hybrid lines. Analyses of hybrid lines carrying each of the patient's chromosomes 17, with 15 regional DNA markers, demonstrated that each of the five patients carried a deletion > 700 kb in size. Minimally, each of the deletions involved the entire 350-kb NF1 gene; the three genes--EVI2A, EVI2B, and OMG--that are contained within an NF1 intron; and considerable flanking DNA. For four of the patients, the deletions mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele presumably produced functional neurofibromin; no gene rearrangements were detected, and RNA-PCR demonstrated that it was transcribed. These data provide compelling evidence that the NF1 disorder results from haploid insufficiency of neurofibromin. Of the three documented de novo deletion cases, two involved the paternal NF1 allele and one the maternal allele. The parental origin of the single remaining expressed NF1 allele had no dramatic effect on patient phenotype. The deletion patients exhibited a variable number of physical anomalies that were not correlated with the extent of their deletion. All five patients with deletions were remarkable for exhibiting a large number of neurofibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:8116612

  20. Deletions spanning the neurofibromatosis I gene: Identification and phenotype of five patients

    SciTech Connect

    Kayes, L.M.; Burke, W.; Bennett, R.; Ehrlich, P.; Stephens, K. ); Riccardi, V.M. ); Rubenstein, A. )

    1994-03-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by marked variation in clinical severity. To investigate the contribution to variability by genes either contiguous to or contained within the NF1 gene, the authors screened six NF1 patients with mild facial dysmorphology, mental retardation, and/or learning disabilities, for DNA rearrangement of the NF1 region. Five of the six patients had NF1 gene deletions on the basis of quantitative densitometry, locus hemizygosity, and analysis of somatic cell hybrid lines. Analysis of hybrid lines carrying each of the patient's chromosomes 17, with 15 regional DNA markers, demonstrated that each of the five patients carried a deletion >700 kb in size. Minimally, each of the deletions involved the entire 350-kb NF1 gene; the three genes - EVI2A, EVI2B, and OMG-that are contained within an NF1 intron; and considerable flanking DNA. For four of the patients, the deletions mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele presumably produced functional neurofibromin; no gene rearrangements were detected, and RNA-PCR demonstrated that it was transcribed. These data provide compelling evidence that the NF1 disorder results from haploid insufficiency of neurofibromin. Of the three documented de novo deletion cases, two involved the paternal NF1 allele and one the maternal allele. The parental origin of the single remaining expresses NF1 allele had no dramatic effect on patient phenotype. The deletion patients exhibited a variable number of physical anomalies that were not correlated with the extent of their deletion. All five patients with deletions were remarkable for exhibiting a large number of neurfibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development. 69 refs., 5 figs., 1 tab.

  1. Choanal atresia in a patient with the deletion (9p) syndrome

    SciTech Connect

    Shashi, V.; Golden, W.L.; Fryburg, J.S.

    1994-01-01

    The authors report on a child with choanal atresia and deletion 9p. A review of the literature documented one previous instance of choanal atresia in a patient with del(9p). Choanal atresia may be part of the spectrum of malformations in the deletion (9p) syndrome and its presence should prompt a search for this particular deletion as part of the differential diagnosis. 9 refs., 3 figs.

  2. Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: Evaluation of 235 patients

    SciTech Connect

    Lowery, M.C.; Brothman, L.J.; Leonard, C.O.

    1995-07-01

    Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as {open_quotes}classic{open_quotes} (n = 114) or{open_quotes}uncertain{close_quotes} (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS. 14 refs., 2 figs., 4 tabs.

  3. A large TAT deletion in a tyrosinaemia type II patient.

    PubMed

    Legarda, Maria; Wlodarczyk, Katarzyna; Lage, Sergio; Andrade, Fernando; Kim, Gwang-Jin; Bausch, Elke; Scherer, Gerd; Aldamiz-Echevarria, Luis Jose

    2011-11-01

    A girl, born to unrelated Spanish parents, presented at 6 months of age with photophobia, keratitis, palmar hyperkeratosis and high plasma tyrosine levels, indicative of tyrosinaemia type II. Analysis of the tyrosine aminotransferase (TAT) gene revealed a paternally inherited frameshift mutation c.1213delCinsAG at codon 405 causing a premature stop codon, and a maternally inherited deletion of 193kb encompassing the complete TAT gene and three neighbouring genes. This is the first complete TAT deletion in tyrosinaemia type II described so far.

  4. Mild developmental delay and obesity in two patients with mosaic 1p36 deletion syndrome.

    PubMed

    Shimada, Shino; Maegaki, Yoshihiro; Osawa, Makiko; Yamamoto, Toshiyuki

    2014-02-01

    We identified mosaic 1p36 deletions in two patients with developmental delay, distinctive features, and obesity, who can walk alone and communicate with others. Thus, their neurological defects are milder than those in typical patients with 1p36 deletion syndrome because most patients with 1p36 deletion cannot acquire expressive language. Chromosomal microarray testing revealed 3.0 and 4.5 Mb aberrations in the subtelomeric region of the short arm of chromosome 1. Mean signal ratios of the identified aberrations were -0.4 and -0.5, indicating mosaicism, which was confirmed by fluorescence in situ hybridization analysis with a mosaic ratio of 70% and 77%, respectively. Previous studies demonstrated that deletion of the distal 2-3 Mb region would be responsible for hyperphagia and obesity seen in patients. On the other hand, the severity of the neurological defect often correlates with the size of the terminal deletion of 1p36, and patients with larger deletions of 1p36 would usually show severely impaired developmental milestones and be immobile and aphasic. In such cases, hyperphagia and obesity could be clinically masked. In this study, two patients with mosaic deletions of 1p36 showed obesity as a consequence of hyperphagia. This study suggests that patients with 1p36 deletion would be at risk for hyperphagia and obesity when they have both risk factors, that is, (1) deletions including the 2-3 Mb critical region and (2) milder phenotypes that allow them to reach food on their own and to overeat.

  5. Microarray Analysis of 8p23.1 Deletion in New Patients with Atypical Phenotypical Traits.

    PubMed

    Khelifa, Hela Ben; Kammoun, Molka; Hannachi, Hanene; Soyah, Najla; Hammami, Saber; Elghezal, Hatem; Sanlaville, Damien; Saad, Ali; Mougou-Zerelli, Soumaya

    2015-12-01

    We describe two patients carrying deletions of chromosome 8p23.1 with a commonly critical region identified by means of oligonucleotide array comparative genomic hybridization (array CGH). They didn't present congenital heart defects or behavioral problems. Only one patient presented with intellectual disability and carrying deletion of TNKS gene. We presumed the inclusion of TNKS gene in the mental impairment. PMID:27617130

  6. FISH analysis of a subtle familial Xp deletion in a female patient with Madelung deformity

    SciTech Connect

    Hsu, T.Y.; Gibson, L.H.; Pober, B.R.

    1994-09-01

    A subtle deletion of Xp [del(X)(p22.32)]was identified by high-resolution chromosome analysis in a twelve-year-old female with short stature (<2 percentile) and Madelung deformity suggestive of Turner syndrome. The proband`s mother, who has short stature (<2 percentile) and demyelinating disorder, also showed this deletion. The maternal grandmother is of normal height and carries two normal X chromosomes. Both the patient and her mother have no other physical abnormalities and are of normal intelligence. To confirm and delineate this Xp deletion, fluorescence in situ hybridization (FISH) was performed on metaphases from the patient and her mother using probes of DXYS20 (a pseudoautosomal locus), DXS232A, and a newly isolated Xp YAC clone, YHX2, whose relative map position is unknown. Hybridization signals of DXS232A were detected on both X chromosomes, and DXYS20 and YHX2 were missing from one of the X`s of both the patient and her mother. YHX2 was thus placed distal to DXS232A (tel-DXYS20-YHX2-S232A-cen). This familial deletion with a breakpoint distal to DXS232A, which is located at -900 Kb telomeric to STS locus, appears to be the smallest Xp deletion reported thus far. Short stature is consistently associated with females carrying Xp deletions. Madelung deformity has been found in some patients with Turner syndrome or Dyschondrosteosis but it has not been reported in patients with Xp deletion. Our results suggest that the phenotype of our patient is associated with her chromosome abnormality. Due to the subtlety of the deletion identified in our patient and her mother, females presenting with short stature warrant careful clinical and cytogenetic evaluation.

  7. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

    PubMed Central

    Juyal, R. C.; Figuera, L. E.; Hauge, X.; Elsea, S. H.; Lupski, J. R.; Greenberg, F.; Baldini, A.; Patel, P. I.

    1996-01-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. Images Figure 2 PMID:8651284

  8. Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

    SciTech Connect

    Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y.

    1994-02-15

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.

  9. Structural Brain Abnormalities in Patients with Schizophrenia and 22q11 Deletion Syndrome

    PubMed Central

    Chow, Eva W.C.; Zipursky, Robert B.; Mikulis, David J.; Bassett, Anne S.

    2012-01-01

    Background 22q11 Deletion Syndrome is a genetic syndrome associated with an increased risk for developing schizophrenia. Brain abnormalities have been reported in 22q11 Deletion Syndrome, but little is known about whether differences in brain structure underlie the psychotic disorders associated with this syndrome. In the current study, we used magnetic resonance imaging to characterize the structural brain abnormalities found in adults who have both 22q11 Deletion Syndrome and schizophrenia. Methods Magnetic resonance imaging brain scans of 14 adults (7 male, 7 female) with 22q11 Deletion Syndrome and schizophrenia and 14 age- and gender-matched healthy volunteers were analyzed to derive measures of gray matter, white matter, and cerebrospinal fluid. Differences between the two groups were tested using student t tests. Results 22q11 Deletion Syndrome and schizophrenia subjects had significantly smaller total gray matter volume (t = 2.88, p < .01) and larger lateral ventricles (t = 4.08, p < .001) than healthy controls. Gray matter deficits were most prominent in the frontal and temporal lobes. Total white matter volumes did not differ between the two groups. Conclusions Findings from this 22q11 Deletion Syndrome and schizophrenia study are similar to those reported in other patients with schizophrenia, but only partially consistent with those reported in nonpsychotic children with 22q11 Deletion Syndrome. 22q11 Deletion Syndrome may provide a valuable genetic neurodevelop-mental model for investigating the relationship between abnormalities in brain development and the expression of schizophrenia. PMID:11839363

  10. Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress.

    PubMed

    Nie, Hezhongrong; Chen, Guorong; He, Jing; Zhang, Fengjiao; Li, Ming; Wang, Qiufeng; Zhou, Huaibin; Lyu, Jianxin; Bai, Yidong

    2016-01-01

    The 4977 bp common deletion is one of the most frequently observed mitochondrial DNA (mtDNA) mutations in human tissues and has been implicated in various human cancer types. It is generally believed that continuous generation of intracellular reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS) is a major underlying mechanism for generation of such mtDNA deletions while antioxidant systems, including Manganese superoxide dismutase (MnSOD), mitigating the deleterious effects of ROS. However, the clinical significance of this common deletion remains to be explored. A comprehensive investigation on occurrence and accumulation of the common deletion and mtDNA copy number was carried out in breast carcinoma (BC) patients, benign breast disease (BBD) patients and age-matched healthy donors in our study. Meanwhile, the representative oxidative (ROS production, mtDNA and lipid oxidative damage) and anti-oxidative features (MnSOD expression level and variation) in blood samples from these groups were also analyzed. We found that the mtDNA common deletion is much more likely to be detected in BC patients at relatively high levels while the mtDNA content is lower. This alteration has been associated with a higher MnSOD level and higher oxidative damages in both BC and BBD patients. Our results indicate that the mtDNA common deletion in blood may serve a biomarker for the breast cancer. PMID:26678158

  11. Novel airway findings in a patient with 1p36 deletion syndrome.

    PubMed

    Ferril, Geoffrey R; Barham, Henry P; Prager, Jeremy D

    2014-01-01

    1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated airway anomalies with this syndrome. We present here a case report and literature review. Prenatally, amniocentesis for chromosomal analysis was performed on our patient, with results consistent with 1p36 deletion syndrome. Respiratory distress and unsuccessful attempts at intubation prompted transfer to Children's Hospital of Colorado. Microlaryngoscopy was subsequently performed, revealing a persistent buccopharyngeal membrane and unidentifiable larynx. Emergent tracheostomy was then performed to secure the airway. Airway anomalies may be associated with 1p36 deletion syndrome.

  12. Two patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia.

    PubMed

    Bassett, J K; Chandler, K E; Douzgou, S

    2016-08-01

    Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS.

  13. Two patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia.

    PubMed

    Bassett, J K; Chandler, K E; Douzgou, S

    2016-08-01

    Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS. PMID:27184501

  14. AB097. Clinical and molecular characterization of patients with 6p25 deletion syndrome

    PubMed Central

    Lim, Jiin Ying; Jamuar, Saumya Shekhar; Cham, Breana Wen Min; Brett, Maggie; Tan, Ee Shien; Ng, Ivy; Law, Hai Yang; Tan, Ene Choo; Lai, Angeline Hwei Meeng

    2015-01-01

    Objective Chromosomal imbalances and rearrangements have been implicated in the etiology of intellectual disability and congenital anomalies. Many of these imbalances are caused by submicroscopic deletions or duplications not detected through conventional cytogenetic analysis. The advances in technology for detecting copy number changes, most notably chromosomal microarray analysis (CMA) has allowed the detection of these submicroscopic deletions or duplications. Submicroscopic 6p25 deletion is now recognized as a clinically identifiable syndrome. Clinical features in this syndrome include intellectual disability, developmental delay, hypotonia, sensorineural hearing loss, midface hypoplasia, ocular anomalies, cardiac defects and varying central nervous system anomalies. The aim of this report is to describe the phenotypic range of individuals with 6p25 deletion syndrome in the South East Asian population. Methods We reviewed the records of patients who are follow up in the Genetics clinic at KK Women’s and Children’s Hospital (KKH) and have CMA carried out using the Agilent 4×400 K and 4×180 K CGH+SNP catalogue array at KK Research Centre and DNA Diagnostic & Research Laboratory, respectively. Results We provide detailed molecular cytogenetic descriptions and clinical presentation of four unrelated patients with submicroscopic 6p25 deletion syndrome. Patient 1 has 5.1 Mb deletion (chr6: 224,712-5,352,662 hg19), while Patient 2 has 2 Mb deletion (chr6: 381,537-2,408,671 hg19). Patient 3 has 1.2 Mb deletion (chr6:1,486,461-2,692,219 hg19) and Patient 4 has 4.1 Mb deletion (chr6: 206,749-4,320,368 hg19). All of these patients have congenital heart defects, developmental delay, dysmorphic features and additional phenotypic abnormalities: Patient 1 has sensorineural hearing loss, hernia, bilateral undescended testes and buried penis, while Patient 2 has mild intellectual disability, bilateral mixed hearing loss, microphthalmia and submucous cleft palate. Patient

  15. A FURTHER PATIENT OF PURE 15q DELETION: CLINICAL AND MOLECULAR CYTOGENETIC FINDINGS.

    PubMed

    Solmaz, A Ece; Durmaz, B; Braekeleer, M D; Cogulu, O; Ozkinay, F

    2016-01-01

    A deletion of the distal long arm of chromosome 15 is generally reported with the formation of ring chromosome 15, whereas an isolated 15q deletion is rarely described. Here we report an 11 year-old girl, from non-consanguineous parents, who was referred to the Pediatric Genetics Department with growth retardation and multiple congenital abnormalities. In her medical history, she had a cleft palate, hip dislocation and crossed renal ectopia. Dysmorphological evaluation revealed a triangular face, low-set ears, fissured cleft tongue, micrognathia, proximally placed hypoplastic thumbs, genu valgus, 2-3 toe skin syndactyly, clinodactyly and nail hypoplasia. Speech problems were also noticed. The karyotype was normal. Subtelomeric fluorescent in-situ hybridisation (FISH) analysis showed a de novo terminal deletion about 755 kb. Furthermore, the breakpoint was located within the CHSY1 gene that is responsible for Temtamy preaxial brachydactyly syndrome which shares clinical features with 15qter deletion syndrome. To the best of our knowledge, this deletion is the smallest among reported patients. It is considered that the patient presented here significant contribution to phenotype-genotype correlation in 15q deletion patients. PMID:27192887

  16. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients.

    PubMed

    Martínez, M C; Bernabé, M J; Gómez, E; Ballesteros, A; Landeras, J; Glover, G; Gíl-Salom, M; Remohí, J; Pellicer, A

    2000-01-01

    Recent investigations have pointed to a high prevalence of Y chromosome submicroscopic deletions in men with severely impaired spermatogenesis. We report on the incidence in 128 infertile men, in whom karyotype, sperm count, and hormonal parameters were evaluated. Patients with abnormal karyotype (other than an abnormal Y chromosome) or sperm concentration of more than 2 million/mL were excluded. Genomic DNA was extracted from the peripheral leukocytes of 57 men with azoospermia and 71 with severe oligospermia. Molecular analysis was performed by 3 multiplex polymerase chain reactions using a set of 9 sequence tagged sites (STSs) from 3 different regions of the Y chromosome: AZFa, AZFb, and AZFc. In 7% of the studied patients Yq microdeletions were detected, with a high prevalence in men with azoospermia (14%). No deletions were detected in the AZFa region. Deletions were present in AZFb, AZFc, or both regions. The deletion observed in 1 patient that did not overlap with the DAZ region demonstrates that genes other than DAZ may also be involved in the pathogenesis of some subsets of male infertility. Furthermore, common Yq deletions present different testicular pictures, suggesting that some unknown factors may be disturbing spermatogenesis. Because men with severe infertility suffer a high risk of Y chromosome deletion, screening for these men is recommended prior to treatment with assisted reproduction.

  17. Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome.

    PubMed

    Dilzell, Kristen; Darcy, Diana; Sum, John; Wallerstein, Robert

    2015-01-01

    This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome. PMID:26064708

  18. Mitochondrial DNA common deletion is not associated with thyroid, breast and colorectal tumors in Turkish patients

    PubMed Central

    2010-01-01

    Recently, efforts have been focused on mitochondrial DNA changes and their relation to human cancers. Among them, a 4977 bp deletion of mitochondrial DNA, named “common deletion”, has been investigated in several types of tumors, with inconsistent results. In this study, we investigated the presence of the common deletion in tissues from 25 breast, 25 colorectal and 50 thyroid tumors and in the adjacent healthy tissues from Turkish patients. Samples from healthy volunteers were also evaluated for comparison. Two PCR-based methods were used for the detection of the common deletion. First, two pairs of primers were used to amplify wild-type and deleted mtDNA. Then, a highly sensitive nested-PCR was performed, to determine low amounts of deleted genomes. By the first method, wild-type mtDNAs were observed in all samples, but a deletion was observed in only six thyroid samples, by using the nested-PCR method. In conclusion, the mitochondrial common deletion was very rare in our study group and did not appear to be not related with cancer. PMID:21637595

  19. TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion

    PubMed Central

    Buntinx, L.; Voets, T.; Morlion, B.; Vangeel, L.; Janssen, M.; Cornelissen, E.; Vriens, J.; de Hoon, J.; Levtchenko, E.

    2016-01-01

    Cystinosis is a rare autosomal recessive disorder characterized by lysosomal cystine accumulation due to loss of function of the lysosomal cystine transporter (CTNS). The most common mutation in cystinosis patients of Northern Europe consists of a 57-kb deletion. This deletion not only inactivates the CTNS gene but also extends into the non-coding region upstream of the start codon of the TRPV1 gene, encoding the capsaicin- and heat-sensitive ion channel TRPV1. To evaluate the consequences of the 57-kb deletion on functional TRPV1 expression, we compared thermal, mechanical and chemical sensitivity of cystinosis patients with matched healthy controls. Whereas patients heterozygous for the 57-kb deletion showed normal sensory responses, homozygous subjects exhibited a 60% reduction in vasodilation and pain evoked by capsaicin, as well as an increase in heat detection threshold. Responses to cold, mechanical stimuli or cinnamaldehyde, an agonist of the related nociceptor channel TRPA1, were unaltered. We conclude that cystinosis patients homozygous for the 57-kb deletion exhibit a strong reduction of TRPV1 function, leading to sensory deficiencies akin to the phenotype of TRPV1-deficient mice. These deficits may account for the reported sensory alterations and thermoregulatory deficits in these patients, and provide a paradigm for life-long TRPV1 deficiency in humans. PMID:27734949

  20. 22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1610 Consecutive Cases

    PubMed Central

    Peyvandi, Shabnam; Lupo, Philip J; Garbarini, Jennifer; Woyciechowski, Stacy; Edman, Sharon; Emanuel, Beverly S; Mitchell, Laura; Goldmuntz, Elizabeth

    2013-01-01

    Background The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. Methods 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. Counts and frequencies for primary lesions and cardiac features were tabulated for those with and without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Results Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status (OR 5.07, 95% CI: 3.66–7.04). In the TOF subset, the strongest predictor of deletion status was an AAA (OR 3.14, 95% CI: 1.87–5.27, p <0.001), followed by pulmonary valve atresia (OR 2.03, 95% CI: 1.02–4.02, p= 0.04). Among those with double outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, five percent of patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, while no one with an IAA-A had a 22q11del. Conclusion A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient. PMID:23604262

  1. A catalog of hemizygous variation in 127 22q11 deletion patients.

    PubMed

    Hestand, Matthew S; Nowakowska, Beata A; Vergaelen, Elfi; Van Houdt, Jeroen; Dehaspe, Luc; Suhl, Joshua A; Del-Favero, Jurgen; Mortier, Geert; Zackai, Elaine; Swillen, Ann; Devriendt, Koenraad; Gur, Raquel E; McDonald-McGinn, Donna M; Warren, Stephen T; Emanuel, Beverly S; Vermeesch, Joris R

    2016-01-01

    The 22q11.2 deletion syndrome is the most common microdeletion disorder, with wide phenotypic variability. To investigate variation within the non-deleted allele we performed targeted resequencing of the 22q11.2 region for 127 patients, identifying multiple deletion sizes, including two deletions with atypical breakpoints. We cataloged ~12,000 hemizygous variant positions, of which 84% were previously annotated. Within the coding regions 95 non-synonymous variants, three stop gains, and two frameshift insertions were identified, some of which we speculate could contribute to atypical phenotypes. We also catalog tolerability of 22q11 gene mutations based on related autosomal recessive disorders in man, embryonic lethality in mice, cross-species conservation and observations that some genes harbor more or less variants than expected. This extensive catalog of hemizygous variants will serve as a blueprint for future experiments to correlate 22q11DS variation with phenotype.

  2. Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal.

    PubMed

    Jakubiczka, S; Schröder, C; Ullmann, R; Volleth, M; Ledig, S; Gilberg, E; Kroisel, P; Wieacker, Peter

    2010-01-01

    Campomelic dysplasia (MIM 114290) is a severe malformation syndrome frequently accompanied by male-to-female sex reversal. Causative are mutations within the SOX9 gene on 17q24.3 as well as chromosomal aberrations (translocations, inversions or deletions) in the vicinity of SOX9. Here, we report on a patient with muscular hypotonia, craniofacial dysmorphism, cleft palate, brachydactyly, malformations of thoracic spine, and gonadal dysgenesis with female external genitalia and müllerian duct derivatives in the presence of a male karyotype. X-ray examination and clinical examinations revealed no signs of campomelia. The combination of molecular cytogenetic analysis and array CGH revealed an unbalanced translocation between one chromosome 7 and one chromosome 17 [46,XY,t(7;17)(q33;q24).ish t(7;17)(wcp7+,wcp17+;wcp7+wcp17+)] with a deletion of approximately 4.2 Mb located about 0.5 Mb upstream of SOX9. STS analysis confirmed the deletion of chromosome 17, which has occurred de novo on the paternal chromosome. The proximal breakpoint on chromosome 17 is localized outside the known breakpoint cluster regions. The deletion on chromosome 17q24 removes several genes. Among these genes PRKAR1A is deleted. Inactivating mutations of PRKAR1A cause Carney complex. To our knowledge, this is the first report of a patient with acampomelic campomelic dysplasia, carrying both a deletion and a translocation. PMID:20453475

  3. Third case of 8q23.3-q24.13 deletion in a patient with Langer-Giedion syndrome phenotype without TRPS1 gene deletion.

    PubMed

    Pereza, Nina; Severinski, Srećko; Ostojić, Saša; Volk, Marija; Maver, Aleš; Dekanić, Kristina Baraba; Kapović, Miljenko; Peterlin, Borut

    2012-03-01

    Langer-Giedion syndrome (LGS) is a contiguous gene syndrome caused by a hemizygous deletion on chromosome 8q23.3-q24.11 involving TRPS1 and EXT1 genes. We report on a girl with LGS phenotype and a 7.5 Mb interstitial deletion at chromosome 8q23.3-q24.13. Array-comparative genomic hybridization (a-CGH) revealed a deletion encompassing only the EXT1 and not the TRPS1 gene. Even though the deletion of TRPS1 and EXT1 genes is responsible for craniofacial and skeletal features of LGS, there have been previous reports of patients with LGS phenotype and 8q24 deletions leaving the TRPS1 gene intact. To our knowledge, this is the third such case. Our patient differs from previously reported LGS patients without TRPS1 gene deletion in that she has the typical LGS facial dysmorphism and skeletal abnormalities. However, the girl is of normal height and has only a mild developmental delay. Additionally, she has dyslalia and premature adrenarche classified as Tanner stage 3 premature pubarche which have not yet been described as features of LGS. We examine the molecular breakpoints and phenotypes of our patient and previously reported cases.

  4. Identification of 1p36 deletion syndrome in patients with facial dysmorphism and developmental delay

    PubMed Central

    Seo, Go Hun; Kim, Ja Hye; Cho, Ja Hyang; Kim, Gu-Hwan; Seo, Eul-Ju; Lee, Beom Hee; Choi, Jin-Ho

    2016-01-01

    Purpose The 1p36 deletion syndrome is a microdeletion syndrome characterized by developmental delays/intellectual disability, craniofacial dysmorphism, and other congenital anomalies. To date, many cases of this syndrome have been reported worldwide. However, cases with this syndrome have not been reported in Korean populations anywhere. This study was performed to report the clinical and molecular characteristics of five Korean patients with the 1p36 deletion syndrome. Methods The clinical characteristics of the 5 patients were reviewed. Karyotyping and multiplex ligation-dependent probe amplification (MLPA) analyses were performed for genetic diagnoses. Results All 5 patients had typical dysmorphic features including frontal bossing, flat right parietal bone, low-set ears, straight eyebrows, down-slanting palpebral fissure, hypotelorism, flat nasal roots, midface hypoplasia, pointed chins, small lips, and variable degrees of developmental delay. Each patient had multiple and variable anomalies such as a congenital heart defect including ventricular septal defect, atrial septal defect, and patent duct arteriosus, ventriculomegaly, cryptorchism, or hearing loss. Karyotyping revealed the 1p36 deletion in only 1 patient, although it was confirmed in all 5 patients by MLPA analyses. Conclusion All the patients had the typical features of 1p36 deletion. These hallmarks can be used to identify other patients with this condition in their early years in order to provide more appropriate care. PMID:26893599

  5. Molecular deletion patterns in Duchenne and Becker muscular dystrophy patients from KwaZulu Natal.

    PubMed

    Hallwirth Pillay, K D; Bill, P L A; Madurai, S; Mubaiwa, L; Rapiti, P

    2007-01-15

    There exists much phenotypic heterogeneity in Duchenne muscular dystrophy and its allelic variant, Becker muscular dystrophy. The molecular findings on 53 patients with Duchenne and 15 patients with Becker type muscular dystrophy in KwaZulu Natal, South Africa are reported. Multiplex PCR was performed using primers targeting 18 hot-spot exons throughout the dystrophin gene. Analysis of the multiplex PCR data revealed that 39/68 (57.0%) patients included in the study showed a deletion (33 DMD and 6 BMD patients). Twenty-five patients were Black, 4 were White and 10 were Indian. Using the Chamberlain and Beggs multiplex PCR assays, the region of the genome most frequently affected by a deletion includes exons 47-51. The distal region of the dystrophin gene was most frequently affected by the deletion in both Black and Indian patients. There were too few White patients for conclusions to be drawn concerning the most frequently affected part of the gene. Although the numbers are insufficient to determine whether ethnic differences are present, the Chamberlain and Beggs multiplex PCR assays detect deletions with the same frequency in South African DMD/BMD patients as that reported in the literature. PMID:17141273

  6. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.

    PubMed Central

    Carlson, C; Sirotkin, H; Pandita, R; Goldberg, R; McKie, J; Wadey, R; Patanjali, S R; Weissman, S M; Anyane-Yeboa, K; Warburton, D; Scambler, P; Shprintzen, R; Kucherlapati, R; Morrow, B E

    1997-01-01

    Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs. PMID:9326327

  7. Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

    PubMed Central

    Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K

    2012-01-01

    Smith–Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. PMID:21897445

  8. Deletion of the long arm of chromosome 6: two new patients and literature review.

    PubMed

    Evers, L J; Schrander-Stumpel, C T; Engelen, J J; Hoorntje, T M; Pulles-Heintzberger, C F; Schrander, J J; Albrechts, J C; Peters, J; Fryns, J P

    1996-09-01

    Two children with a partial monosomy 6q are reported: a girl with an interstitial deletion [46,XX,del(6)(q16.2q23.1)], and a boy with a terminal deletion [46,XY,del(6)(q25.1)]. Both children presented with developmental delay, facial dysmorphism and a cardiac defect. The patients have been studied using G banding and cosmid probes specific for the long arm of chromosome 6. Clinical data are compared with patients reported in the literature.

  9. Molecular and clinical characterization of patients with overlapping 10p deletions.

    PubMed

    Lindstrand, Anna; Malmgren, Helena; Verri, Annapia; Benetti, Elisa; Eriksson, Maud; Nordgren, Ann; Anderlid, Britt-Marie; Golovleva, Irina; Schoumans, Jacqueline; Blennow, Elisabeth

    2010-05-01

    Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings. PMID:20425828

  10. A patient with 22q11.2 deletion syndrome: case report.

    PubMed

    Eryılmaz, Sema Kabataş; Baş, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin

    2009-01-01

    22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia.

  11. A patient with 22q11.2 deletion syndrome: case report.

    PubMed

    Eryılmaz, Sema Kabataş; Baş, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin

    2009-01-01

    22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia. PMID:21274400

  12. Novel deletion in a patient with an isolated peroxisoml acyl-CoA oxidase deficiency

    SciTech Connect

    Poll-The, B.T.; Fournier, B.; Clevers, H.; Wanders, R.J.A.

    1994-09-01

    Disorders with defective peroxisome assembly are associated with multiple peroxisomal enzymatic abnormalities. Besides these diseases patients have been described suspected of having a single enzyme defect in the peroxisomal {beta}-oxidation pathway. Laboratory findings for these patients include elevated plasma very long chain fatty acids (VLCFA) and impaired VLCFA oxidation in fibroblasts. Complementation analysis between these patients and those with a proven single enzyme deficiency, using peroxisomal {beta}-oxidation of VLCFA as the criterion for complementation, has been used to show whether the patients are deficient in acyl-CoA oxidase, peroxisomal trifunctional protein or thiolase activity. Fibroblasts from a patient showing the clinical and biochemical abnormalities of isolated acyl-CoA oxidase deficiency (using cell complementation) were analyzed at the molecular level. Isolation of RNA from patient`s fibroblasts was followed by random reverse transcription of RNA and PCR amplification. PCR products were blotted and hybridized with the human acyl-CoA oxidase cDNA. A fragment 150 bp shorter than normal was found. Upon sequencing, exon 7 was found to be deleted leading to a frameshift in the acyl-CoA oxidase mRNA. Southern blot analysis of the patient`s DNA did not reveal any deletion in contrast to two siblings previously reported as having a deletion of at least 17 kb in the acyl-CoA oxidase gene.

  13. RAI1 variations in Smith–Magenis syndrome patients without 17p11.2 deletions

    PubMed Central

    Girirajan, S; Elsas, L; Devriendt, K; Elsea, S

    2005-01-01

    Background: Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviours, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births. Heterozygous frameshift mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions. Objective: Analysis of four individuals with features consistent with SMS for variations in RAI1, using a polymerase chain reaction and sequencing strategy. None of these patients carry 17p11.2 deletions. Results: Two patients had small deletions in RAI1 resulting in frameshift and premature truncation of the protein. Missense mutations were identified in the other two. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo, as all parental samples were normal. Several polymorphisms were also observed, including new and reported SNPs. The patients' clinical features differed from those found in 17p11.2 deletion by general absence of short stature and lack of visceral anomalies. All four patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioural anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in one patient of the cohort. Conclusions: Haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms. PMID:15788730

  14. Acute Dystonia in a Patient with 22q11.2 Deletion Syndrome

    PubMed Central

    Kontoangelos, Konstantinos; Maillis, Antonis; Maltezou, Maria; Tsiori, Sofia; Papageorgiou, Charalambos C.

    2015-01-01

    The 22q11.2 deletion syndrome (di George syndrome) is one of the most prevalent genetic disorders. The clinical features of the syndrome are distinct facial appearance, velopharyngeal insufficiency, conotruncal heart disease, parathyroid and immune dysfunction; however, little is known about possible neurodegenerative diseases. We describe the case of an 18-year old patient suffering from 22q11.2 deletion syndrome. Since adolescence, he presented with behavioral disorders, recommended treatment with 2 mg aloperidin and he presented cervical dystonia and emergence of torticollis and trunk dystonia. Antipsychotic medications either accelerate or reveal dystonic symptoms. PMID:26605035

  15. Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome.

    PubMed

    Saito, Yoshiaki; Kubota, Masaya; Kurosawa, Kenji; Ichihashi, Izumi; Kaneko, Yuu; Hattori, Ayako; Komaki, Hirofumi; Nakagawa, Eiji; Sugai, Kenji; Sasaki, Masayuki

    2011-05-01

    A 3-months-old boy presented with partial seizures that soon evolved into infantile spasms. Magnetic resonance imaging revealed bilateral perisylvian polymicrogyria with right-sided predominance. ACTH therapy successfully controlled epilepsy and electroencephalograms were normalized. Conventional G-banded chromosomal analysis was performed due to his distinctive features and a derivative chromosome 1 derived from parental balanced translocation with a karyoptype of 46,XY,der(1)t(1;4)(p36.23;q35) was detected. Fluorescent in situ hybridization analysis confirmed the deleted region of 1p36 as large as 8.6Mb. This is the first delineation of concurrent complications of infantile spasms and polymicrogyria in patient with 1p36 deletion. 1p36 deletion syndrome should be broadly recognized as a differential diagnosis of regional polymicrogyria and/or infantile spasms.

  16. Deletion 1q43 encompassing only CHRM3 in a patient with autistic disorder.

    PubMed

    Petersen, Andrea Klunder; Ahmad, Ausaf; Shafiq, Mustafa; Brown-Kipphut, Brigette; Fong, Chin-To; Anwar Iqbal, M

    2013-02-01

    Deletions on the distal portion of the long arm of chromosome 1 result in complex and highly variable clinical phenotypes which include intellectual disability, autism, seizures, microcephaly/craniofacial dysmorphology, corpus callosal agenesis/hypogenesis, cardiac and genital anomalies, hand and foot abnormalities and short stature. Genotype-phenotype correlation reported a minimum region of 2 Mb at 1q43-q44. We report on a 3 ½ year old male patient diagnosed with autistic disorder who has social withdrawal, eating problems, repetitive stereotypic behaviors including self-injurious head banging and hair pulling, and no seizures, anxiety, or mood swings. Array comparative genomic hybridization (aCGH) showed an interstitial deletion of 473 kb at 1q43 region (239,412,391-239,885,394; NCBI build37/hg19) harboring only CHRM3 (Acetylcholine Receptor, Muscarinic, 3; OMIM: 118494). Recently, another case with a de novo interstitial deletion of 911 kb at 1q43 encompassing three genes including CHRM3 was reported. The M3 muscarinic receptor influences a multitude of central and peripheral nervous system processes via its interaction with acetylcholine and may be an important modulator of behavior, learning and memory. We propose CHRM3 as a candidate gene responsible for our patient's specific phenotype as well as the overlapping phenotypic features of other patients with 1q43 or 1q43-q44 deletions.

  17. Xp21 contiguous gene syndromes: Deletion quantitation with bivariate flow karyotyping allows mapping of patient breakpoints

    SciTech Connect

    McCabe, E.R.B.; Towbin, J.A. ); Engh, G. van den; Trask, B.J. )

    1992-12-01

    Bivariate flow karyotyping was used to estimate the deletion sizes for a series of patients with Xp21 contiguous gene syndromes. The deletion estimates were used to develop an approximate scale for the genomic map in Xp21. The bivariate flow karyotype results were compared with clinical and molecular genetic information on the extent of the patients' deletions, and these various types of data were consistent. The resulting map spans >15 Mb, from the telomeric interval between DXS41 (99-6) and DXS68 (1-4) to a position centromeric to the ornithine transcarbamylase locus. The deletion sizing was considered to be accurate to [plus minus]1 Mb. The map provides information on the relative localization of genes and markers within this region. For example, the map suggests that the adrenal hypoplasia congenita and glycerol kinase genes are physically close to each other, are within 1-2 Mb of the telomeric end of the Duchenne muscular dystrophy (DMD) gene, and are nearer to the DMD locus than to the more distal marker DXS28 (C7). Information of this type is useful in developing genomic strategies for positional cloning in Xp21. These investigations demonstrate that the DNA from patients with Xp21 contiguous gene syndromes can be valuable reagents, not only for ordering loci and markers but also for providing an approximate scale to the map of the Xp21 region surrounding DMD. 44 refs., 3 figs.

  18. Patterns of dystrophin gene deletion in Egyptian Duchenne/Becker muscular dystrophy patients

    PubMed Central

    El Sherif, RM; Aly Fahmy, N; Nonaka, I; Etribi, MA

    2007-01-01

    Summary Large variations in the proportion of intragenic deletion in the dystrophin gene have been observed in different populations. Although dystrophin gene deletion was extensively studied all over the world, only few studies were done on Egyptian population and there was no account on the dystrophin gene duplication. In this study, we present our results on the pattern of deletion of the dystrophin gene together with the usage of quantitative polymerase chain reaction (PCR) as a method for duplication analysis within the dystrophin gene in Egyptian patients. Forty one Duchene/Becker muscular dystrophy patients were included in this study. The diagnosis was based on detailed clinical assessment, serum creatine kinase (CK) level, neurophysiologic study and muscle biopsy for histopathological analysis. DNA was extracted from ten milliliter peripheral blood according to basic protocol, and multiplex polymerase chain reaction for dystrophin gene using both Chamberlin and Beggs sets of primers amplifying eighteen exons covering the two main dystrophin gene hot spots. In addition primers from Abbs set were used when it was necessary to check the exon borders. DNA from cases with no detectable deletion was analyzed for dystrophin gene duplication using quantitative PCR technique. We had a percentage of 61.1% deletion which is higher than data from previous Egyptian studies and most of the deletion was localized in the major hotspot region between exons 44 and 52 and we had 5% of the cases with duplication. Our results were compared with previous studies from Egypt and with studies from different populations especially with data recorded in the Middle East and North Africa. PMID:18646563

  19. Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome.

    PubMed

    Taine, L; Goizet, C; Wen, Z Q; Petrij, F; Breuning, M H; Aymé, S; Saura, R; Arveiler, B; Lacombe, D

    1998-07-01

    The Rubinstein-Taybi syndrome (RTS) is a well-defined entity characterized by growth and mental retardation, broad thumbs and halluces, and typical face. The RTS locus was assigned to 16p13.3, and interstitial submicroscopic deletions of this region (RT1 cosmid, D16S237) were initially identified in 25% of RTS patients. The gene for the human CREB binding protein, the transcriptional coactivator CBP, is included in the RT1 cosmid, and mutations in CBP have recently been identified in nondeleted RTS patients. We investigated 30 French patients with RTS. Among these patients, 3 had the RT1 microdeletion (frequency 10%). There is no obvious phenotypic difference between the patients with and without the RT1 deletion. The RT1 probe appears useful for confirmation of the diagnosis but is of little interest as a screening tool. By pooling data including the previous series and our current series, the cumulative frequency of the 16p13.3 microdeletion is 11.9% (19 in 159). This frequency of approximately 12% deleted patients appears more accurate than the 25% previously reported. Molecular investigations of CBP are in process in our series to clarify the cause of RTS.

  20. Focal segmental glomerulosclerosis in patients with complete deletion of one WT1 allele.

    PubMed

    Iijima, Kazumoto; Someya, Tomonosuke; Ito, Shuichi; Nozu, Kandai; Nakanishi, Koichi; Matsuoka, Kentaro; Ohashi, Hirofumi; Nagata, Michio; Kamei, Koichi; Sasaki, Satoshi

    2012-06-01

    The renal prognosis of patients with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation syndrome (WAGR) is poor. However, the renal histology and its mechanisms are not well understood. We performed renal biopsies in 3 patients with WAGR syndrome who had heavy proteinuria. The complete deletion of one WT1 allele was detected in each patient by constitutional chromosomal deletion at 11p13 using G-banding, high-resolution G-banding, and fluorescence in situ hybridization. The patients exhibited proteinuria at the ages of 6, 10, and 6 years and were diagnosed as having focal segmental glomerulosclerosis (FSGS) at the ages of 7, 16 and 19 years, respectively. They exhibited normal or mildly declined renal function at the time of biopsy. Re-examination of a nephrectomized kidney from 1 patient revealed that some glomeruli showed segmental sclerosis, although he did not have proteinuria at the time of nephrectomy. The other 2 patients did not develop Wilms' tumor and thus did not undergo nephrectomy, chemotherapy, or radiotherapy, thereby eliminating any effect of these therapies on the renal histology. In conclusion, complete deletion of one WT1 allele may induce the development of FSGS. Our findings suggest that haploinsufficiency of the WT1 could be responsible for the development of FSGS.

  1. Aneuploidies, deletion, and overexpression of TP53 gene in intestinal metaplasia of patients without gastric cancer.

    PubMed

    César, Ana Cristina Gobbo; Borim, Aldenis Albaneze; Caetano, Alaor; Cury, Patrícia Maluf; Silva, Ana Elizabete

    2004-09-01

    Gastric carcinogenesis is attributable to interacting environmental and genetic factors, through a sequence of events including intestinal metaplasia. Using a fluorescence in situ hybridization technique, we investigated the occurrence of aneuploidies of chromosomes 3, 7, 8, 9, and 17, TP53 gene deletion, and expression of p53 in 21 intestinal metaplasia (IM) samples from cancer-free patients and in 20 gastric adenocarcinoma samples. Aneuploidies were found in 71% (15/21) of the IM samples. Trisomy of chromosomes 7 and 9 occurred mainly in complete-type IM; in the incomplete type, trisomy of chromosomes 7 and 8 were more commonly found. The TP53 gene deletion was observed in 60% (3/5) of the IM cases, and immunohistochemistry revealed p53 overexpression in 12% (2/17) of the analyzed IM cases. All gastric adenocarcinoma cases presented higher frequencies of trisomy or tetrasomy of chromosomes 3, 7, 8, 9, and 17. The TP53 deletion was found in all three of the gastric adenocarcinoma analyzed for it, and immunohistochemistry detected overexpression of protein p53 in 80% (12/15) of the analyzed cases. Our study revealed for the first time the presence of aneuploidies of chromosomes 7, 8, 9, and 17 and of TP53 gene deletion and overexpression in IM samples from cancer-free patients. These results suggest that IM and gastric adenocarcinoma may share the same genetic alterations. PMID:15350302

  2. Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions

    SciTech Connect

    Scire, G.; Bonaiuto, F.; Galasso, C.; Boscherini, B.; Dallapiccola, B.; Mingarelli, R.; Iannetti, P.

    1994-10-01

    We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The phenotypic manifestations of the observed patients were consistent with velo-cardiofacial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of parathtroid function and molecular analysis of the 22q11 region hybridization studies. 10 refs., 5 figs., 2 tabs.

  3. Disease progression in patients with single, large-scale mitochondrial DNA deletions.

    PubMed

    Grady, John P; Campbell, Georgia; Ratnaike, Thiloka; Blakely, Emma L; Falkous, Gavin; Nesbitt, Victoria; Schaefer, Andrew M; McNally, Richard J; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; McFarland, Robert

    2014-02-01

    Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.

  4. CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

    PubMed Central

    Muntinghe, Friso L.H.; Verduijn, Marion; Zuurman, Mike W.; Grootendorst, Diana C.; Carrero, Juan Jesus; Qureshi, Abdul Rashid; Luttropp, Karin; Nordfors, Louise; Lindholm, Bengt; Brandenburg, Vincent; Schalling, Martin; Stenvinkel, Peter; Boeschoten, Elisabeth W.; Krediet, Raymond T.; Navis, Gerjan; Dekker, Friedo W.

    2009-01-01

    The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5Δ32) leads to deficiency of the receptor. We hypothesized that CCR5Δ32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP ≤ 10 mg/L (n = 225), those carrying the deletion allele with hsCRP ≤ 10 mg/L (n = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP > 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5Δ32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD. PMID:19389855

  5. Christianson syndrome in a patient with an interstitial Xq26.3 deletion.

    PubMed

    Tzschach, Andreas; Ullmann, Reinhard; Ahmed, Alischo; Martin, Thomas; Weber, Georg; Decker-Schwering, Oliver; Pauly, Fernand; Shamdeen, Mohammed Ghiath; Reith, Wolfgang; Oehl-Jaschkowitz, Barbara

    2011-11-01

    Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.

  6. Fragile X phenotype in a patient with a large de novo deletion in Xq27-q28

    SciTech Connect

    Albright, S.G.; Rao, K.W.; Tennison, M.B.; Aylsworth, A.S.; Lachiewicz, A.M.; Tarleton, J.C.; Schwartz, C.E.; Richie, R.

    1994-07-15

    A 2-year-old boy with manifestations of the fragile X syndrome was found to have a cytogenetically visible deletion of Xq27-q28 including deletion of FMR-1. Molecular analysis of the patient was recently described in Tarleton et al. and the deletion was estimated to be at least 3 megabases (Mb). His mother had 2 FMR-1 alleles with normal numbers of CGG repeats, 20 and 32, respectively. Thus, the deletion occurred as a de novo event. The patient does not appear to have clinical or laboratory findings other than those typically associated with fragile X syndrome, suggesting that the deletion does not remove other contiguous genes. This report describes the phenotype of the patient, including psychological studies. 23 refs., 3 figs.

  7. Mullerian Duct Cyst Causing Bladder Outlet Obstruction in a Patient with HNF-1β Gene Deletion

    PubMed Central

    Honore, Matthew; Fowler, Ross; Kiosoglous, Anthony J.

    2016-01-01

    A 24-year-old male was referred to a tertiary hospital for a possible prostatic abscess. The patient went into acute urinary retention. Transurethral drainage was performed. MRI pelvis three days post-operatively identified the prostatic cystic structure as a müllerian duct cyst. Several other phenotypical features were noted on examination as well as findings on investigations. From these diagnosis of hepatocyte nuclear factor-1β (HNF-1β) gene deletion was made. PMID:27390584

  8. Craniosynostosis in 10q26 deletion patients: A consequence of brain underdevelopment or altered suture biology?

    PubMed

    Faria, Ágatha Cristhina; Rabbi-Bortolini, Eliete; Rebouças, Maria R G O; de S Thiago Pereira, Andréia L A; Frasson, Milena G Tonini; Atique, Rodrigo; Lourenço, Naila Cristina V; Rosenberg, Carla; Kobayashi, Gerson S; Passos-Bueno, Maria Rita; Errera, Flávia Imbroisi Valle

    2016-02-01

    Approximately a hundred patients with terminal 10q deletions have been described. They present with a wide range of clinical features always accompanied by delayed development, intellectual disability and craniofacial dysmorphisms. Here, we report a girl and a boy with craniosynostosis, developmental delay and other congenital anomalies. Karyotyping and molecular analysis including Multiplex Ligation dependent probe amplification (MLPA) and Array Comparative Genomic Hybridization (aCGH) were performed in both patients. We detected a 13.1 Mb pure deletion at 10q26.12-q26.3 in the girl and a 10.9 Mb pure deletion at 10q26.13-q26.3 in the boy, both encompassing about 100 genes. The clinical and molecular findings in these patients reinforce the importance of the DOCK1 smallest region of overlap I (SRO I), previously suggested to explain the clinical signs, and together with a review of the literature suggest a second 3.5 Mb region important for the phenotype (SRO II). Genotype-phenotype correlations and literature data suggest that the craniosynostosis is not directly related to dysregulated signaling in suture development, but may be secondary to alterations in brain development instead. Further, genes at 10q26 may be involved in the molecular crosstalk between brain and cranial vault. PMID:26566760

  9. Craniosynostosis in 10q26 deletion patients: A consequence of brain underdevelopment or altered suture biology?

    PubMed

    Faria, Ágatha Cristhina; Rabbi-Bortolini, Eliete; Rebouças, Maria R G O; de S Thiago Pereira, Andréia L A; Frasson, Milena G Tonini; Atique, Rodrigo; Lourenço, Naila Cristina V; Rosenberg, Carla; Kobayashi, Gerson S; Passos-Bueno, Maria Rita; Errera, Flávia Imbroisi Valle

    2016-02-01

    Approximately a hundred patients with terminal 10q deletions have been described. They present with a wide range of clinical features always accompanied by delayed development, intellectual disability and craniofacial dysmorphisms. Here, we report a girl and a boy with craniosynostosis, developmental delay and other congenital anomalies. Karyotyping and molecular analysis including Multiplex Ligation dependent probe amplification (MLPA) and Array Comparative Genomic Hybridization (aCGH) were performed in both patients. We detected a 13.1 Mb pure deletion at 10q26.12-q26.3 in the girl and a 10.9 Mb pure deletion at 10q26.13-q26.3 in the boy, both encompassing about 100 genes. The clinical and molecular findings in these patients reinforce the importance of the DOCK1 smallest region of overlap I (SRO I), previously suggested to explain the clinical signs, and together with a review of the literature suggest a second 3.5 Mb region important for the phenotype (SRO II). Genotype-phenotype correlations and literature data suggest that the craniosynostosis is not directly related to dysregulated signaling in suture development, but may be secondary to alterations in brain development instead. Further, genes at 10q26 may be involved in the molecular crosstalk between brain and cranial vault.

  10. Analysis of 22q11.2 deletions by FISH in a series of velocardiofacial syndrome patients

    SciTech Connect

    Ravnan, J.B.; Golabi, M.; Lebo, R.V.

    1994-09-01

    Deletions in chromosome 22 band q11.2 have been associated with velocardiofacial (VCF or Shprintzen) syndrome and the DiGeorge anomaly. A study of VCF patients evaluated at the UCSF Medical Center was undertaken to correlate disease phenotype with presence or absence of a deletion. Patients referred for this study had at least two of the following: dysmorphic facial features, frequent ear infections or hearing loss, palate abnormalities, thymic hypoplasia, hypocalcemia, congenital heart defect, hypotonia, and growth or language delay. Fluorescence in situ hybridization (FISH) using the DiGeorge critical region probe N25 was used to classify patients according to the presence or absence of a deletion in 22q11.2, and the results were compared to clinical characteristics. We have completed studies on 58 patients with features of VCF. Twenty-one patients (36%) were found to have a deletion in 22q11.2 by FISH. A retrospective study of archived slides from 14 patients originally studied only by prometaphase GTG banding found six patients had a deletion detected by FISH; of these, only two had a microscopically visible chromosome deletion. Our study of 11 sets of parents of children with the deletion found two clinically affected mothers with the deletion, including one with three of three children clinically affected. A few patients who did not fit the classical VCF description had a 22q11.2 deletion detected by FISH. These included one patient with both cleft lip and palate, and another with developmental delay and typical facial features but no cardiac or palate abnormalities. Both patients with the DiGeorge anomaly as part of VCF had the deletion. On the other hand, a number of patients diagnosed clinically with classical VCF did not have a detectable deletion. This raises the question whether they represent a subset of patients with a defect of 22q11.2 not detected by the N25 probe, or whether they represent a phenocopy of VCF.

  11. Exon skipping and translation in patients with frameshift deletions in the dystrophin gene

    SciTech Connect

    Sherratt, T.G.; Dubowitz, V.; Sewry, C.A.; Strong, P.N. ); Vulliamy, T. )

    1993-11-01

    Although many Duchenne muscular dystrophy patients have a deletion in the dystrophin gene which disrupts the translational reading frame, they express dystrophin in a small proportion of skeletal muscle fibers ([open quotes]revertant fibers[close quotes]). Antibody studies have shown, indirectly, that dystrophin synthesis in revertant fibers is facilitated by a frame-restoring mechanism; in the present study, the feasibility of mRNA splicing was investigated. Dystrophin transcripts were analyzed in skeletal muscle from individuals possessing revertant fibers and a frameshift deletion in the dystrophin gene. In each case a minor in-frame transcript was detected, in which exons adjacent to those deleted from the genome had been skipped. There appeared to be some correlation between the levels of in-frame transcripts and the predicted translation products. Low levels of alternatively spliced transcripts were also present in normal muscle. The results provide further evidence of exon skipping in the dystrophin gene and indicate that this may be involved in the synthesis of dystrophin by revertant fibers. 44 refs., 12 figs.

  12. 8p23.1 Interstitial Deletion in a Patient with Congenital Cardiopathy, Neurobehavioral Disorders, and Minor Signs Suggesting 22q11.2 Deletion Syndrome.

    PubMed

    Molck, Miriam C; Monteiro, Fabíola P; Simioni, Milena; Gil-da-Silva-Lopes, Vera L

    2015-09-01

    Copy number variation studies of known disorders have the potential to improve the characterization of clinical phenotypes and may help identifying candidate genes and their pathways. The authors described a child with congenital heart disease, microcephaly, facial dysmorphisms, developmental delay, learning difficulties, and behavioral problems. There was initially a clinical suspicion of 22q11.2 deletion syndrome (22q11.2 DS), but molecular cytogenetic analysis (array genomic hybridization [aGH]) showed the presence of a de novo 3.6-Mb interstitial microdeletion in 8p23.1. The main features of 8p23.1 DS include congenital heart disease and behavioral problems, in addition to minor dysmorphisms and mental delay. Therefore, this article highlights the application of aGH to investigate 8p23.1 deletion in nonconfirmed 22q11.2 DS patients presenting neurobehavioral disorders, congenital cardiopathy, and minor dysmorphisms.

  13. Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia.

    PubMed

    Martin, A K; Robinson, G; Reutens, D; Mowry, B

    2014-10-01

    Total burden of copy number deletions has been implicated in schizophrenia risk and has been associated with reduced cognitive functioning. The current study aims to replicate the cognitive findings and investigate regional grey and white matter volumes. Moreover, it will explore resting-state networks for correlations between functional connectivity and total deletion burden. All imaging differences will be investigated for correlations with cognitive differences. Seventy-eight patients with chronic schizophrenia, who formed a subset of a large genome-wide association study (GWAS), were assessed for intelligence, 34 had structural magnetic resonance imaging, 33 had resting-state functional magnetic resonance imaging, and 32 had diffusion tensor imaging (DTI). Total deletion burden was negatively associated with IQ performance and positively associated with regional volumes in the striatum bilaterally and in the right superior temporal gyrus and white-matter in the corpus callosum. Correlations were identified between deletion burden and both hyper and hypoconnectivity within the default-mode network and hypoconnectivity within the cognitive control network. The functional connectivity correlations with deletion burden were also correlated with the IQ differences identified. Total deletion burden affects regional volumes and resting-state functional connectivity in key brain networks in patients with schizophrenia. Moreover, effects of deletions on cognitive functioning in may be due to inefficiency of key brain networks as identified by dysconnectivity in resting-state networks. PMID:25036426

  14. Interstitial 1p32.1p32.3 deletion in a patient with multiple congenital anomalies.

    PubMed

    Kehrer, Martin; Schäferhoff, Karin; Bonin, Michael; Jauch, Anna; Bevot, Andrea; Tzschach, Andreas

    2015-10-01

    Interstitial deletions encompassing chromosome bands 1p32.1p32.3 are rare. Only nine unrelated patients with partially overlapping 1p32.1p32.3 deletions of variable size and position have been reported to date. We report on a 17-month-old boy with choanal atresia, hearing loss, urogenital anomalies, and microcephaly in whom an interstitial de novo deletion of 6.4 Mb was detected in 1p32.1p32.3 (genomic position chr1:54,668,618-61,113,264 according to GRCh37/hg19). The deleted region harbors 31 RefSeq genes. Notable genes in the region are PCSK9, haploinsufficiency of which caused low LDL cholesterol plasma levels in the patient, and DAB1, which is a candidate gene for cognitive deficits, microcephaly, and cerebral abnormalities such as ventriculomegaly and agenesis of the corpus callosum. Choanal atresia, microcephaly, and severe hearing loss were previously not known to be associated with 1p32 deletions. Our reported patient thus broadens the spectrum of clinical findings in this chromosome region and further facilitates genotype-phenotype correlations. Additional patients with overlapping deletions and/or point mutations in genes of this region need to be identified to elucidate the role of individual genes for the complex clinical manifestations.

  15. Multiple mitochondrial DNA deletions and persistent hyperthermia in a patient with Brachmann-de Lange phenotype

    SciTech Connect

    Melegh, B.; Bock, I.; Mehes, K.

    1996-10-02

    In a newborn boy with characteristics of Brachmann-de Lange syndrome (BDLS), high temperatures were observed on the second day after birth and recurred 2-6 times daily during the 7 months of the patient`s life. After, transient hypertonia hypotonia developed. In muscle biopsy specimen taken on the 51st day of life, serious and progressive distortion of mitochondria was observed. In several mitochondria the cristae structure was broken, other mitochondria were shrunken and the damage progressed towards further deterioration in other organelles. At several points between the myofibrils, amorphous material was seen, possibly debris of destroyed mitochondria. Most myofibrils seemed to be intact; however, in some areas myolytic signs were present. Analysis of the mitochondrial DNA (mtDNA) showed multiple deletions in skeletal and heart muscles, liver, lung and kidney. Since the mtDNA encodes several proteins of the respiratory complexes, the deleted mtDNA certainly affected the integrity of the mitochondrial oxidative phosphorylation process by synthesis of abnormal proteins. In the present case the hyperthermia may have been a result of the mtDNA damage. 13 refs.

  16. Subtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations.

    PubMed

    Linhares, Natália D; Svartman, Marta; Rodrigues, Tatiane C; Rosenberg, Carla; Valadares, Eugênia R

    2015-05-01

    The 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype-phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06 Mb 6p25.1-pter deletion associated with a contiguous 1 Mb 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones resembling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype. PMID:25817395

  17. 17q12 Deletion in a patient with Williams syndrome: Case report and review of the literature

    PubMed Central

    Cohen, Lilian; Samanich, Joy; Pan, Quilu; Mehta, Lakshmi; Marion, Robert

    2012-01-01

    Williams syndrome (WS) is a complex genomic disorder entailing distinctive facial dysmorphism, cardiovascular abnormalities, intellectual disabilities, unusual behavioral features, and a specific cognitive profile with considerable variability. Additional symptoms include endocrine abnormalities, renal anomalies and connective tissue disorders. We report a monozygotic twin patient with WS who presented with multicystic kidneys in the newborn period, and, in addition to the typical WS deletion at 7q11.23, was found to have a de novo 1.7 Mb deletion in the 17q12 region on microarray comparative genomic hybridization. The co-twin was selectively terminated at 23 wk of gestation after being diagnosed with bilateral multicystic dysplastic kidneys and anhydramnios. Review of the literature shows that deletion of chromosome 17q12, encompassing hepatocyte nuclear factor 1beta gene, is associated with cystic renal disease and is the first recurrent genomic deletion associated with maturity onset diabetes of the young. In addition, reports of female reproductive tract malformations and patients with neurocognitive or psychiatric phenotypes have recently been described. This review of the literature summarizes 47 other cases involving 17q12 deletions with wide variability in phenotype, possibly suggesting a contiguous gene syndrome. It is likely that the additional 17q12 deletion has played a role in modifying the phenotype in our patient. This case highlights the importance of using array comparative genomic hybridization in the clinical setting to uncover the etiology of atypical findings in individuals with known microdeletion syndromes.

  18. Subtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations.

    PubMed

    Linhares, Natália D; Svartman, Marta; Rodrigues, Tatiane C; Rosenberg, Carla; Valadares, Eugênia R

    2015-05-01

    The 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype-phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06 Mb 6p25.1-pter deletion associated with a contiguous 1 Mb 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones resembling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype.

  19. Evidence for a distinct region causing a cat-like cry in patients with 5p deletions

    SciTech Connect

    Gersh, M.; Goodart, S.A.; Overhauser, J.

    1995-06-01

    The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth, which is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on four families in which patients with 5p deletions have only the characteristic cat-like cry, with normal to mildly delayed development. The precise locations of the deletions in each family were determined by FISH using lambda phage and cosmic clones. All of the deletion breakpoints map distal to a chromosomal region that is implicated with the facial features and severe mental and developmental delay in the cri-du-chat syndrome. DNA clones mapping in the chromosomal region associated with the cat-like cry feature will be useful diagnostic tools. They will allow for the distinction between 5p deletions that will result in the severe delay observed in most cri-du-chat syndrome patients and those deletions that result in the isolated cat-like cry feature, which is associated with a better prognosis. 19 refs., 5 figs., 1 tab.

  20. 17q12 Deletion in a patient with Williams syndrome: Case report and review of the literature.

    PubMed

    Cohen, Lilian; Samanich, Joy; Pan, Quilu; Mehta, Lakshmi; Marion, Robert

    2012-06-01

    Williams syndrome (WS) is a complex genomic disorder entailing distinctive facial dysmorphism, cardiovascular abnormalities, intellectual disabilities, unusual behavioral features, and a specific cognitive profile with considerable variability. Additional symptoms include endocrine abnormalities, renal anomalies and connective tissue disorders. We report a monozygotic twin patient with WS who presented with multicystic kidneys in the newborn period, and, in addition to the typical WS deletion at 7q11.23, was found to have a de novo 1.7 Mb deletion in the 17q12 region on microarray comparative genomic hybridization. The co-twin was selectively terminated at 23 wk of gestation after being diagnosed with bilateral multicystic dysplastic kidneys and anhydramnios. Review of the literature shows that deletion of chromosome 17q12, encompassing hepatocyte nuclear factor 1beta gene, is associated with cystic renal disease and is the first recurrent genomic deletion associated with maturity onset diabetes of the young. In addition, reports of female reproductive tract malformations and patients with neurocognitive or psychiatric phenotypes have recently been described. This review of the literature summarizes 47 other cases involving 17q12 deletions with wide variability in phenotype, possibly suggesting a contiguous gene syndrome. It is likely that the additional 17q12 deletion has played a role in modifying the phenotype in our patient. This case highlights the importance of using array comparative genomic hybridization in the clinical setting to uncover the etiology of atypical findings in individuals with known microdeletion syndromes. PMID:27625814

  1. 13q Deletion and central nervous system anomalies: further insights from karyotype–phenotype analyses of 14 patients

    PubMed Central

    Ballarati, Lucia; Rossi, Elena; Bonati, Maria Teresa; Gimelli, Stefania; Maraschio, Paola; Finelli, Palma; Giglio, Sabrina; Lapi, Elisabetta; Bedeschi, Maria Francesca; Guerneri, Silvana; Arrigo, Giulia; Patricelli, Maria Grazia; Mattina, Teresa; Guzzardi, Oriana; Pecile, Vanna; Police, Adalgisa; Scarano, Gioacchino; Larizza, Lidia; Zuffardi, Orsetta; Giardino, Daniela

    2007-01-01

    Background Chromosome 13q deletion is associated with varying phenotypes, which seem to depend on the location of the deleted segment. Although various attempts have been made to link the 13q deletion intervals to distinct phenotypes, there is still no acknowledged consensus correlation between the monosomy of distinct 13q regions and specific clinical features. Methods 14 Italian patients carrying partial de novo 13q deletions were studied. Molecular–cytogenetic characterisation was carried out by means of array‐comparative genomic hybridisation (array‐CGH) or fluorescent in situ hybridisation (FISH). Results Our 14 patients showed mental retardation ranging from profound–severe to moderate–mild: eight had central nervous system (CNS) anomalies, including neural tube defects (NTDs), six had eye abnormalities, nine had facial dysmorphisms and 10 had hand or feet anomalies. The size of the deleted regions varied from 4.2 to 75.7 Mb. Conclusion This study is the first systematic molecular characterisation of de novo 13q deletions, and offers a karyotype–phenotype correlation based on detailed clinical studies and molecular determinations of the deleted regions. Analyses confirm that patients lacking the 13q32 band are the most seriously affected, and critical intervals have been preliminarily assigned for CNS malformations. Dose‐sensitive genes proximal to q33.2 may be involved in NTDs. The minimal deletion interval associated with the Dandy–Walker malformation (DWM) was narrowed to the 13q32.2–33.2 region, in which the ZIC2 and ZIC5 genes proposed as underlying various CNS malformations are mapped. PMID:17209130

  2. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients

    SciTech Connect

    Christian, S.L.; Huang, B.; Ledbetter, D.H.

    1995-07-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11{minus}q13. Approximately 70% of these patients have a large deletion of {approximately}4 Mb extending from D15S9 (ML34) through D15S12 (IR10A). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated for YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of these markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542. 46 refs., 2 figs., 3 tabs.

  3. 6p22.3 deletion: report of a patient with autism, severe intellectual disability and electroencephalographic anomalies

    PubMed Central

    2013-01-01

    Background The interstitial 6p deletions, involving the 6p22-p24 chromosomal region, are rare events characterized by variable phenotypes and no clear genotype-phenotype correlation has been established so far. Results High resolution array-CGH identified 1 Mb de novo interstitial deletion in 6p22.3 chromosomal region in a patient affected by severe Intellectual Disability (ID), Autism Spectrum Disorders (ASDs), and electroencephalographic anomalies. This deletion includes ATXN1, DTNBP1, JARID2 and MYLIP genes, known to play an important role in the brain, and the GMPR gene whose function in the nervous system is unknown. Conclusions We support the suggestion that ATXN1, DTNBP1, JARID2 and MYLIP are candidate genes for the pathophysiology of ASDs and ID, and we propose that deletion of DTNBP1 and/or JARID2 contributes to the hypotonia phenotype. PMID:23324214

  4. JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms

    PubMed Central

    Ma, Wanlong; Kantarjian, Hagop; Zhang, Xi; Wang, Xiuqiang; Zhang, Zhong; Yeh, Chen-Hsiung; O'Brien, Susan; Giles, Francis; Bruey, Jean Marie; Albitar, Maher

    2010-01-01

    Background The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Δexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing. Methodology/Principal Findings We investigated the possibility that MPN patients may express the JAK2 Δexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR–based fluorescent fragment analysis method to quantify JAK2 Δexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Δexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean  = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression  = 5.41% [2.13%–26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression  = 3.88% [2.08%–12.22%]). Immunoprecipitation studies demonstrated that patients expressing Δexon14 mRNA expressed a corresponding truncated JAK2 protein. The Δexon14 variant was not detected in the 46 control subjects. Conclusions/Significance These data suggest that expression of the JAK2 Δexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for

  5. Characterisation of two deletions involving NPC1 and flanking genes in Niemann-Pick type C disease patients.

    PubMed

    Rodríguez-Pascau, Laura; Toma, Claudio; Macías-Vidal, Judit; Cozar, Mónica; Cormand, Bru; Lykopoulou, Lilia; Coll, Maria Josep; Grinberg, Daniel; Vilageliu, Lluïsa

    2012-12-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal disorder characterised by the accumulation of a complex pattern of lipids in the lysosomal-late endosomal system. More than 300 disease-causing mutations have been identified so far in the NPC1 and NPC2 genes, including indel, missense, nonsense and splicing mutations. Only one genomic deletion, of more than 23 kb, has been previously reported. We describe two larger structural variants, encompassing NPC1 and flanking genes, as a cause of the disease. QMPSF, SNP inheritance and CytoScan® HD Array were used to confirm and further characterise the presence of hemizygous deletions in two patients. One of the patients (NPC-57) bore a previously described missense mutation (p.T1066N) and an inherited deletion that included NPC1, C18orf8 and part of ANKRD29 gene. The second patient (NPC-G1) had a 1-bp deletion (c.852delT; p.F284Lfs*26) and a deletion encompassing the promoter region and exons 1-10 of NPC1 and the adjacent ANKRD29 and LAMA3. This study characterised two novel chromosomal microdeletions at 18q11-q12 that cause NPC disease and provide insight into missing NPC1 mutant alleles. PMID:23142039

  6. Breakpoint analysis of Turner patients with partial Xp deletions: implications for the lymphoedema gene location

    PubMed Central

    Boucher, C.; Sargent, C.; Ogata, T.; Affara, N.

    2001-01-01

    BACKGROUND—Turner syndrome is characterised by a 45,X karyotype and a variety of skeletal, lymphoedemic, and gonadal anomalies. Genes involved in the Turner phenotype are thought to be X/Y homologous with the X genes escaping X inactivation. Haploinsufficiency of the SHOX gene has been reported to cause the short stature seen in Turner syndrome patients. More recently, mutations of this gene have been shown to be associated with other skeletal abnormalities, suggesting that haploinsufficiency of SHOX causes all the Turner skeletal anomalies. No such gene has yet been identified for the lymphoedemic features.
METHODS—Fluorescence in situ hybridisation (FISH) analysis with PAC clones on nine patients with partially deleted X chromosomes was performed.
RESULTS/DISCUSSION—The Turner syndrome stigmata for each patient are described and correlation between the breakpoint and the phenotype discussed. A lymphoedema critical region in Xp11.4 is proposed and its gene content discussed with respect to that in the previously reported Yp11.2 lymphoedema critical region.


Keywords: Turner syndrome; lymphoedema; Xp11.4 PMID:11546827

  7. Clinical features of patients with dystrophinopathy sharing the 45-55 exon deletion of DMD gene.

    PubMed

    Taglia, Antonella; Petillo, Roberta; D'Ambrosio, Paola; Picillo, Esther; Torella, Annalaura; Orsini, Chiara; Ergoli, Manuela; Scutifero, Marianna; Passamano, Luigia; Palladino, Alberto; Nigro, Gerardo; Politano, Luisa

    2015-05-01

    Becker muscular dystrophy (BMD) was first described in 1953 by Emile Becker as a benign variant of Duchenne muscular Dystrophy (DMD). Compared with DMD, BMD is clinically more heterogeneous, with initial presentation in the teenage years and loss of ambulation beyond the age of 16 and a wide spectrum of clinical presentations, ranging from only myalgias and muscle cramps to exercise intolerance and myoglobinuria, asymptomatic elevation of serum creatin-kinase, or mild limb-girdle weakness and quadriceps myopathy. About 50% of patients become symptomatic by the age of 10 and the most part by the age of 20 years. However few patients can be free of symptoms till their fifties and cases of late-onset Becker Muscular Dystrophy have also been described. In this report we describe the clinical features of patients with dystrophinopathy sharing a deletion of exons 45-55, occasionally or retrospectively diagnosed. These data are important for both the prognostic aspects of children presenting this dystrophin gene mutation, and for the genetic counseling in these families (reassuring them on the benign course of the disease), and last but not least to keep in mind a diagnosis of BMD in asymptomatic adults with mild hyperckemia. PMID:26155064

  8. Identification of a Novel Deletion in AVP-NPII Gene in a Patient with Central Diabetes Insipidus.

    PubMed

    Deniz, Ferhat; Acar, Ceren; Saglar, Emel; Erdem, Beril; Karaduman, Tugce; Yonem, Arif; Cagiltay, Eylem; Ay, Seyit Ahmet; Mergen, Hatice

    2015-01-01

    Central Diabetes Insipidus (CDI) is caused by a deficiency of antidiuretic hormone and characterized by polyuria, polydipsia and inability to concentrate urine. Our objective was to present the results of the molecular analyses of AVP-neurophysin II (AVP-NPII) gene in a large familial neurohypophyseal (central) DI pedigree. A male patient and his family members were analyzed and the prospective clinical data were collected. The proband applied to hospital for eligibility to be a recruit in Armed Forces. The patient had severe polyuria (20 L/day), polydipsia (20.5 L/day), fatique, and deep thirstiness. CDI was confirmed with the water deprivation-desmopressin test according to an increase in urine osmolality from 162 mOsm/kg to 432 mOsm/kg after desmopressin acetate injection. To evaluate the coding regions of AVP-NPII gene, polymerase chain reactions were performed and amplified regions were submitted to direct sequence analysis. We detected a heterozygous three base pair deletion at codon 69-70 (207_209delGGC) in exon 2, which lead to a deletion of the amino acid alanine. A three-dimensional protein structure prediction was shown for the deleted AVP-NPII and compared with the wild type. The three base pair deletion may yield an abnormal AVP precursor in neurophysin moiety, but further functional analyses are needed to understand the function of the deleted protein.

  9. Loss of the N-myc oncogene in a patient with a small interstitial deletion of the short arm of chromosome 2

    SciTech Connect

    Saal, H.M.; Johnson, R.C.; Carr, A.G.; Samango-Sprouse, C.

    1996-12-30

    To our knowledge, only four previous cases of distal chromosome 2p deletions exist in the literature. We present a patient with minor facial anomalies who had a distal interstitial deletion of the short arm of chromosome 2, del(2)(p24.2p25.1). This patient had many features seen in other patients with distal 2p deletion including short stature, {open_quotes}rectangular{close_quotes} facies, microcephaly, hypotonia, and mental retardation. This patient also has sensorineural hearing loss which has been described in one other patient with a similar deletion. The N-myc oncogene has been mapped to 2p24. By fluorescence in situ hybridization using a cDNA probe for the N-myc oncogene, this patient was found to have a deletion of the N-myc oncogene. This confirms the previous map location for N-myc. 17 refs., 3 figs., 1 tab.

  10. Hypertension and ace gene insertion/deletion polymorphism in pediatric renal transplant patients.

    PubMed

    Serdaroglu, Erkin; Mir, Sevgi; Berdeli, Afig

    2005-10-01

    The objective of the present study was to define the risk factors for hypertension and to analyze the influence of insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) on hypertension in pediatric renal transplant recipients. Twenty-six pediatric renal transplant recipients with stable renal function and treated with the same immunosuppression protocol were included in the study. Their mean age was 12.5 +/- 3.3 yr and mean time after transplantation was 38.5 +/- 39.8 month. Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed by SpaceLabs (90207) device. The I/D polymorphism of the ACE was determined by PCR and ACE serum level was analyzed by colorimetric method. Hypertension was present in 15 patients (57.7%) by causal blood pressure measurements and 19 patients (73.1%) by ABPM. Twenty-two patients (84.6%) were found to be non-dipper and eight of them had reverse dipping. Only time after transplantation (38 +/- 31 vs. 79 +/-49 month, p = 0.016) and cyclosporin A trough plasma levels (206 +/-78 vs. 119 +/- 83 ng/mL, p = 0.020) influenced the presence of hypertension by multiple logistic regression analysis. The distribution of genotypes were II = 2 (7.7%), ID = 8 (30.8%), DD = 16 (61.5%). There was no effect of ACE gene I/D polymorphism or serum ACE levels on hypertension prevalence and circadian variability of blood pressures. Hypertension was related to the time after transplantation and cyclosporin A levels. The ACE gene I/D polymorphism and serum ACE levels did not influence the blood pressure values or circadian variability of blood pressure among pediatric renal transplant patients. PMID:16176418

  11. Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion

    SciTech Connect

    Boultwood, J.; Rack, K.; Buckle, V.J.; Wainscoat, J.S. ); Kelly, S. ); Madden, J.; Oscier, D.G. ); Sakaguchi, A.Y.; Wang, Lingmei )

    1991-07-15

    A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R. The authors have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromsome 5, in 10 patients with myelodysplasia and a 5q deletion. They have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R. The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides. This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromsome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.

  12. Analysis of sporadic tuberous sclerosis patients with the TSC2 cDNA reveals several gene rearrangements and deletions

    SciTech Connect

    Wilson, P.J.; Short, M.P.; Bove, C.

    1994-09-01

    Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by hamartomas and hamartias in many organs including brain, skin, heart and kidneys. Two TSC genes have been localized through linkage analysis, TSC1 to 9q34 and TSC2 to 16p13.3. TSC2 was recently cloned. The distribution of sporadic TSC patients between TSC1 and TSC2 is at present unknown, but tests of genetic heterogeneity in families suggest that each is equally represented. Genetic heterogeneity may account for some of the variation in clinical expression; however, there is no evidence at present to support differences in clinical phenotypes between the 2 genetic loci. With the isolation of the TSC2 gene we have commenced mutation studies of our familial and sporadic TSC patients. Thus far six chromosome 16-linked families have been screened with the TSC2 cDNA and no detectable changes were observed using Southern analysis. In addition, 85 sporadic TSC patients were analyzed by Southern analysis. Using multiple restriction digests, nine patients revealed altered patterns, including three patients that appeared to have complete deletions. RT-PCR was performed on these patients confirming that the TSC2 gene was deleted. However, the remaining patients showed normal patterns, indicating that they either have TSC1 mutations or they possess more subtle small deletions or point mutations. At present we are designing an SSCP-based approach to determine the nature of the mutations in our 16 linked TSC families.

  13. Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27

    PubMed Central

    Peddibhotla, Sirisha; Nagamani, Sandesh CS; Erez, Ayelet; Hunter, Jill V; Holder Jr, J Lloyd; Carlin, Mary E; Bader, Patricia I; Perras, Helene MF; Allanson, Judith E; Newman, Leslie; Simpson, Gayle; Immken, LaDonna; Powell, Erin; Mohanty, Aaron; Kang, Sung-Hae L; Stankiewicz, Pawel; Bacino, Carlos A; Bi, Weimin; Patel, Ankita; Cheung, Sau W

    2015-01-01

    Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype–phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies. PMID:24736736

  14. Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27.

    PubMed

    Peddibhotla, Sirisha; Nagamani, Sandesh C S; Erez, Ayelet; Hunter, Jill V; Holder, J Lloyd; Carlin, Mary E; Bader, Patricia I; Perras, Helene M F; Allanson, Judith E; Newman, Leslie; Simpson, Gayle; Immken, LaDonna; Powell, Erin; Mohanty, Aaron; Kang, Sung-Hae L; Stankiewicz, Pawel; Bacino, Carlos A; Bi, Weimin; Patel, Ankita; Cheung, Sau W

    2015-01-01

    Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.

  15. Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.

    PubMed

    Kellogg, Gregory; Sum, John; Wallerstein, Robert

    2013-06-01

    Several recent reports of interstitial deletions at the terminal end of the short arm of chromosome 3 have helped to define the critical region whose deletion causes 3p deletion syndrome. We report on an 11-year-old girl with intellectual disability, obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array-CGH. This deletion overlaps with interstitial 3p25 deletions reported in three recent case reports. These deletions share a 124 kb overlap region including only three RefSeq annotated genes, THUMPD3, SETD5, and LOC440944. The current patient had phenotypic similarities, including intellectual disability, hypotonia, depressed nasal bridge, and long philtrum, with previously reported patients, while she did not have the cardiac defects, seizures ormicrocephaly reported in patients with larger deletions. Therefore, this patient furthers our knowledge of the consequences of 3p deletions, while suggesting genotype-phenotype correlations.

  16. Influence of clone and deletion size on outcome in chronic lymphocytic leukemia patients with an isolated deletion 13q in a population-based analysis in British Columbia, Canada.

    PubMed

    Huang, Steven J T; Gillan, Tanya L; Gerrie, Alina S; Hrynchak, Monica; Karsan, Aly; Ramadan, Khaled; Smith, Adam C; Toze, Cynthia L; Bruyere, Helene

    2016-01-01

    Deletion of the long arm of chromosome 13 (del(13q)) as the sole abnormality in chronic lymphocytic leukemia (CLL) portends a good prognosis; however, there is great outcome heterogeneity within this subgroup. The percentage of cells with a del(13q) (clone size) and the extent of the deletion are two factors that may affect outcome in CLL patients with isolated del(13q). We analyzed 248 CLL patients from the BC Provincial CLL database identified as having isolated del(13q) detected pretreatment by interphase fluorescence in situ hybridization to determine what impact clone and deletion size had on overall survival (OS) and treatment free survival (TFS). Patients with 60% or more of nuclei with a del(13q) had shorter TFS and shorter OS. A large deletion, encompassing the RB1 gene locus, was detected in half of the 90 cases with available specimens for testing, and there was no significant difference in OS and TFS between RB1-deleted and RB1-not-deleted cases. Further study in a larger sample size is required to determine the clinical interest of RB1 locus testing; however, clone size of del(13q) does predict TFS and OS and may better refine prognosis in this clinically heterogeneous population.

  17. Occupational hydrocarbon exposure among fathers of Prader-Willi syndrome patients with and without deletions of 15q

    SciTech Connect

    Cassidy, S.B.; Gainey, A.J.; Butler, M.G.

    1989-06-01

    Prader-Willi syndrome (PWS) is a multiple-anomaly disorder in which 50%-70% of cases are associated with a de novo interstitial deletion (del 15(q11-13)) on prometaphase cytogenetic analysis, the remainder having apparently normal chromosomes. In most instances, the paternally derived chromosome has become deleted in the affected child, suggesting the possibility of a predisposing environmental factor. Strakowski and Butler found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations in this population. This observation may suggest a causal relationship to PWS. To determine whether this association may distinguish the cytogenetically different groups, we identified 81 patients with the disorder who were physically and cytogenetically examined in three centers, and we compared the frequency of possible periconceptional occupational hydrocarbon exposure between fathers of patients who demonstrate a 15q deletion and those who do not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half of the fathers had been employed in hydrocarbon-exposing jobs. These findings suggest lack of etiologic heterogeneity between the cytogenetically different groups for PWS and affirm the need to seek submicroscopic deletions through molecular genetic studies. These data also provide additional evidence that hydrocarbon exposure among fathers of children with PWS may be causally related to the disorder, and they also suggest the need for more accurate assessment of exposure via a large, controlled study.

  18. Supernumerary inv dup (15) in a patient with Angelman syndome and a deletion of 15q11-q13

    SciTech Connect

    Spinner, N.B.; Zackai, E.; Knoll, J.H.M.

    1995-05-22

    We have studied a patient with Angelman syndrome (AS) and a 47,XY,+inv dup(15) (pter{r_arrow}q11::q11{r_arrow}pter) karyotype. Molecular cytogenetic studies demonstrated that one of the apparently normal 15s was deleted at loci D15S9, GABRB3, and D15S12. There were no additional copies of these loci on the inv dup(15). The inv dup(15) contained only the pericentromeric sequence D15Z1. Quantitative DNA analysis confirmed these findings and documented a standard large deletion of sequences from 15q11-q13, as usually seen in patients with AS. DNA methylation testing at D15S63 showed a deletion of the maternally derived chromosome. AS in this patient can be explained by the absence of DNA sequences from chromosome 15q11-q13 on one of the apparently cytogenetically normal 15s, and not by the presence of an inv dup(15). This is the fourth patient with an inv dup(15) and AS or Prader Willi syndrome, who has been studied at the molecular level. In all cases an additional alteration of chromosome 15 was identified, which was hypothesized to be the cause of the disease. Patients with inv dup(15)s may be at increased risk for other chromosome abnormalities involving 15q11-q13. 29 refs., 3 figs.

  19. A Comprehensive Evaluation of the Prognostic Significance of 13q Deletions in Patients with B-Chronic Lymphocytic Leukemia

    PubMed Central

    Van Dyke, Daniel L.; Shanafelt, Tait D.; Call, Timothy G.; Zent, Clive S.; Smoley, Stephanie A.; Rabe, Kari G.; Schwager, Susan M.; Sonbert, Jessica C.; Slager, Susan L.; Kay, Neil E.

    2009-01-01

    Summary Deletion 13q14 on fluorescence in situ hybridization (FISH) analysis is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and is a favorable prognostic biomarker when detected as a sole abnormality. We intensively interrogated clinical outcome in 323 consecutive, untreated CLL patients with isolated 13q- identified within two years of diagnosis. We also analyzed outcome in 217 additional patients with deletion 11q22.3 or 17p13.1, or trisomy 12 based on whether these occurred in isolation or in conjunction with 13q-. Patients with a heterozygous 13q- and those with a homozygous deletion had similar time to first treatment (TFT) and overall survival (OS). In contrast, a higher percentage of 13q- nuclei was associated with significantly shorter TFT (p<0.001). The 5-year untreated rate was 79% for patients with isolated 13q- in ≤65.5% of nuclei compared to 38% among those with 13q- in >65.5% of nuclei (p<0.001). The percentage of nuclei exhibiting 13q- remained an independent predictor of TFT after controlling for ZAP-70, IgVH, or CD38 (all p<0.001). Among patients with 13q- plus one other FISH abnormality, concomitant 13q- appeared to attenuate the shorter survival associated with 17p- (p=0.019). The clinical implications of 13q- in CLL appear more complex than originally appreciated. PMID:19895615

  20. Failure to thrive as primary feature in two patients with subtle chromosomal aneuploidy: Interstitial deletion 2q33

    SciTech Connect

    Grace, K.; Mulla, W.; Stump, T.

    1994-09-01

    It is well known that patients with chromosomal aneuploidy present with multiple congenital anomalies and dysmorphia, and that they may have associated failure to thrive. However, rarely is failure to thrive the predominant presenting feature. We report two such patients. Patient 1 had a marked history of failure to thrive, (weight 50% for 5 1/2 months at 20 months, length 50% for 15 months at 20 months). Patient 2 was noted to be growth retarded at 2 months upon presenting to the hospital with respiratory symptoms (weight 50% for a newborn, length 50% for 36 weeks gestation). There was relative head sparing in both patients. Chromosome analysis in patient 1, prompted by a negative work-up for the failure to thrive, and emerging evidence of developmental delay, revealed a 46,XY,del(2)(q32.2q33) karyotype. Chromosome analysis in patient 2, done as part of a complete workup for the failure to thrive, revealed a 46,XX,del(2)(q33.2q33.2 or q33.2q33.3) karyotype. On careful examination, subtle dysmorphic features were seen. In both patients these included a long flat philtrum, thin upper lip and high arched palate. Patient 1 also had a small posterior cleft of the palate. These patients have the smallest interstitial deletions of chromosome 2 so far reported. Their deletions overlap within 2q33 although they are not identical. Review of the literature reveals 15 patients with interstitial deletions which include 2q33. Marked growth retardation is reported in 14 of these cases. Cleft palate/abnormal uvula were frequently associated. These cases illustrate the need to include high resolution chromosomal studies as part of a complete work-up for unexplained failure to thrive.

  1. Interstitial deletions of the short arm of chromosome 4 in patients with a similar combination of multiple minor anomalies and mental retardation

    SciTech Connect

    White, D.M.; Pillers, D.A.M.; Magenis, R.E.

    1995-07-17

    Interstitial deletions of chromosome 4 have been described rarely and have had variable presentations. We describe the phenotypic characteristics associated with interstitial deletion of the p14-16 region of chromosome 4 in 7 patients with multiple minor anomalies in common, and with mental retardation. A review of published cases of interstitial deletions of the short arm of chromosome 4 is provided. These deletions present a distinct phenotype which is different from that of Wolf-Hirschhorn syndrome. 52 refs., 12 figs., 2 tabs.

  2. An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome

    PubMed Central

    Tastuzawa, Yasutaka; Sekinaka, Kanako; Suda, Tetsufumi; Matsumoto, Hiroshi; Otabe, Hiroyuki; Nonoyama, Shigeaki; Yoshino, Aihide

    2015-01-01

    In addition to causing polymalformative syndrome, 22q11.2 deletion can lead to various neuropsychiatric disorders including mental retardation, psychosis, and epilepsy. However, few reports regarding epilepsy-related psychosis in 22q11.2 deletion syndrome (22q11.2DS) exist. We describe the clinical characteristics and course of 22q11.2DS in a Japanese patient with comorbid mild mental retardation, childhood-onset localization-related epilepsy, and adult-onset, interictal schizophrenia-like psychosis. From a diagnostic viewpoint, early detection of impaired intellectual functioning and hyperprolinemia in patients with epilepsy with 22q11.2DS may be helpful in predicting the developmental timing of interictal psychosis. From a therapeutic viewpoint, special attention needs to be paid to phenytoin-induced hypocalcemia in this syndrome. PMID:25870791

  3. Neurodevelopmental outcome in patients with terminal deletion of the short arm of chromosome 20

    SciTech Connect

    Frazer, C.H.; Hobbs, N.; Rappaport, L.

    1994-09-01

    Clinical geneticists and genetic counselors are often expected to provide information concerning anticipated neurodevelopmental outcome in children with chromosome abnormalities. Accurate prediction, however, may be impossible, and is at the least hampered by insufficient data and by natural variation in expression. Our experience with a now 27-month-old boy with terminal 20p- underscores this issue. A newborn male with multiple congenital anomalies, including pulmonary artery stenosis, vertebral anomalies, posterior ocular embryotoxon and multiple dysmorphic features was found to have 46,XY,del(20)(p11.23ter) de novo, including the location for Alagille Syndrome (AS). Early clinical course was also notable for obstructive apnea and cardiorespiratory arrests. Available literature suggested a poor neurodevelopmental prognosis. At age 27 months, he exhibits hypotonia and gross motor skills assessed at 12-15 months. However, cognitive and language skills were at the 20 months level. No structural neurological lesions have been identified. We attempted to obtain updated outcome information on previous cases for comparison. 11 previously published reports with similar extent of deletion of 20p demonstrated varied, but often more severe neurodevelopmental impairment. The majority described early global delays, with significant motor delay. However, little longitudinal or functional information was available. In contrast, our patient demonstrates good neurodevelopmental and functional progress. Caution should be exercised in counseling regarding neurodevelopmental outcome in cases of chromosomal anomaly, due to lack of information and natural variability. Standardized assessment and reporting of longitudinal neurodevelopmental follow-up are necessary for more appropriate counseling concerning outcome in chromosomal anomalies.

  4. Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

    PubMed

    Barone, Chiara; Bianca, Sebastiano; Luciano, Daniela; Di Benedetto, Daniela; Vinci, Mirella; Fichera, Marco

    2013-06-01

    Intellectual disability affects approximately 2% of the population, with affected males outnumbering affected female, partly due to disturbances involving X-linked genes. To date >90 genes associated with X-linked intellectual disability have been identified and, among these, IL1RAPL1 (interleukin 1 receptor accessory protein-like 1), was first described and mapped to Xp21.3-22.1 in 1999. Intragenic deletions of IL1RAPL1, only rarely identified, have mostly been associated with nonspecific intellectual disability (IDX) and autism spectrum disorder. Array-CGH analysis performed in our patient with intellectual disability, mild dysmorphic signs and changes in behavior identified a 285 Kb deletion in chromosome Xp21.3-21.2, with breakpoints lying in IL1RAPL1 gene intron 2 and intron 3. This is the first patient reported in literature with deletion of only exon 3 of IL1RAPL1 gene. Our patient also exhibits bilateral progressive neurosensorial deafness, which has not been previously associated with IL1RAPL1 mutations. PMID:23613341

  5. [Catch-22? Wide variety of phenotypes associated with the chromosome 22q11 deletion syndrome in two patients].

    PubMed

    Till, Ágnes; Hadzsiev, Kinga; Lőcsei-Fekete, Anett; Czakó, Márta; Duga, Balázs; Melegh, Béla

    2015-11-01

    The chromosome 22q11 deletion syndrome may present with a variety of phenotypes. Its symptoms generally include a characteristic facial dysmorphisms and multiplex developmental disorders. Fluorescence in situ hybridization is the current method of choice for the diagnosis if typical multiple defects and/or symptoms are present. The authors present the history of two patients who were followed-up for minor anomalies and various developmental disorders for several years in the genetic counseling office of the authors, but definitive diagnosis was not established. However, when DNA samples of the two patients were recently tested with array comparative genome hybridization, a diagnostic method which has already been used in their institute for several years, the results indicated deletion of the 11.2 region on the long arm of chromosome 22 in both patients. The authors draw attention to the incidence and wide phenotypic spectrum of the chromosome 22q11 deletion syndrome, and show that its identification can be aided with the novel molecular cytogenetic method available in their laboratory.

  6. Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion.

    PubMed

    Kayano, Shuji; Kure, Shigeo; Suzuki, Yoichi; Kanno, Kiyoshi; Aoki, Yoko; Kondo, Shinji; Schutte, Brian C; Murray, Jeffrey C; Yamada, Atsushi; Matsubara, Yoichi

    2003-01-01

    Three Japanese families with Van der Woude syndrome (VWS) were screened for mutations in the interferon regulatory factor 6 gene (IRF6) by sequencing its entire coding region. Two novel missense mutations, R45Q in exon 3 and P396S in exon 9, were identified in families 1 and 2, respectively. In family 3, no causative base change was found by the sequencing analysis, but a deletion involving exons 4-9 was suggested by multiplex PCR analysis. To confirm the deletion and to determine its 5'- and 3'-boundaries, we amplified a DNA fragment containing a heterozygous polymorphic site in exon 2 by using a 5'-upstream forward PCR primer and eight different reverse primers located 3'-downstream of exon 2. The amplified product was subjected to nested PCR to generate a DNA fragment containing the polymorphic site. When a reverse primer located within the deletion was used for the first PCR amplification, only the nondeletion allele was detected after the second PCR. Repeated analyses with eight different reverse primers allowed us to map the boundaries of the deletion, and subsequently a heterozygous 17,162-bp deletion involving exons 4-9 was identified. Since IRF6 mutations in a significant portion of VWS patients remain undetected by conventional sequencing analysis, it may be important to search for a large deletion in those patients. Our simple methods to identify deletions and to determine the boundaries of a deletion would facilitate the identification of such patients.

  7. A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa.

    PubMed

    Meindl, A; Carvalho, M R; Herrmann, K; Lorenz, B; Achatz, H; Lorenz, B; Apfelstedt-Sylla, E; Wittwer, B; Ross, M; Meitinger, T

    1995-12-01

    X-linked retinitis pigmentosa (XLRP) is characterized by retinal degeneration with night blindness and progressive reduction of the visual fields. By linkage and deletion analysis a gene locus (RP3) has been mapped to the short arm of the X chromosome between the genes CYBB and OTC. Analysis of transcript in this region has revealed a gene which is abundantly expressed in human retina and encodes a putative membrane protein with significant homologies to short consensus repeat (SCR/sushi) domains known from selections and complement proteins. The gene termed SRPX (sushi-repeat-containing protein, x chromosome) is deleted in an RP patient who also suffers from chronic granulomatous disease and McLeod syndrome. A 75 kb deletion removing exon 1 of the gene was also found in two brothers of a second XLRP family. However, no further functionally significant mutations were detected by SSCP screening of all 10 exons in 34 unrelated XLRP patients nor by full length RT-PCR sequencing in two RP3 families. The role of this highly conserved retinal gene in the pathogenesis of RP therefore remains to be determined.

  8. Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15.

    PubMed

    Cassidy, S B; Forsythe, M; Heeger, S; Nicholls, R D; Schork, N; Benn, P; Schwartz, S

    1997-02-11

    Prader-Willi syndrome (PWS) is a complex multiple anomaly syndrome that has been shown to result from deficient expression of paternal chromosome 15(q11-q13). In most cases, it is caused either by deletion of this region in the paternally inherited chromosome 15 or by maternal uniparental disomy (UPD) of chromosome 15. In order to determine whether there are phenotypic differences between patients whose PWS is caused by these two different mechanisms, 54 affected individuals (37 with deletion, 17 with UPD) were personally examined and studied using molecular techniques. The previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the two groups, those with UPD were less likely to have a "typical" facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average. Possible mechanisms by which these differences could occur and the implications of these differences for diagnosis are described. PMID:9021017

  9. Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9.

    PubMed

    Katoh-Fukui, Yuko; Igarashi, Maki; Nagasaki, Keisuke; Horikawa, Reiko; Nagai, Toshiro; Tsuchiya, Takayoshi; Suzuki, Erina; Miyado, Mami; Hata, Kenichiro; Nakabayashi, Kazuhiko; Hayashi, Keiko; Matsubara, Yoichi; Baba, Takashi; Morohashi, Ken-Ichirou; Igarashi, Arisa; Ogata, Tsutomu; Takada, Shuji; Fukami, Maki

    2015-11-01

    SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1-3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C-terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short-nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C-terminal missense substitutions which lead to target-gene-specific protein dysfunction, and enhancer-containing upstream microdeletions mediated by nonhomologous end-joining. PMID:26740947

  10. Unusual presentation of pelizaeus-merzbacher disease: female patient with deletion of the proteolipid protein 1 gene.

    PubMed

    Brender, Teva; Wallerstein, Donna; Sum, John; Wallerstein, Robert

    2015-01-01

    Pelizaeus-Merzbacher disease (PMD) is neurodegenerative leukodystrophy caused by dysfunction of the proteolipid protein 1 (PLP1) gene on Xq22, which codes for an essential myelin protein. As an X-linked condition, PMD primarily affects males; however there have been a small number of affected females reported in the medical literature with a variety of different mutations in this gene. No affected females to date have a deletion like our patient. In addition to this, our patient has skewed X chromosome inactivation which adds to her presentation as her unaffected mother also carries the mutation. PMID:25789183

  11. Unusual Presentation of Pelizaeus-Merzbacher Disease: Female Patient with Deletion of the Proteolipid Protein 1 Gene

    PubMed Central

    Brender, Teva; Wallerstein, Donna; Sum, John; Wallerstein, Robert

    2015-01-01

    Pelizaeus-Merzbacher disease (PMD) is neurodegenerative leukodystrophy caused by dysfunction of the proteolipid protein 1 (PLP1) gene on Xq22, which codes for an essential myelin protein. As an X-linked condition, PMD primarily affects males; however there have been a small number of affected females reported in the medical literature with a variety of different mutations in this gene. No affected females to date have a deletion like our patient. In addition to this, our patient has skewed X chromosome inactivation which adds to her presentation as her unaffected mother also carries the mutation. PMID:25789183

  12. Mitochondrial DNA deletion in a patient with combined features of Leigh and Pearson syndromes

    SciTech Connect

    Blok, R.B.; Thorburn, D.R.; Danks, D.M.

    1994-09-01

    We describe a heteroplasmic 4237 bp mitochondrial DNA (mtDNA) deletion in an 11 year old girl who has suffered from progressive illness since birth. She has some features of Leigh syndrome (global developmental delay with regression, brainstem dysfunction and lactic acidosis), together with other features suggestive of Pearson syndrome (history of pancytopenia and failure to thrive). The deletion was present at a level greater than 50% in skeletal muscle, but barely detectable in skin fibroblasts following Southern blot analysis, and only observed in blood following PCR analysis. The deletion spanned nt 9498 to nt 13734, and was flanked by a 12 bp direct repeat. Genes for cytochrome c oxidase subunit III, NADH dehydrogenase subunits 3, 4L, 4 and 5, and tRNAs for glycine, arginine, histidine, serine({sup AGY}) and leucine({sup CUN}) were deleted. Southern blotting also revealed an altered Apa I restriction site which was shown by sequence analysis to be caused by G{r_arrow}A nucleotide substitution at nt 1462 in the 12S rRNA gene. This was presumed to be a polymorphism. No abnormalities of mitochondrial ultrastructure, distribution or of respiratory chain enzyme complexes I-IV in skeletal muscle were observed. Mitochondrial disorders with clinical features overlapping more than one syndrome have been reported previously. This case further demonstrates the difficulty in correlating observed clinical features with a specific mitochondrial DNA mutation.

  13. Deletion 17p11.2 (Smith-Magenis syndrome) is relatively common among patients having mental retardation and myopia

    SciTech Connect

    Finucane, B.; Jaeger, E.R.; Freitag, S.K.

    1994-09-01

    We recently reported the finding of moderate to severe myopia in 6 of 10 patients with Smith-Magenis syndrome (SMS). To investigate the prevalence of SMS among mentally retarded people having myopia, we surveyed a cohort of patients residing at a facility for individuals with mental retardation (MR). Of 547 institutionalized individuals with MR, 72 (13.2%) had moderate to high myopia defined as a visual acuity of minus 3 diopters or more. It should be noted that our institution does not specifically select for people with visual impairment; rather, the facility serves people with a primary diagnosis of MR. Sixty-five of 72 (90.3%) myopic individuals identified were available for cytogenetic analysis. Seventeen (26.2%) of these patients had trisomy 21. Down syndrome (DS) is well known to be associated with eye abnormalities, including myopia. Of 48 individuals with moderate to high myopia not having DS, 5 (10.4%) were shown to have deletions of 17p11.2. This is a high prevalence considering the relative rarity of SMS. By contrast, in a randomized sample of 48 patients without significant myopia at the same facility, we found no individuals with deletion 17p11.2. We conclude that the diagnosis of SMS should be considered in any non-Down syndrome individual having MR and myopia, and that ophthalmologists serving people with MR should be made aware of this deletion syndrome. Furthermore, our results suggest that significant numbers of people having SMS could be identified through selective institutional screening of patients having a combination of MR and moderate to severe myopia.

  14. Abnormal protein in the cerebrospinal fluid of patients with a submicroscopic X-chromosomal deletion associated with Norrie disease: preliminary report.

    PubMed

    Joy, J E; Poglod, R; Murphy, D L; Sims, K B; de la Chapelle, A; Sankila, E M; Norio, R; Merril, C R

    1991-01-01

    Norrie disease is an X-linked recessive disorder characterized by congenital blindness and, in many cases, mental retardation. Some Norrie disease cases have been shown to be associated with a submicroscopic deletion in chromosomal region Xp11.3. Cerebrospinal fluid (CSF) was collected from four male patients with an X-chromosomal deletion associated with Norrie disease. CSF proteins were resolved using two-dimensional gel electrophoresis and then analyzed by computer using the Elsie V program. Our analysis revealed a protein that appears to be altered in patients with Norrie disease deletion.

  15. Schizophrenia and chromosomal deletions

    SciTech Connect

    Lindsay, E.A.; Baldini, A.; Morris, M. A.

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  16. Array-CGH in patients with Kabuki-like phenotype: Identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration

    PubMed Central

    Cuscó, Ivon; del Campo, Miguel; Vilardell, Mireia; González, Eva; Gener, Blanca; Galán, Enrique; Toledo, Laura; Pérez-Jurado, Luis A

    2008-01-01

    Background Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has not been confirmed in other patients. The molecular basis of KS remains unknown. Methods We have studied 16 Spanish patients with a clinical diagnosis of KS or KS-like to search for genomic imbalances using genome-wide array technologies. All putative rearrangements were confirmed by FISH, microsatellite markers and/or MLPA assays, which also determined whether the imbalance was de novo or inherited. Results No duplication at 8p23.1-p22 was observed in our patients. We detected complex rearrangements involving 2q in two patients with Kabuki-like features: 1) a de novo inverted duplication of 11 Mb with a 4.5 Mb terminal deletion, and 2) a de novo 7.2 Mb-terminal deletion in a patient with an additional de novo 0.5 Mb interstitial deletion in 16p. Additional copy number variations (CNV), either inherited or reported in normal controls, were identified and interpreted as polymorphic variants. No specific CNV was significantly increased in the KS group. Conclusion Our results further confirmed that genomic duplications of 8p23 region are not a common cause of KS and failed to detect other recurrent rearrangement causing this disorder. The detection of two patients with 2q37 deletions suggests that there is a phenotypic overlap between the two conditions, and screening this region in the Kabuki-like patients should be considered. PMID:18405349

  17. A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

    PubMed

    Poirsier, Céline; Besseau-Ayasse, Justine; Schluth-Bolard, Caroline; Toutain, Jérôme; Missirian, Chantal; Le Caignec, Cédric; Bazin, Anne; de Blois, Marie Christine; Kuentz, Paul; Catty, Marie; Choiset, Agnès; Plessis, Ghislaine; Basinko, Audrey; Letard, Pascaline; Flori, Elisabeth; Jimenez, Mélanie; Valduga, Mylène; Landais, Emilie; Lallaoui, Hakima; Cartault, François; Lespinasse, James; Martin-Coignard, Dominique; Callier, Patrick; Pebrel-Richard, Céline; Portnoi, Marie-France; Busa, Tiffany; Receveur, Aline; Amblard, Florence; Yardin, Catherine; Harbuz, Radu; Prieur, Fabienne; Le Meur, Nathalie; Pipiras, Eva; Kleinfinger, Pascale; Vialard, François; Doco-Fenzy, Martine

    2016-06-01

    Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.

  18. Isochromosome 15q of maternal origin in two Prader-Willi syndrome patients previously diagnosed erroneously as cytogenetic deletions

    SciTech Connect

    Saitoh, Shinji; Niikawa, Norio; Mutirangura, A.; Kuwano, A.; Ledbetter, D.H.

    1994-03-01

    Since a previous report on two Prader-Willi syndrome (PWS) patients with t(15q;15q) was erroneous, the authors report new data and a corrected interpretation. Reexamination of the parental origin of their t(15q;15q) using polymorphic DNA markers that are mapped to various regions of 15q documented no molecular deletions at the 15q11-q13 region in either patient. Both patients were homozygous at all loci examined and their haplotypes on 15q coincided with one of those in their respective mothers. These results indicate that the presumed t(15q;15q) in each patient was actually an isochromosome 15q producing maternal uniparental disomy, consistent with genomic imprinting at the PWS locus. 30 refs., 1 fig., 3 tabs.

  19. Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region.

    PubMed

    Nicita, Francesco; Garone, Giacomo; Spalice, Alberto; Savasta, Salvatore; Striano, Pasquale; Pantaleoni, Chiara; Spartà, Maria Valentina; Kluger, Gerhard; Capovilla, Giuseppe; Pruna, Dario; Freri, Elena; D'Arrigo, Stefano; Verrotti, Alberto

    2016-01-01

    Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene-deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro-clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro-clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2.

  20. Chromosome 10p deletion in a patient with hypoparathyroidism, severe mental retardation, autism and basal ganglia calcifications.

    PubMed

    Verri, Annapia; Maraschio, Paola; Devriendt, Koen; Uggetti, Carla; Spadoni, Emanuela; Haeusler, Edward; Federico, Antonio

    2004-01-01

    Chromosome 10p terminal deletions have been associated with a DiGeorge like phenotype. Haploinsufficiency of the region 10p14-pter, results in hypoparathyroidism, sensorineural deafness, renal anomaly, that is the triad that features the HDR syndrome. Van Esch (2000) identified in a HDR patient, within a 200 kb critical region, the GATA3 gene, a transcription factor involved in the embryonic development of the parathyroids, auditory system and kidneys. We describe a new male patient, 33-year-old, with 10p partial deletion affected by hypocalcemia, basal ganglia calcifications and a severe autistic syndrome associated with mental retardation. Neurologically he presented severe impairment of language, hypotonia, clumsiness and a postural dystonic attitude. A peripheral involvement of auditory pathways was documented by auditory evoked potentials alterations. CT scan documented basal ganglia calcifications. Hyperintensity of the lentiform nuclei was evident at the MRI examination. Renal ultrasound scan was normal. Haploinsufficiency for GATA3 gene was documented with FISH analysis using cosmid clone 1.2. Phenotypic spectrum observed in del (10p) is more severe than the classical DGS spectrum. GATA3 has been found to regulate the development of serotoninergic neurons. A serotoninergic dysfunction may be linked with autism in this patient. PMID:15337474

  1. Screening Duchenne and Becker muscular dystrophy patients for deletions in 30 exons of the dystrophin gene by three-multiplex PCR

    SciTech Connect

    Risch, N. )

    1992-09-01

    Deletion mutations of the dystrophin gene may cause either the severe Duchenne muscular dystrophy (DMD) or the milder, allelic Becker muscular dystrophy (BMD) and are clustered in two high-frequency-deletion regions (HFDRs) located, respectively, 500 kb and 1,200 kb downstream from the 5[prime] end of the gene. Three PCR reactions described allowed the analysis of a total of 30 exons and led, to the identification of three additional deletions involving the following exons: (a) 42 only, (b) 28-42, and (c) 16 only, none of which were detected with the two original multiplex reactions. Therefore, the three modified multiplexes detected 95 of the 96 deletions identified among the 152 patients studied so far by using Southern analysis and cDNA probes. The only deletion that remained undetected with this system involves exons 22-25 and generates the junction fragment described elsewhere. The percentage of deletion mutations among DMS/BMD patients amounts to 63%, which is in agreement with similar estimates from other laboratories. When field-inversion gel electrophoresis is coupled to Southern analysis, the detection rate of deletion and duplication mutations reaches 65%.

  2. Mapping of chromosome 20 for loss of heterozygosity in childhood ALL reveals a 1,000-kb deletion in one patient.

    PubMed

    Couque, N; Chambon-Pautas, C; Cavé, H; Bardet, V; Duval, M; Vilmer, E; Grandchamp, B

    1999-12-01

    The long arm of chromosome 20 displays recurrent loss of heterozygosity (LOH) for microsatellite markers in blast cells from children with acute lymphoblastic leukemia. To further characterize the region of deletion and to precisely establish its frequency, we searched for LOH in 103 children with ALL using polymorphic markers in the previously described region of interest, namely between D20S101 and D20S887. LOH was detected in nine patients (ie with a frequency of 8.7%). Interestingly, in one patient, a small deletion was found, flanked proximally by D20S850 and distally by M201, a dinucleotide repeat identified from chromosome 20 sequences. The distance between these two markers is approximately 1000 kb. The occurrence of non-random deletions of the long arm of chromosome 20 has previously been observed in myeloid malignancies (myeloproliferative disorders and myelodysplastic syndromes) in 5-10% of patients. The small deletion in our patient is located within the common region of deletion of myeloproliferative disorders suggesting that a tumor suppressor gene may be the common target of the deletions in various types of hematological malignancies.

  3. Telomeric 1p36.3 deletion and Ki-67 expression in B-Non-Hodgkin's Lymphoma patients associated with chronic hepatitis C virus infection.

    PubMed

    Mosad, E; Said Abd El-Rahman Allam, M; Moustafa, H M; Mohammed, A Eliaw; El kebeer, A M; Abdel-Moneim, S S

    2014-12-01

    The hepatitis C virus (HCV) core protein is able to accumulate genetic p53 mutations and may be considered co-oncogenic. This study investigates 1p36.3 telomere deletion in B-non-Hodgkin's lymphoma (NHL) patients with chronic HCV infection using fluorescence in situ hybridization (FISH) in relation to survival to assess Ki-67 antigen expression. A study group and a control group of 100 patients with B-NHL (50 HCV positive and 50 HCV negative) and 60 control bone marrow biopsies were subjected to FISH for the detection of 1P36.3 deletion and to immunohistochemical staining with Ki-67 antigens. 1p36.3 deletion by FISH was detected in 40% of the study group, and Ki-67 was expressed in approximately 74% of patients. A significant difference was found between positive and negative HCV patients in their overall survival, the qualitative expression of Ki-67 and the quantitative detection of 1p36.3 deletion by FISH. The overall survival was shorter with the presence of an 1p36 deletion by FISH and HCV positive. We concluded that the coexistence of Ki-67 positivity, HCV positivity and 1p36.3 deletion may contribute to infection-related cancers at the 1p36.3 locus.

  4. Frequent intragenic deletion of the P gene in Tanzanian patients with Type II oculocutaneous albinism (OCA2)

    SciTech Connect

    Spritz, R.; Fukai, K.; Holmes, S.A.

    1995-06-01

    Type II oculocutaneous albinism (OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. OCA2, which results from mutations of the P gene, is the most frequent type of albinism in African and African-American patients. OCA2 is especially frequent in Tanzania, where it occurs with an incidence of {approximately}1/1,400. We have identified abnormalities of the P gene in each of 13 unrelated patients with OCA2 from Tanzania. One of these, a deletion of exon 7, is strongly predominant, accounting for {approximately}77% of mutant alleles in this group of patients. 20 refs., 2 figs.

  5. Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes

    PubMed Central

    Botta, A; Novelli, G; Mari, A; Novelli, A; Sabani, M; Korenberg, J; Osborne, L; Digilio, M; Giannotti, A; Dallapiccola, B

    1999-01-01

    We present two patients with the full Williams syndrome (WS) phenotype carrying a smaller deletion than typically observed. The deleted region spans from the elastin gene to marker D7S1870. This observation narrows the minimal region of deletion in WS and suggests that the syntaxin 1A and frizzled genes are not responsible for the major features of this developmental disorder and provides important insight into understanding the genotype-phenotype correlation in WS.


Keywords: Williams syndrome; elastin; syntaxin; frizzled PMID:10874638

  6. 22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization

    PubMed Central

    Gollo Dantas, Anelisa; Bortolai, Adriana; Moysés-Oliveira, Mariana; Takeno Herrero, Sylvia; Azoubel Antunes, Adriana; Tavares Costa-Carvalho, Beatriz; Ayres Meloni, Vera; Melaragno, Maria Isabel

    2016-01-01

    We report on a patient conceived via in vitro fertilization (IVF) with a 22q11.2 deletion due to an unusual unbalanced translocation involving chromosomes 6 and 22 in a karyotype with 45 chromosomes. Cytogenomic studies showed that the patient has a 3.3-Mb deletion of chromosome 22q and a 0.4-Mb deletion of chromosome 6p, which resulted in haploinsufficiency of the genes responsible for the 22q11.2 deletion syndrome and also of the IRF4 gene, a member of the interferon regulatory factor family of transcription factors, which is expressed in the immune system cells. The rearrangement could be due to the manipulation of the embryo or as a sporadic event unrelated to IVF. Translocation involving chromosome 22 in a karyotype with 45 chromosomes is a rare event, with no previous reports involving chromosomes 6p and 22q. PMID:26997945

  7. Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome.

    PubMed

    Koh, Ji Won; Kang, So Young; Kim, Gu Hwan; Yoo, Han Wook; Yu, Jeesuk

    2013-06-01

    X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita. PMID:24904859

  8. Detection of hepatitis D virus RNA carrying large fragment deletions in patients with severe hepatitis B/D receiving oral antiviral therapy.

    PubMed

    Hsu, Chao-Wei; Chao, Mei; Chen, Yi-Cheng; Chang, Ming-Ling; Huang, Shiu-Feng; Yeh, Chau-Ting

    2015-04-01

    A chronic lymphocytic leukemia patient had achieved complete virological suppression of hepatitis B virus (HBV) by oral antiviral therapy. Unexpectedly, fulminant hepatitis D virus (HDV) reactivation occurred, resulting in mortality. Cloning and sequence analysis identified a novel large fragment HDV deletion mutant containing only 69% of the standard genome. Reverse transcription-PCR assay revealed persistence of this mutant with variations of the wild-type-to-mutant ratios during the clinical course. Serum samples from 405 patients with chronic hepatitis B were then submitted for HDV RNA analysis. Of them, 20 (4.9%) were positive for HDV RNA and 5 HDV RNA large fragment deletions were identified in three patients, all under entecavir treatment. Two of them suffered from acute hepatitis exacerbations leading to liver failure while the third had repeated hepatitis flares. The peak bilirubin levels in these three patients were significantly higher than the others without large fragment deletions (P = 0.003). The deleted regions (527-702 bases) encompassed two ribozyme domains as well as part of the hepatitis D antigen (HDAg) reading frame. In conclusion, exacerbations of hepatitis D could occur, leading to fulminant hepatitis, even after complete virological suppression of HBV. Large fragment HDV RNA deletions were identified in some hepatitis D patients who were treated with entecavir but still experiencing severe hepatitis.

  9. Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome

    PubMed Central

    Lassi, Glenda; Priano, Lorenzo; Maggi, Silvia; Garcia-Garcia, Celina; Balzani, Edoardo; El-Assawy, Nadia; Pagani, Marco; Tinarelli, Federico; Giardino, Daniela; Mauro, Alessandro; Peters, Jo; Gozzi, Alessandro; Grugni, Graziano; Tucci, Valter

    2016-01-01

    Study Objectives: Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome. Methods: We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr m+/p− heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects. Results: By studying the mouse mutant line PWScrm+/p−, we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScrm+/p− mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients. Conclusions: Our study indicates that paternally expressed

  10. A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients

    PubMed Central

    Widdershoven, Josine C.C.; Bowser, Mark; Sheridan, Molly B.; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Solot, Cynthia B.; Kirschner, Richard E.; Beemer, Frits A.; Morrow, Bernice E.; Devoto, Marcella; Emanuel, Beverly S.

    2014-01-01

    Objective Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. Methods Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. Results Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ≤0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. Conclusions Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients. PMID:23121717

  11. Interstitial deletion of the long arm of chromosome 6 associated with unusual limb anomalies: report of two new patients and review of the literature.

    PubMed

    Pandya, A; Braverman, N; Pyeritz, R E; Ying, K L; Kline, A D; Falk, R E

    1995-10-23

    We report on unusual manifestations in 2 unrelated children with interstitial deletion of 6q, with nearly identical breakpoints of 6q16.2q23.1 and 6q16.3q22.3. Major findings include growth retardation, profound developmental delay, microcephaly, facial anomalies, sparse hair, congenital heart defects, and striking hand malformations. Discordant anomalies were duodenal atresia and hypoplastic genitalia in 1 child. Split-hand defect, polydactyly, gastrointestinal anomalies, and ectodermal dysplasia have not been described previously in children with 6q deletion. The presence of hand malformations in 2 children with similar deletion breakpoints strongly suggests that this is a candidate region for one or more genes involved in limb development. Comparison of the clinical findings of other patients with 6q2 deletion suggests a recognizable phenotype.

  12. Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies

    PubMed Central

    Rinnenthal, Jan Leo; Zimmermann, Hanna; Mikolajczak, Janine; Oberwahrenbrock, Timm; Papazoglou, Sebastian; Pfüller, Caspar F.; Schinzel, Johann; Tackenberg, Björn; Paul, Friedemann; Hahn, Katrin; Bellmann-Strobl, Judith

    2016-01-01

    Background The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Methods Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). Results All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. Conclusion PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a

  13. A novel deletion and two recurrent substitutions on type VII collagen gene in seven Iranian patients with epidermolysis bullosa

    PubMed Central

    Hamidi, Armita Kakavand; Moghaddam, Mohammad; Hatamnejadian, Nasim; Ebrahimi, Ahmad

    2016-01-01

    Objective(s): Epidermolysis bullosa is one of the most important series of mechano-bullous heritable skin disorders which is categorized into four major types according to the layer that bullae forms within basement membrane zone. In dystrophic form of the disease, blisters are made in the sublamina densa zone, at the level of type VII collagen protein which produce anchoring fibrils. Type VII collagen gene is the only responsible gene for this form. The aim of this study was to survey causative mutations of type VII collagen gene among Iranian patients with epidermolysis bullosa. Materials and Methods: For this purpose, exons 73-75 were investigated by polymerase chain reaction followed by direct sequencing. Results: In current study, we found three different point mutations in type VII collagen alleles in 7 out of 50 patients. Four patients were homozygous for a new deletion which resulted in frame shift (p.Pro2089fs). Two patients were homozygous for a recurrent glycine substitution (p.G2031S) and one patient was detected with an allele carrying a substitution (p.R2069C). Conclusion: The results emphasized heterogeneity in the type VII collagen gene and will provide a sign for early diagnosis and future study of the disease pathogenesis. PMID:27746867

  14. Micromegakaryocytes in a patient with partial deletion of the long arm of chromosome 11 [del(11)(q24.2qter)] and chronic thrombocytopenic purpura

    SciTech Connect

    Gangarossa, S.; Mattina, T.; Romano, V.; Milana, G.; Mollica, F.; Schiliro, G.

    1996-03-15

    Thrombocytopenia or pancytopenia is frequently reported in patients with partial 11q deletion but there are no reports on bone marrow morphology of these patients. We report on a patient with partial deletion of the long arm of chromosome 11 [del(11)(q24.2qter)] and its classical clinical manifestations including chronic thrombocytopenic purpura in whom micromegakaryocytes were found in the bone marrow aspirate. This is the first report of the presence of micromegakaryocytes in the bone marrow of a patient with 11q deletion. Accurate examination of the bone marrow of other patients with the 11q deletion may clarify whether the observation of micromegakaryocytes is common in these patients. Micromegakaryocytes may indicate a defect of development. Two genes for two DNA binding proteins that are likely to be involved in hematopoiesis map in the 11q region: Ets-1, that maps to 11q24, close to D11S912, and the nuclear-factor-related-kB gene that maps to 11q24-q25. It is possible that these genes, when present in only one copy, result in thrombocytopenia or pancytopenia as observed in this patient. 23 refs., 2 figs., 1 tab.

  15. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma.

    PubMed

    Jenkins, Robert B; Blair, Hilary; Ballman, Karla V; Giannini, Caterina; Arusell, Robert M; Law, Mark; Flynn, Heather; Passe, Sandra; Felten, Sara; Brown, Paul D; Shaw, Edward G; Buckner, Jan C

    2006-10-15

    Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/19p12 fusion (P < 0.001, chi(2) test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients.

  16. Interstitial deletions are not the main mechanism leading to 18q deletions

    SciTech Connect

    Strathdee, G.; Harrison, W.; Goodart, S.A.; Overhauser, J. ); Riethman, H.C. )

    1994-06-01

    Most patients who present with the 18q- syndrome have an apparent terminal deletion of the long arm of chromosome 18. For precise phenotypic mapping of this syndrome, it is important to determine whether the deletions are terminal deletions or interstitial deletions. A human telomeric YAC clone has been identified that hybridizes specifically to the telomeric end of 18q. This clone was characterized and used to analyze seven patients with 18q deletions. By FISH and Southern blotting analysis, all patients were found to lack this chromosomal region on their deleted chromosome, demonstrating that the patients do not have cryptic interstitial deletions. 30 refs., 3 figs.

  17. Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge.

    PubMed

    Veerapandiyan, Aravindhan; Abdul-Rahman, Omar A; Adam, Margaret P; Lyons, Michael J; Manning, Melanie; Coleman, Karlene; Kobrynski, Lisa; Taneja, Deeksha; Schoch, Kelly; Zimmerman, Holly H; Shashi, Vandana

    2011-09-01

    Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals. PMID:21834039

  18. Juvenile polyposis of infancy associated with paracentric inversion and deletion of chromosome 10 in a Hispanic patient: a case report.

    PubMed

    Vargas-González, Roberto; de la Torre-Mondragón, Luis; Aparicio-Rodríguez, Juan Manuel; Paniagua-Morgan, Froylan; López-Hernández, Gerardo; Garrido-Hernández, Miguel Angel; Nuñez-Barrera, Sandra

    2010-01-01

    Juvenile polyposis of infancy is a rare genetic disorder, involving multiple hamartomatous polyps of the gastrointestinal tract, which usually has a very aggressive clinical course and is often fatal. It is characterized by early onset (during the 1st months of life) and by diffuse juvenile polyposis with anemia, recurrent gastrointestinal bleeding, diarrhea, rectal prolapse, intussusception, protein-losing enteropathy, starvation, and malnutrition. There is a hypothesis that mutation of the tumor-suppressor genes BMPR1A and PTEN, located on the long arm of chromosome 10, is associated with the development of this disease. Medical treatment for this disorder is challenging and should be conservative whenever possible. We present the case of a 3-year-old girl with juvenile polyposis of infancy who eventually died from mesenteric artery thrombosis during surgical colectomy. Karyotype of the patient showed a paracentric inversion in 10q and a deletion in 10p. We will briefly comment on some genetic considerations of this disease.

  19. Analysis of p16 gene mutation, deletion and methylation in patients with arseniasis produced by indoor unventilated-stove coal usage in Guizhou, China.

    PubMed

    Zhang, Ai-Hua; Bin, Hai-Hua; Pan, Xue-Li; Xi, Xu-Guang

    2007-06-01

    The aim of this study was to determine p16 gene mutation, deletion, and promoter 5' CpG island hypermethylation in peripheral blood mononuclear leukocyte of patients with arseniasis as attributed to exposure to indoor unventilated coal stove. The role of the aberrant change of p16 gene in the induction and development of carcinogenesis in endemic arsenisiasis region in China was also examined. Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP), multiplex PCR (mPCR), methylation-specific PCR (MSP), and sequencing techniques were performed to detect (1) mutation of the p16 gene exon 2, (2) homozygous deletion of the p16 gene exon 1 and exon 2, and (3) hypermethylation of the promoter CpG island in peripheral blood mononuclear leukocyte of patients with arseniasis. Results showed no mutation was found in exon 2 of p16 gene. The homozygous deletion frequency of p16 gene was 5 and 15% in control and arseniasis patients, respectively. The homozygous deletion occurred mainly in exon 2, with significant deletion frequencies of 9, 13, and 20% in mild, intermediate, and severe arseniasis groups. The significant homozygous deletion frequency was 9 and 39% in noncarcinoma and carcinoma individuals. The positive rate of p16 gene promoter CpG island hyermethylation was 42 and 2% in the exposed group and the control group, respectively. The positive rate was 26, 42, and 50% in mild, intermediate, and severe arseniasis. The marked different positive rate was 22 and 56% in noncarcinoma and carcinoma individuals, respectively. In conclusion, homozygous deletion and hypermethylation of p16 gene may play an important role in the initiation and development of manifestations seen in endemic arseniasis including carcinogenesis.

  20. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome

    PubMed Central

    Costain, G.; Chow, E. W. C.; Ray, P. N.; Bassett, A. S.

    2015-01-01

    Background Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help justify widespread use of new and expensive genetic technologies. Methods We conducted a survey of caregivers on the value of a genetic/aetiologic diagnosis of 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in ID. We also surveyed the opinion of a high-functioning subset of adults with 22q11.2DS themselves. We used standard quantitative and qualitative methods to analyse the responses. Results In total, 73 of 118 surveys were returned (61.9%). There was convergence of quantitative and qualitative results, and consistency between adult patient and caregiver responses. A definitive molecular diagnosis of 22q11.2DS was a critical event with diverse positive repercussions, even if occurring later in life. Frequently cited benefits included greater understanding and certainty, newfound sense of purpose and a platform for advocacy, and increased opportunities to optimise medical, social and educational needs. Conclusions This is the first study to characterise the impact of a diagnosis of this representative microdeletion syndrome on adult patients and their families. The results both validate and expand on the theoretical benefits proposed by clinicians and researchers. The use of genome-wide microarray technologies will provide an increasing number of molecular diagnoses. The importance of a diagnosis of 22q11.2DS demonstrated here therefore has implications for changing attitudes about molecular genetic diagnosis that could benefit individuals with ID of currently unknown cause and their families. PMID:22142442

  1. Velopharyngeal incompetence diagnosed in a series of cardiac patients prompted by the finding of a 22q11.2 deletion

    SciTech Connect

    Driscoll, D.A.; Emanuel, B.S.; Goldmuntz, E.

    1994-09-01

    Congenital heart disease is very common and may occur as an isolated malformation or as part of a well-defined syndrome. In some syndromes, specific types are overrepresented as compared to their incidence in the general population. Conotruncal anomalies are one such example where they are seen as part of DiGeorge syndrome (DGS) and Velo-Cardio-Facial syndrome (VCFS). Often, the diagnosis of VCFS is not suspected because mild facial dysmorphia is frequently not appreciated in the newborn period. While overt cleft palate, a characteristic finding in VCFS, would be detected early, a submucousal cleft palate or velopharyngeal incompetence (VPI) may go unrecognized in the pre-verbal child and may remain undiagnosed in the older patient who is not referred for a palatal evaluation. In patients with either DGS or VCFS, microdeletions of chromosome 22q11.2 have been demonstrated in almost 90% of patients. As part of our ongoing study, twenty patients with a conotruncal cardiac anomaly, without an overt cleft palate, were referred for 22q11.2 deletion analysis. 13/20 patients were found to have a deletion. All 13 deleted patients underwent palatal evaluations by a plastic surgeon and speech pathologist. 7 patients were noted to have VPI. Intervention including speech therapy and/or posterior pharyngeal flap surgery for these previously undiagnosed abnormalities is underway. These results suggest that palatal abnormalities are underdiagnosed in a significant proportion of patients with conotruncal cardiac defects. We therefore propose deletion studies in these patients followed by prompt palatal evaluations when the deletion is present. Early diagnosis of VPI and submucousal cleft palate should lead to early intervention and appropriate management of the speech difficulties encountered by these individuals.

  2. Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

    PubMed Central

    Calì, Francesco; Ragalmuto, Alda; Chiavetta, Valeria; Calabrese, Giuseppe; Fichera, Marco; Vinci, Mirella; Ruggeri, Giuseppa; Schinocca, Pietro; Sturnio, Maurizio; Romano, Salvatore; Elia, Maurizio

    2010-01-01

    Angelman syndrome (AS) is a severe neurobehavioural disorder caused by failure of expression of the maternal copy of the imprinted domain located on 15q11-q13. There are different mechanisms leading to AS: maternal microdeletion, uniparental disomy, defects in a putative imprinting centre, mutations of the E3 ubiquitin protein ligase (UBE3A) gene. However, some of suspected cases of AS are still scored negative to all the latter mutations. Recently, it has been shown that a proportion of negative cases bear large deletions overlapping one or more exons of the UBE3A gene. These deletions are difficult to detect by conventional gene-scanning methods due to the masking effect by the non-deleted allele. In this study, we have used for the first time multiplex ligation-dependent probe amplification (MLPA) and comparative multiplex dosage analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients. PMID:21072004

  3. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome.

    PubMed

    Giardino, Giuliana; Cirillo, Emilia; Maio, Filomena; Gallo, Vera; Esposito, Tiziana; Naddei, Roberta; Grasso, Fiorentino; Pignata, Claudio

    2014-03-01

    OBJECTIVE. Enteropathy is a very common feature in patients with primary immunodeficiencies. In patients with Del22 gastrointestinal (GI) alterations, including feeding disorders and congenital abnormalities have been often reported, mostly in the first year of life. MATERIAL AND METHODS. Aim of this monocentric study is to better define the GI involvement in a cohort of 26 patients affected with Del22 syndrome. Anamnestic information was retrospectively collected for each patient. Weight and height parameters at the time of the screening were recorded. Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured. RESULTS. A GI involvement was identified in the 58% of patients. The prominent problems were abdominal pain, vomiting, gastroesophageal reflux and chronic constipation. Weight deficiency, short stature and failure to thrive were reported in 54, 42, and 30% of the patients, respectively. The evidence of sideropenic anemia, in keeping with hypoproteinemia, impaired acid steatocrit or cellobiose/mannitol test suggested an abnormal intestinal permeability. In this cohort, a high prevalence of AGA IgA and IgG positivity was observed. Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology. In this patient, a long-lasting gluten-free diet failed to restore the intestinal architecture. CONCLUSIONS. In conclusion, GI involvement is a very common feature in Del22 patients. A better characterization of GI involvement would be very useful to improve the management of these patients.

  4. Prolidase Deficiency in a Mexican-American Patient Identified by Array CGH Reveals a Novel and the Largest PEPD Gene Deletion

    PubMed Central

    Hintze, Jonathan P.; Kirby, Amelia; Torti, Erin; Batanian, Jacqueline R.

    2016-01-01

    Prolidase deficiency (PD) is a rare genetic disorder caused by mutations in the peptidase D (PEPD) gene, affecting collagen degradation. Features include lower extremity ulcers, facial dysmorphism, frequent respiratory infections, and intellectual disability, though there is significant intra- and interfamilial variability. Twenty-eight mutations have been previously reported, all either small deletions/duplications or point mutations discovered by enzyme or DNA assays. PD has been reported in patients of various ethnic backgrounds, but never in the Mexican-American population. We describe the first Mexican-American patient with PD, who presented with typical facial features, developmental delay, microcephaly, and xerosis. Chromosome microarray analysis (CMA) revealed a homozygous deletion in the region of 19q13.11, estimated to be between 124.79 and 195.72 kb in size, representing the largest PEPD gene deletion reported to date and the first discovered by CMA. PMID:27385964

  5. Prolidase Deficiency in a Mexican-American Patient Identified by Array CGH Reveals a Novel and the Largest PEPD Gene Deletion.

    PubMed

    Hintze, Jonathan P; Kirby, Amelia; Torti, Erin; Batanian, Jacqueline R

    2016-05-01

    Prolidase deficiency (PD) is a rare genetic disorder caused by mutations in the peptidase D (PEPD) gene, affecting collagen degradation. Features include lower extremity ulcers, facial dysmorphism, frequent respiratory infections, and intellectual disability, though there is significant intra- and interfamilial variability. Twenty-eight mutations have been previously reported, all either small deletions/duplications or point mutations discovered by enzyme or DNA assays. PD has been reported in patients of various ethnic backgrounds, but never in the Mexican-American population. We describe the first Mexican-American patient with PD, who presented with typical facial features, developmental delay, microcephaly, and xerosis. Chromosome microarray analysis (CMA) revealed a homozygous deletion in the region of 19q13.11, estimated to be between 124.79 and 195.72 kb in size, representing the largest PEPD gene deletion reported to date and the first discovered by CMA. PMID:27385964

  6. A 1.3-Mb 7q11.23 Atypical Deletion Identified in a Cohort of Patients with Williams-Beuren Syndrome

    PubMed Central

    Delgado, L.M.; Gutierrez, M.; Augello, B.; Fusco, C.; Micale, L.; Merla, G.; Pastene, E.A.

    2013-01-01

    Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype-phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene. PMID:23653586

  7. Two high throughput technologies to detect segmental aneuploidies identify new Williams‐Beuren syndrome patients with atypical deletions

    PubMed Central

    Howald, C; Merla, G; Digilio, M C; Amenta, S; Lyle, R; Deutsch, S; Choudhury, U; Bottani, A; Antonarakis, S E; Fryssira, H; Dallapiccola, B; Reymond, A

    2006-01-01

    Objective To develop and compare two new technologies for diagnosing a contiguous gene syndrome, the Williams‐Beuren syndrome (WBS). Methods The first proposed method, named paralogous sequence quantification (PSQ), is based on the use of paralogous sequences located on different chromosomes and quantification of specific mismatches present at these loci using pyrosequencing technology. The second exploits quantitative real time polymerase chain reaction (QPCR) to assess the relative quantity of an analysed locus. Results A correct and unambiguous diagnosis was obtained for 100% of the analysed samples with either technique (n = 165 and n = 155, respectively). These methods allowed the identification of two patients with atypical deletions in a cohort of 182 WBS patients. Both patients presented with mild facial anomalies, mild mental retardation with impaired visuospatial cognition, supravalvar aortic stenosis, and normal growth indices. These observations are consistent with the involvement of GTF2IRD1 or GTF2I in some of the WBS facial features. Conclusions Both PSQ and QPCR are robust, easy to interpret, and simple to set up. They represent a competitive alternative for the diagnosis of segmental aneuploidies in clinical laboratories. They have advantages over fluorescence in situ hybridisation or microsatellites/SNP genotyping for detecting short segmental aneuploidies as the former is costly and labour intensive while the latter depends on the informativeness of the polymorphisms. PMID:15994861

  8. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

    PubMed

    Denora, Paola S; Schlesinger, David; Casali, Carlo; Kok, Fernando; Tessa, Alessandra; Boukhris, Amir; Azzedine, Hamid; Dotti, Maria Teresa; Bruno, Claudio; Truchetto, Jeremy; Biancheri, Roberta; Fedirko, Estelle; Di Rocco, Maja; Bueno, Clarissa; Malandrini, Alessandro; Battini, Roberta; Sickl, Elisabeth; de Leva, Maria Fulvia; Boespflug-Tanguy, Odile; Silvestri, Gabriella; Simonati, Alessandro; Said, Edith; Ferbert, Andreas; Criscuolo, Chiara; Heinimann, Karl; Modoni, Anna; Weber, Peter; Palmeri, Silvia; Plasilova, Martina; Pauri, Flavia; Cassandrini, Denise; Battisti, Carla; Pini, Antonella; Tosetti, Michela; Hauser, Erwin; Masciullo, Marcella; Di Fabio, Roberto; Piccolo, Francesca; Denis, Elodie; Cioni, Giovanni; Massa, Roberto; Della Giustina, Elvio; Calabrese, Olga; Melone, Marina A B; De Michele, Giuseppe; Federico, Antonio; Bertini, Enrico; Durr, Alexandra; Brockmann, Knut; van der Knaap, Marjo S; Zatz, Mayana; Filla, Alessandro; Brice, Alexis; Stevanin, Giovanni; Santorelli, Filippo M

    2009-03-01

    Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

  9. Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors.

    PubMed

    Roversi, Gaia; Picinelli, Chiara; Bestetti, Ilaria; Crippa, Milena; Perotti, Daniela; Ciceri, Sara; Saccheri, Fabiana; Collini, Paola; Poliani, Pietro L; Catania, Serena; Peissel, Bernard; Pagni, Fabio; Russo, Silvia; Peterlongo, Paolo; Manoukian, Siranoush; Finelli, Palma

    2015-01-01

    Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases. PMID:26482194

  10. Carbonic anhydrase II deficiency: Single-base deletion in exon 7 is the predominant mutation in Caribbean Hispanic patients

    SciTech Connect

    Hu, P.Y.; Ernst, A.R.; Sly, W.S. ); Venta, P.J. ); Skaggs, L.A.; Tashian, R.E. )

    1994-04-01

    To date, three different structural gene mutations have been identified in patients with carbonic anhydrase II deficiency (osteopetrosis with renal tubular acidosis and cerebral calcification). These include a missense mutation (H107Y) in two families, a splice junction mutation in intron 5 in one of these families, and a splice junction mutation in intron 2 for which many Arabic patients are homozygous. The authors report here a novel mutation for which carbonic anhydrase II-deficient patients from seven unrelated Hispanic families were found to be homozygous. The proband was a 2 1/2-year-old Hispanic girl of Puerto Rican ancestry who was unique clinically, in that she had no evidence of renal tubular acidosis, even though she did have osteopetrosis, developmental delay, and cerebral calcification. She proved to be homozygous for a single-base deletion in the coding region of exon 7 that produces a frameshift that changes the next 12 amino acids before leading to chain termination and that also introduces a new MaeIII restriction site. The 27-kD truncated enzyme produced when the mutant cDNA was expressed in COS cells was enzymatically inactive, present mainly in insoluble aggregates, and detectable immunologically at only 5% the level of the 29-kD normal carbonic anhydrase II expressed from the wild-type cDNA. Metabolic labeling revealed that this 27-kD mutant protein has an accelerated rate of degradation. Six subsequent Hispanic patients of Caribbean ancestry, all of whom had osteopetrosis and renal tubular acidosis but who varied widely in clinical severity, were found to be homozygous for the same mutation. These findings identify a novel mutation common to Hispanic patients from the Caribbean islands and provide a ready means for PCR-based diagnosis of the [open quotes]Hispanic mutation.[close quotes] The basis for their phenotypic variability is not yet clear. 15 refs., 5 figs., 1 tab.

  11. A novel interstitial deletion of 2q22.3 q23.3 in a patient with dysmorphic features, epilepsy, aganglionosis, pure red cell aplasia, and skeletal malformations.

    PubMed

    Bravo-Oro, Antonio; Lurie, Iosif W; Elizondo-Cárdenas, Gabriela; Peña-Zepeda, Claudia; Salazar-Martínez, Abel; Correa-González, Cecilia; Castrillo, José Luis; Avila, Silvia; Esmer, Carmen

    2015-08-01

    Many chromosomal deletions encompassing the 2q23.1 region have been described ranging from small deletions of 38 kb up to >19 Mb. Most phenotypic features of the 2q23.1 deletion syndrome are due to a MBD5 gene loss independent of the size of the deletion. Here, we describe a male patient harboring a novel interstitial deletion encompassing the 2q22.3 q23.3 chromosomal region. Array-CGH revealed a 7.1 Mb deletion causing haploinsufficiency of several genes including MBD5, ACVR2, KIF5C, and EPC2. This patient presents with additional findings to those already described in individuals who have deletions of MBD5 including toes absence of halluces, pure red cell aplasia, and intestinal aganglionosis. Interestingly, in the deleted region there are previously identified regulatory sequences which are located upstream to ZEB2, which is associated with Hirschsprung disease (HSCR). Several genes have been associated with pure red cell aplasia, but to our knowledge, this is the first time that 2q deletion is associated with this phenotype. These additional findings should be added to the list of manifestations associated with 2q deletion, and provide support for the hypothesis that this individual has a true contiguous gene deletion syndrome. PMID:25988649

  12. A novel interstitial deletion of 2q22.3 q23.3 in a patient with dysmorphic features, epilepsy, aganglionosis, pure red cell aplasia, and skeletal malformations.

    PubMed

    Bravo-Oro, Antonio; Lurie, Iosif W; Elizondo-Cárdenas, Gabriela; Peña-Zepeda, Claudia; Salazar-Martínez, Abel; Correa-González, Cecilia; Castrillo, José Luis; Avila, Silvia; Esmer, Carmen

    2015-08-01

    Many chromosomal deletions encompassing the 2q23.1 region have been described ranging from small deletions of 38 kb up to >19 Mb. Most phenotypic features of the 2q23.1 deletion syndrome are due to a MBD5 gene loss independent of the size of the deletion. Here, we describe a male patient harboring a novel interstitial deletion encompassing the 2q22.3 q23.3 chromosomal region. Array-CGH revealed a 7.1 Mb deletion causing haploinsufficiency of several genes including MBD5, ACVR2, KIF5C, and EPC2. This patient presents with additional findings to those already described in individuals who have deletions of MBD5 including toes absence of halluces, pure red cell aplasia, and intestinal aganglionosis. Interestingly, in the deleted region there are previously identified regulatory sequences which are located upstream to ZEB2, which is associated with Hirschsprung disease (HSCR). Several genes have been associated with pure red cell aplasia, but to our knowledge, this is the first time that 2q deletion is associated with this phenotype. These additional findings should be added to the list of manifestations associated with 2q deletion, and provide support for the hypothesis that this individual has a true contiguous gene deletion syndrome.

  13. Interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on survival in hemodialyzed patients.

    PubMed

    Kiss, István; Ambrus, Csaba; Kulcsár, Imre; Szegedi, János; Kerkovits, Lóránt; Tislér, András; Kiss, Zoltán

    2014-12-01

    The association between ACE (angiotensin-converting enzyme) gene insertion/deletion (I/D) polymorphism and mortality has been inconsistently observed in earlier studies in patients on maintenance hemodialysis. We hypothesized that the effect of ACE gene I/D polymorphism on mortality may be influenced by concurrent ACE inhibitor therapy in this population. In this prospective, multicenter cohort, observational study, data was collected from 716 prevalent chronic hemodialysis patients, blood samples were genotyped for I/D single nucleotide polymorphism. Patient mortality was assessed in tree genotype groups insertion/insertion, insertion/deletion and deletion/deletion (I/I, I/D, and D/D) using multivariate Cox proportional hazard models. The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. The mean age was 54.9±15.5 years, 53.2% of all patients were male and in the total group the prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before blood sampling was 23.8 months (IQR 11.2-47.1). Patients were followed for 10 years, the median follow-up time was 29.8 months (IQR 12.6-63.4). Patient characteristics were well balanced among the genotype groups. D/D genotype, was associated with inferior survival (I/I vs D/D: log-rank test: P=0.04) in patients not receiving ACE inhibitor therapy, and the presence of this therapy diminished this difference. There was no difference in survival among unselected patients with different genotypes. In multivariate Cox regression models, D/D genotype (compared to I/I) was a significant predictor of mortality only in patients without ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, P=0.03). Our data suggests that hemodialyzed patients with the deletion/deletion (D/D) genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup. PMID:25526485

  14. Two patients with intellectual disability, overlapping facial features, and overlapping deletions in 6p25.1p24.3.

    PubMed

    Kuipers, Bart C W; Vulto-van Silfhout, Anneke T; Marcelis, Carlo; Pfundt, Rolph; de Leeuw, Nicole; de Vries, Bert B A

    2013-01-01

    The clinical and molecular characterizations of two patients with a 1.4 Mb overlapping deletion in the 6p25.1p24.3 region are reported. In addition to the mild intellectual disability, they shared feeding problems in infancy and several dysmorphic facial features including a prominent forehead, almond-shaped eyes, a short philtrum, and low-set ears with square helices. The overlapping deleted region harbors six genes (RREB1, NRN1, CAGE1, LY86, SSR1, and F13A1), of which NRN1 and RREB1 are considered as candidate genes for the intellectual disability and the overlapping dysmorphism, respectively. PMID:23183317

  15. Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors

    PubMed Central

    Roversi, Gaia; Picinelli, Chiara; Bestetti, Ilaria; Crippa, Milena; Perotti, Daniela; Ciceri, Sara; Saccheri, Fabiana; Collini, Paola; Poliani, Pietro L.; Catania, Serena; Peissel, Bernard; Pagni, Fabio; Russo, Silvia; Peterlongo, Paolo; Manoukian, Siranoush; Finelli, Palma

    2015-01-01

    Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin’s lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient’s phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases. PMID:26482194

  16. Gene deletions in patients with haemophilia B and anti-factor IX antibodies.

    PubMed

    Giannelli, F; Choo, K H; Rees, D J; Boyd, Y; Rizza, C R; Brownlee, G G

    Christmas disease, or haemophilia B, is an inherited X-linked haemorrhagic disease which at present occurs in 798 known cases in the United Kingdom, corresponding to a frequency of about 1 in 30,000 males. Patients are deficient in the intrinsic clotting factor IX and are treated by replacement of this protein prepared from pooled plasma obtained from normal individuals. Occasionally treatment is complicated by the appearance of specific anti-factor IX antibodies. It seemed to us that this might be due to the absence of 'self' factor IX causing the immune system to regard the infused normal factor IX as foreign. The absence of all or part of the factor IX gene was an obvious possible reason for this, which we have now tested using our previously isolated gene probe. We have found four patients with gross gene defects.

  17. A Hunter Patient with a Severe Phenotype Reveals Two Large Deletions and Two Duplications Extending 1.2 Mb Distally to IDS Locus.

    PubMed

    Zanetti, Alessandra; Tomanin, Rosella; Rampazzo, Angelica; Rigon, Chiara; Gasparotto, Nicoletta; Cassina, Matteo; Clementi, Maurizio; Scarpa, Maurizio

    2014-01-01

    Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an X-linked lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS), an enzyme involved in the glycosaminoglycans (GAGs) degradation. We here report the case of a 9-year-old boy who was diagnosed with an extremely severe form of MPS II at 10 months of age. Sequencing of the IDS gene revealed the deletion of exons 1-7, extending distally and removing the entire pseudogene IDSP1. The difficulty to define the boundaries of the deletion and the particular severity of the patient phenotype suggested to verify the presence of pathological copy number variations (CNVs) in the genome, by the array CGH (aCGH) technology. The examination revealed the presence of two deletions alternate with two duplications, overall affecting a region of about 1.2 Mb distally to IDS gene. This is the first complex rearrangement involving IDS and extending to a large region located distally to it described in a severe Hunter patient, as evidenced by the CNVs databases interrogated. The analysis of the genes involved in the rearrangement and of the disorders correlated with them did not help to clarify the phenotype observed in our patient, except for the deletion of the IDS gene, which explains per se the Hunter phenotype. However, this cannot exclude a potential "contiguous gene syndrome" as well as the future rising of additional pathological symptoms associated with the other extra genes involved in the identified rearrangement.

  18. Deletion mutations of the Bs-alpha gene in patients with Albright hereditary osteodystrophy: Possible mutation hot-spot in exon 7

    SciTech Connect

    Weinstein, L.S.; Hainline, B.E.; Schuster, V.

    1994-09-01

    Albright hereditary osteodystrophy (AHO) is an autosomal dominant disease characterized by short stature, centripetal obesity, subcutaneous ossifications and focal brachydactyly. Patients with this disorder may have these features alone (pseudopseudohypoparathyroidism) or these features in association with resistance to multiple hormones which raise intracellular cAMP (pseudohypoparathyroidism, PHP). In most kindreds, affected members have decreased function of the G protein Gs and decreased levels of the Gs{alpha}-subunit. Heterozygous inactivating mutations of the Gs{alpha} gene have been previously identified in AHO. Exons 2-13 of the Gs{alpha} gene and their splice junctions were PCR-amplified and the products analyzed by temperature gradient gel electrophoresis (TGGE) and direct sequencing. Using this approach, a new heterozygous 2 bp deletion in exon 4 creating a premature stop codon was identified in 5 affected members of a previously reported family. The mutation was not present in an unaffected family member. We also have identified a previously reported 4 bp deletion in the coding region of exon 7 in 2 further unrelated sporadic cases of PHP. In one case, the mutation was absent in her siblings and in both parents, confirming that this is a de novo mutation in this patient. This specific 4 bp deletion has now been reported in 4 PHP patients, at least 3 of whom are unrelated. These results suggest that this region of the Gs{alpha} gene may be a hot-spot for deletions.

  19. Co-Deletion of Chromosome 1p/19q and IDH1/2 Mutation in Glioma Subsets of Brain Tumors in Chinese Patients

    PubMed Central

    Ren, Xiaohui; Cui, Xiangli; Lin, Song; Wang, Junmei; Jiang, Zhongli; Sui, Dali; Li, Jing; Wang, Zhongcheng

    2012-01-01

    Objective To characterize co-deletion of chromosome 1p/19q and IDH1/2 mutation in Chinese brain tumor patients and to assess their associations with clinical features. Methods In a series of 528 patients with gliomas, pathological and radiological materials were reviewed. Pathological constituents of tumor subsets, incidences of 1p/19q co-deletion and IDH1/2 mutation in gliomas by regions and sides in the brain were analyzed. Results Overall, 1p and 19q was detected in 339 patients by FISH method while the sequence of IDH1/2 was determined in 280 patients. Gliomas of frontal, temporal and insular origin had significantly different pathological constituents of tumor subsets (P<0.001). Gliomas of frontal origin had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively) (P<0.001), while gliomas of temporal origin had significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively) (P = 0.013 and P = 0.003, respectively). Subgroup analysis confirmed these findings in oligoastrocytic and oligodendroglial tumors, respectively. Although the difference of 1p/19q co-deletion was not statistically significant in temporal oligodendroglial tumors, the trend was marginally significant (P = 0.082). However, gliomas from different sides of the brain did not show significant different pathological constituents, incidences of 1p/19q co-deletion or IDH1/2 mutation. Conclusion Preferential distribution of pathological subsets, 1p/19q co-deletion and IDH1/2 mutation were confirmed in some brain regions in Chinese glioma patients, implying their distinctive tumor genesis and predictive value for prognosis. PMID:22427879

  20. A 63bp deletion in the promoter of rage correlates with a decreased risk for nephropathy in patients with type 2 diabetes.

    PubMed

    Rudofsky, G; Isermann, B; Schilling, T; Schiekofer, S; Andrassy, M; Schneider, J G; Morcos, M; Humpert, P M; Sayed, A A R; Witte, S; Renn, W; Pfohl, M; Hamann, A; Nosikov, V; Schleicher, E; Häring, H-U; Rudofsky, G; Ritz, E; Nawroth, P P; Bierhaus, A

    2004-03-01

    Several polymorphisms have been identified in the RAGE-promoter region that might modulate the outcome of disease. Here we analyse the association of a 63bp deletion (delta63) spanning from bp - 407 to bp - 345 with diabetic nephropathy. The deletion was determined using the polymerase chain reaction (PCR) in a cross-sectional study with 1087 patients with type 1 diabetes (n = 559) and type 2 diabetes (n = 528). 475 patients with osteoporosis served as disease independent control. The prevalence of the heterozygous genotype did not significantly differ between the three groups (type 1: 2.15 %, type 2: 2.27 %, controls: 1.47 %), indicating that heterozygous delta63 is not related to the manifestation of diabetes. Homozygous carriers were not identified in this study. The heterozygous delta63 genotype, was associated with a reduced prevalence of diabetic nephropathy in patients with type 2 diabetes (OR = 0.06; 95 % CI: [0.05, 0.07]), but not in patients with type 1 (OR = 1.49; 95 % CI: [1.14, 1.94]). We conclude, that patients with type 2 diabetes and the 63bp deletion in the promoter of RAGE seem to be protected from diabetic nephropathy. The observed difference between type 1 and type 2 diabetes might point to diverse pathomechanisms of nephropathy in both types of diabetes.

  1. Intronic breakpoint definition and transcription analysis in DMD/BMD patients with deletion/duplication at the 5' mutation hot spot of the dystrophin gene.

    PubMed

    Gualandi, F; Rimessi, P; Trabanelli, C; Spitali, P; Neri, M; Patarnello, T; Angelini, C; Yau, S C; Abbs, S; Muntoni, F; Calzolari, E; Ferlini, A

    2006-03-29

    Dystrophin mutations occurring at the 5' end of the gene frequently behave as exceptions to the "frame rule," their clinical severity being variable and often not related to the perturbation of the translation reading frame. The molecular mechanisms underlying the phenotypic variability of 5' dystrophin mutations have not been fully clarified. We have characterized the genomic breakpoints within introns 2, 6 and 7 and identified the splicing profiles in a cohort of DMD/BMD patients with deletion of dystrophin exons 3-7, 3-6 and duplication of exons 2-4. Our findings indicate that the occurrence of intronic cryptic promoter as well as corrective splicing events are unlikely to play a role in exons 3-7 deleted patients phenotypic variability. Our data suggest that re-initiation of translation could represent a major mechanism responsible for the production of a residual dystrophin in some patients with exons 3-7 deletion. Furthermore, we observed that the out-of-frame exon 2a is almost constantly spliced into a proportion of the dystrophin transcripts in the analysed patients. In the exons 2-4 duplicated DMD patient, producing both in-frame and out-of-frame transcripts, this splicing behaviour might represent a critical factor contributing to the severe phenotype. In conclusion, we suggest that multiple mechanisms may have a role in modulating the outcome of 5' dystrophin mutations, including recoding mechanisms and unusual splicing choices.

  2. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

    SciTech Connect

    Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

    2011-07-29

    Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

  3. Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1----q22.3 in a patient with tyrosinemia type II.

    PubMed

    Natt, E; Westphal, E M; Toth-Fejel, S E; Magenis, R E; Buist, N R; Rettenmeier, R; Scherer, G

    1987-12-01

    Tyrosinemia II is an autosomal-recessively inherited condition caused by deficiency in the liver-specific enzyme tyrosine aminotransferase (TAT; EC 2.6.1.5). We have restudied a patient with typical symptoms of tyrosinemia II who in addition suffers from multiple congenital anomalies including severe mental retardation. Southern blot analysis using a human TAT cDNA probe revealed a complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to be maternally inherited, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele results from a small de novo interstitial deletion, del 16 (pter----q22.1::q22.3----qter), in the paternally inherited chromosome 16. Three additional loci previously assigned to 16q22 were studied in our patient: haptoglobin (HP), lecithin: cholesterol acyltransferase (LCAT), and the metallothionein gene cluster MT1,MT2. Of these three markers, only the HP locus was found to be codeleted with the TAT locus on the del(16) chromosome.

  4. Paracentric inversion of chromosome 2 associated with cryptic duplication of 2q14 and deletion of 2q37 in a patient with autism.

    PubMed

    Devillard, Françoise; Guinchat, Vincent; Moreno-De-Luca, Daniel; Tabet, Anne-Claude; Gruchy, Nicolas; Guillem, Pascale; Nguyen Morel, Marie-Ange; Leporrier, Nathalie; Leboyer, Marion; Jouk, Pierre-Simon; Lespinasse, James; Betancur, Catalina

    2010-09-01

    We describe a patient with autism and a paracentric inversion of chromosome 2q14.2q37.3, with a concurrent duplication of the proximal breakpoint at 2q14.1q14.2 and a deletion of the distal breakpoint at 2q37.3. The abnormality was derived from his mother with a balanced paracentric inversion. The inversion in the child appeared to be cytogenetically balanced but subtelomere FISH revealed a cryptic deletion at the 2q37.3 breakpoint. High-resolution single nucleotide polymorphism array confirmed the presence of a 3.5 Mb deletion that extended to the telomere, and showed a 4.2 Mb duplication at 2q14.1q14.2. FISH studies using a 2q14.2 probe showed that the duplicated segment was located at the telomeric end of chromosome 2q. This recombinant probably resulted from breakage of a dicentric chromosome. The child had autism, mental retardation, speech and language delay, hyperactivity, growth retardation with growth hormone deficiency, insulin-dependent diabetes, and mild facial dysmorphism. Most of these features have been previously described in individuals with simple terminal deletion of 2q37. Pure duplications of the proximal chromosome 2q are rare and no specific syndrome has been defined yet, so the contribution of the 2q14.1q14.2 duplication to the phenotype of the patient is unknown. These findings underscore the need to explore apparently balanced chromosomal rearrangements inherited from a phenotypically normal parent in subjects with autism and/or developmental delay. In addition, they provide further evidence indicating that chromosome 2q terminal deletions are among the most frequently reported cytogenetic abnormalities in individuals with autism.

  5. A Williams syndrome patient with a familial t(6;7) translocation and deletion of the elastin gene

    SciTech Connect

    Pober, B.R.; Gibson, L.H.; Yang-Feng, T.L.

    1994-09-01

    Discovery of a {open_quotes}balanced{close_quotes} reciprocal translocation [46,XX,t(6;7)(q11.2;q11.23)] on routine amniocentesis prompted clinical and cytogenetic study of additional family members. The same t(6;7) translocation was found in the clincally normal father and in a sibling with Williams syndrome (WS). WS had been diagnosed previously according to clinical criteria including distinctive facial features, supravalvar aortic stenosis requiring surgical repair, dental abnormalties and developmental delay. A clinically normal female was delivered and the translocation was confirmed with a cord blood specimen. Hemizygosity for the gene, elastin, (which has been mapped to the chromosome 7 translocation breakpoint, 7q11.23, in this family) appears to be a cause of WS. We therefore investigated whether the t(6;7) in the phenotypically normal father represented more than a simple reciprocal translocation. FISH using a chromosome 7 specific library revealed no differences between the cytogenetically identical, yet phenotypically distinct, father and son. Hybridization with a cosmid MR127D4 containing elastin sequence showed that the WS patient was missing one allele from the derivative chromosome 7 whereas both his mother and father had two copies of the elastin gene. This family indicates that the de novo loss of one copy of the elastin gene produces the recognizable phenotype of Williams syndrome. Molecular characterization (with additional probes) of the extent of this de novo deletion near the translocation breakpoint is in progress. This information will be valuable for defining the WS-critical region and will lead to a better understanding of the molecular basis for WS.

  6. Biallelic losses of 13q do not confer a poorer outcome in chronic lymphocytic leukaemia: analysis of 627 patients with isolated 13q deletion.

    PubMed

    Puiggros, Anna; Delgado, Julio; Rodriguez-Vicente, Ana; Collado, Rosa; Aventín, Anna; Luño, Elisa; Grau, Javier; Hernandez, José Ángel; Marugán, Isabel; Ardanaz, Maite; González, Teresa; Valiente, Alberto; Osma, Mar; Calasanz, Maria José; Sanzo, Carmen; Carrió, Ana; Ortega, Margarita; Santacruz, Rodrigo; Abrisqueta, Pau; Abella, Eugènia; Bosch, Francesc; Carbonell, Félix; Solé, Francesc; Hernández, Jesús Maria; Espinet, Blanca

    2013-10-01

    Losses in 13q as a sole abnormality confer a good prognosis in chronic lymphocytic leukaemia (CLL). Nevertheless, its heterogeneity has been demonstrated and the clinical significance of biallelic 13q deletions remains controversial. We compared the clinico-biological characteristics of a series of 627 patients harbouring isolated 13q deletions by fluorescence in situ hybridization (FISH), either monoallelic (13q × 1), biallelic (13q × 2), or the coexistence of both clones (13qM). The most frequent 13q deletion was 13q × 1 (82·1%), while 13q × 2 and 13qM represented 8·6% and 9·3% of patients respectively. The median percentage of altered nuclei significantly differed across groups: 55%, 72·5% and 80% in 13q × 1, 13q × 2 and 13qM (P < 0·001). However, no significant differences in the clinical outcome among 13q groups were found. From 84 patients with sequential FISH studies, eight patients lost the remaining allele of 13q whereas none of them changed from 13q × 2 to the 13q × 1 group. The percentage of abnormal cells detected by FISH had a significant impact on the five-year cumulative incidence of treatment and the overall survival, 90% being the highest predictive power cut-off. In conclusion, loss of the remaining 13q allele is not enough to entail a worse prognosis in CLL. The presence of isolated 13q deletion can be risk-stratified according to the percentage of altered cells.

  7. Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

    PubMed Central

    Klaassens, Merel; Morrogh, Deborah; Rosser, Elisabeth M; Jaffer, Fatima; Vreeburg, Maaike; Bok, Levinus A; Segboer, Tim; van Belzen, Martine; Quinlivan, Ros M; Kumar, Ajith; Hurst, Jane A; Scott, Richard H

    2015-01-01

    De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall–Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear. PMID:25118028

  8. From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks.

    PubMed

    Negri, Gloria; Magini, Pamela; Milani, Donatella; Colapietro, Patrizia; Rusconi, Daniela; Scarano, Emanuela; Bonati, Maria Teresa; Priolo, Manuela; Crippa, Milena; Mazzanti, Laura; Wischmeijer, Anita; Tamburrino, Federica; Pippucci, Tommaso; Finelli, Palma; Larizza, Lidia; Gervasini, Cristina

    2016-02-01

    Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ∼55% and ∼8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP-negative RSTS patients from our cohort led us to identify six novel mutations: a 376-kb deletion depleting EP300 gene; an exons 17-19 deletion (c.(3141+1_3142-1)_(3590+1_3591-1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878-12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300-mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300-mutated patients, this study provides further insights into the EP300-specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300-mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype-phenotype correlation.

  9. Biallelic losses of 13q do not confer a poorer outcome in chronic lymphocytic leukaemia: analysis of 627 patients with isolated 13q deletion.

    PubMed

    Puiggros, Anna; Delgado, Julio; Rodriguez-Vicente, Ana; Collado, Rosa; Aventín, Anna; Luño, Elisa; Grau, Javier; Hernandez, José Ángel; Marugán, Isabel; Ardanaz, Maite; González, Teresa; Valiente, Alberto; Osma, Mar; Calasanz, Maria José; Sanzo, Carmen; Carrió, Ana; Ortega, Margarita; Santacruz, Rodrigo; Abrisqueta, Pau; Abella, Eugènia; Bosch, Francesc; Carbonell, Félix; Solé, Francesc; Hernández, Jesús Maria; Espinet, Blanca

    2013-10-01

    Losses in 13q as a sole abnormality confer a good prognosis in chronic lymphocytic leukaemia (CLL). Nevertheless, its heterogeneity has been demonstrated and the clinical significance of biallelic 13q deletions remains controversial. We compared the clinico-biological characteristics of a series of 627 patients harbouring isolated 13q deletions by fluorescence in situ hybridization (FISH), either monoallelic (13q × 1), biallelic (13q × 2), or the coexistence of both clones (13qM). The most frequent 13q deletion was 13q × 1 (82·1%), while 13q × 2 and 13qM represented 8·6% and 9·3% of patients respectively. The median percentage of altered nuclei significantly differed across groups: 55%, 72·5% and 80% in 13q × 1, 13q × 2 and 13qM (P < 0·001). However, no significant differences in the clinical outcome among 13q groups were found. From 84 patients with sequential FISH studies, eight patients lost the remaining allele of 13q whereas none of them changed from 13q × 2 to the 13q × 1 group. The percentage of abnormal cells detected by FISH had a significant impact on the five-year cumulative incidence of treatment and the overall survival, 90% being the highest predictive power cut-off. In conclusion, loss of the remaining 13q allele is not enough to entail a worse prognosis in CLL. The presence of isolated 13q deletion can be risk-stratified according to the percentage of altered cells. PMID:23869550

  10. Review of Disrupted Sleep Patterns in Smith-Magenis Syndrome and Normal Melatonin Secretion in a Patient with an Atypical Interstitial 17p11.2 Deletion

    PubMed Central

    Boudreau, Eilis A.; Johnson, Kyle P.; Jackman, Angela R.; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, MaryPat; Chandrasekharappa, Settara C.; Lewy, Alfred J.; Smith, Ann C. M.; Magenis, R. Ellen

    2009-01-01

    Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body’s signal for nighttime darkness. Published reports of 24-hour melatonin secretion patterns in two independent SMS cohorts (US & France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion (∼6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.1p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern. PMID:19530184

  11. Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

    PubMed Central

    Dubourg, C.; Bonnet-Brilhault, F.; Toutain, A.; Mignot, C.; Jacquette, A.; Dieux, A.; Gérard, M.; Beaumont-Epinette, M.-P.; Julia, S.; Isidor, B.; Rossi, M.; Odent, S.; Bendavid, C.; Barthélémy, C.; Verloes, A.; David, V.

    2014-01-01

    Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions. PMID:24715852

  12. Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

    PubMed

    Ramocki, Melissa B; Bartnik, Magdalena; Szafranski, Przemyslaw; Kołodziejska, Katarzyna E; Xia, Zhilian; Bravo, Jaclyn; Miller, G Steve; Rodriguez, Diana L; Williams, Charles A; Bader, Patricia I; Szczepanik, Elżbieta; Mazurczak, Tomasz; Antczak-Marach, Dorota; Coldwell, James G; Akman, Cigdem I; McAlmon, Karen; Cohen, Melinda P; McGrath, James; Roeder, Elizabeth; Mueller, Jennifer; Kang, Sung-Hae L; Bacino, Carlos A; Patel, Ankita; Bocian, Ewa; Shaw, Chad A; Cheung, Sau Wai; Mazurczak, Tadeusz; Stankiewicz, Paweł

    2010-12-10

    We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

  13. Recurrent Distal 7q11.23 Deletion Including HIP1 and YWHAG Identified in Patients with Intellectual Disabilities, Epilepsy, and Neurobehavioral Problems

    PubMed Central

    Ramocki, Melissa B.; Bartnik, Magdalena; Szafranski, Przemyslaw; Kołodziejska, Katarzyna E.; Xia, Zhilian; Bravo, Jaclyn; Miller, G. Steve; Rodriguez, Diana L.; Williams, Charles A.; Bader, Patricia I.; Szczepanik, Elżbieta; Mazurczak, Tomasz; Antczak-Marach, Dorota; Coldwell, James G.; Akman, Cigdem I.; McAlmon, Karen; Cohen, Melinda P.; McGrath, James; Roeder, Elizabeth; Mueller, Jennifer; Kang, Sung-Hae L.; Bacino, Carlos A.; Patel, Ankita; Bocian, Ewa; Shaw, Chad A.; Cheung, Sau Wai; Mazurczak, Tadeusz; Stankiewicz, Paweł

    2010-01-01

    We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180–500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1−/−) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function. PMID:21109226

  14. Deletion (2)(q37)

    SciTech Connect

    Stratton, R.F.; Tolworthy, J.A.; Young, R.S.

    1994-06-01

    We report on a 5-month-old girl with widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Initial clinical assessment suggested the diagnosis of Ullrich-Turner syndrome. Chromosome analysis showed a 46,XX,del(2)(q37) karyotype in peripheral lymphocytes. We compare her findings to those of other reported patients with terminal deletions of 2q. 8 refs., 2 figs., 1 tab.

  15. Molecular Analysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17p11.2 Deletion

    PubMed Central

    Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K.; Cox, Gerald F.; Deshpande, Charu; Introne, Wendy J.; Gahl, William A.; Smith, Ann C. M.; Huizing, Marjan

    2011-01-01

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS. PMID:21857958

  16. Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion.

    PubMed

    Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K; Cox, Gerald F; Deshpande, Charu; Introne, Wendy J; Gahl, William A; Smith, Ann C M; Huizing, Marjan

    2011-01-01

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.

  17. Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation.

    PubMed

    Probst, Frank J; Roeder, Elizabeth R; Enciso, Victoria B; Ou, Zhishuo; Cooper, M Lance; Eng, Patricia; Li, Jiangzhen; Gu, Yanghong; Stratton, Robert F; Chinault, A Craig; Shaw, Chad A; Sutton, V Reid; Cheung, Sau Wai; Nelson, David L

    2007-06-15

    Chromosomal microarray analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test for the detection of well-characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7-9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6-year-old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X-inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X-inactivation and iduronate 2-sulfatase (IDS) enzyme activity were therefore examined. X-inactivation was found to be random in the child's peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.

  18. A homozygous contiguous gene deletion in chromosome 16p13.3 leads to autosomal recessive osteopetrosis in a Jordanian patient.

    PubMed

    Pangrazio, Alessandra; Frattini, Annalisa; Valli, Roberto; Maserati, Emanuela; Susani, Lucia; Vezzoni, Paolo; Villa, Anna; Al-Herz, Waleed; Sobacchi, Cristina

    2012-10-01

    Human malignant autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. Mutations in the CLCN7 gene are responsible not only for a substantial portion of ARO patients but also for other forms of osteopetrosis characterized by different severity and inheritance. The lack of a clear genotype/phenotype correlation makes genetic counseling a tricky issue for CLCN7-dependent osteopetrosis. Here, we characterize the first homozygous interstitial deletion in 16p13.3, detected by array comparative genomic hybridization in an ARO patient of Jordanian origin. The deletion involved other genes besides CLCN7, while the proband displayed a classic ARO phenotype; however, her early death did not allow more extensive clinical investigations. The identification of this novel genomic deletion involving a large part of the CLCN7 gene is of clinical relevance, especially in prenatal diagnosis, and suggests the possibility that this kind of mutation has been underestimated so far. These data highlight the need for alternative approaches to genetic analysis also in other ARO-causative genes.

  19. Caregiver and Adult Patient Perspectives on the Importance of a Diagnosis of 22q11.2 Deletion Syndrome

    ERIC Educational Resources Information Center

    Costain, G.; Chow, E. W. C.; Ray, P. N.; Bassett, A. S.

    2012-01-01

    Background: Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help…

  20. AB086. Chromosomal microarray analysis—detection of both duplication and deletion in patients with multiple congenital anomalies and/or developmental delay

    PubMed Central

    Ee, Hui Jing; Yon, Hui Yi; Tan, Mui Li; Roch, Robin; Brett, Maggie; Yong, Min Hwee; Law, Hai Yang; Lai, Angeline

    2015-01-01

    Background and objective Chromosomal microarray analysis (CMA) is recommended as first-tier genetic testing for patients with multiple congenital anomalies, developmental delay/intellectual disability and/or autism spectrum disorder. It detects chromosomal imbalance at a higher resolution than conventional chromosomal analysis. CMA diagnostic service was launched in our hospital in February 2014. The aim of this report is to review the incidence of detecting both duplication and deletion in patients referred for this test. Methods DNA was extracted using Gentra Puregene Blood Kit. CMA was performed using the Agilent 4×180 K CGH + SNP array and analysed with Agilent CytoGenomics. G-banding analysis was carried out on stimulated lymphocytes culture. Targeted fluorescence in-situ hybridization (FISH) was performed using locus specific probes. Results From 1 February 2014 to 31 May 2015, a total of 205 patients were tested. Seven (3.4%) were identified to have both duplication and deletion of chromosomal segments that were pathogenic [5] or of uncertain clinical significance [2]. We present a case of a 1-day-old Chinese girl with oligohydramnios, prematurity (35+5 weeks) and multiple congenital anomalies including heart defect, cleft palate, ear anomalies, microcephaly, vaginal skin tag, bilateral clinodactyly and wide anterior fontanelle. Karyotyping and FISH analysis for 22q11 deletion were normal. CMA revealed a pathogenic gain of 2.143 Mb at 16p13.3 and a pathogenic loss of 0.271 Mb at 16q24.2q24.3. The gain at 16p13.3 affects 67 genes including CREBBP. The 16p13.3 duplication syndrome is a contiguous gene syndrome characterized by normal to moderate intellectual disability, normal growth, mild arthrogryposis, frequently small and proximally implanted thumbs, characteristic facial features and occasionally, developmental defects of the heart, genitalia, palate or eyes. The 0.271 Mb deletion at 16q24.3 affects four genes including ANKRD11 and CDH15. The clinical

  1. Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis.

    PubMed

    Van Esch, Hilde; Hollanders, Karen; Badisco, Liesbeth; Melotte, Cindy; Van Hummelen, Paul; Vermeesch, Joris Robert; Devriendt, Koen; Fryns, Jean-Pierre; Marynen, Peter; Froyen, Guy

    2005-07-01

    X-linked ichthyosis (XLI) is often associated with a recurrent microdeletion at Xp22.31 due to non-allelic homologous recombination between the CRI-S232 low-copy repeat regions flanking the STS gene. The clinical features of these patients may include mental retardation (MR) and the VCX-A gene has been proposed as the candidate MR gene. Analysis of DNA from four XLI patients with MR by array-comparative genomic hybridization (array-CGH) on a 150 kb resolution X chromosome-specific array revealed a 1.5 Mb interstitial microdeletion with breakpoints in the CRI-S232 repeat sequences, each of which harbors a VCX gene. We demonstrate that the recombination sites in all four cases are situated in the 1 kb repeat unit 2 region present at the 3' ends of the VCX-A and VCX-B genes thereby deleting VCX-A and VCX-B1 but not VCX-B and VCX-C. Array-CGH with DNA of an XLI patient with MR and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all four VCX genes and duplication of both VCY homologs. These data confirm the role of VCX-A in the occurrence of MR in XLI patients. Moreover, we propose a VCX/Y teamwork-dependent mechanism for the incidence of mental impairment in XLI patients.

  2. A patient with interstitial deletion of the short arm of chromosome 3 (pter{yields}p21.2::p12{yields}qter) and a CHARGE-like phenotype

    SciTech Connect

    Wieczorek, D.; Gillessen-Kaesbach, G.

    1997-04-14

    We report on a 4-month-old boy with a de novo interstitial deletion of the short arm of chromosome 3 (pter {r_arrow} p21.2::p12 {r_arrow} qter) and clinical findings typical of proximal 3p deletion together with coloboma of iris, heart defect, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies. Family history was unremarkable and parental chromosomes were normal. The clinical manifestations of the patient are compared with those of 10 patients previously described with a proximal 3p deletion. The additional CHARGE- like phenotype is discussed. 20 refs., 4 figs., 1 tab.

  3. DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia.

    PubMed

    Tan, Jin Ai Mary Anne; Kho, Siew Leng; Ngim, Chin Fang; Chua, Kek Heng; Goh, Ai Sim; Yeoh, Seoh Leng; George, Elizabeth

    2016-01-01

    Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (α(codon 59)α/α(CS)α) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (α(codon 59)α/α(Paksé)α) after nine years of being misdiagnosis with Hb Adana and HbCS (α(codon 59)α/α(CS)α). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations. PMID:27271331

  4. DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia

    PubMed Central

    Tan, Jin Ai Mary Anne; Kho, Siew Leng; Ngim, Chin Fang; Chua, Kek Heng; Goh, Ai Sim; Yeoh, Seoh Leng; George, Elizabeth

    2016-01-01

    Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α3.7), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (αcodon 59α/αCSα) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (αcodon 59α/αPakséα) after nine years of being misdiagnosis with Hb Adana and HbCS (αcodon 59α/αCSα). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations. PMID:27271331

  5. FISH analysis of a patient with a constitutional 1p36 deletion defines a region for a neuroblastoma tumor suppressor gene

    SciTech Connect

    Biegel, J.; Hilliard, C.; White, P.

    1994-09-01

    Molecular and cytogenetic studies of neuroblastoma have implicated the presence of one or more tumor suppressor genes on chromosome 1p. We previously reported a neuroblastoma patient with a constitutional interstitial deletion of 1p36. As one means of further defining the deleted region, we have analyzed a series of chromosome 1p36 specific probes by FISH to metaphase chromosomes from a lymphoblastoid cell line established from the patient. We have also tested these probes on a neuroblastoma cell line, NGP, which has a t(1;15) translocation involving 1p36. The probes analyzed to date in order from centromere to telomere include ID-3 (heir-1), D1S56, D1S160, and CDC2L1 (p58). Cosmids for ID-3 and D1S56 were present in 2 copies and proximal to the breakpoint in the constitutional case, and retained on the derivative 1 in NGP. CDC2L1 was also present in 2 copies in the constitutional case, but is distal to the deletion. In NGP, CDC2L1 was translocated to the derivative 15. The D1S160 locus was deleted from one of the chromosomes 1 in the constitutional case, and was present in three copies in NGP: on the normal chromosome 1, the derivative chromosome 1, and the derivative chromosome 15. Molecular studies have suggested that there is a duplication involving this region in NGP, and so it is not clear where the translocation breakpoint is in this cell line. These studies have localized a critical region for a neuroblastoma tumor suppressor gene to 1p36.2, distal to D1S56, proximal to CDC2L1, and including D1S160. This region overlaps with the smallest area of deletion defined by loss of heterozygosity studies of primary neuroblastomas and neuroblastoma cell lines. Additional studies with probes that flank the D1S160 locus will facilitate a molecular cloning approach for a neuroblastoma tumor suppressor gene.

  6. Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome

    PubMed Central

    Robinson, J. Elliott; Wolfe, Stephanie M.; Kaiser-Rogers, Kathleen; Greenwood, Robert S.

    2016-01-01

    Hemiconvulsion–hemiplegia–epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient’s complex genetic background. PMID:27199890

  7. Cytogenetic follow-up by karyotyping and fluorescence in situ hybridization: implications for monitoring patients with myelodysplastic syndrome and deletion 5q treated with lenalidomide

    PubMed Central

    Göhring, Gudrun; Giagounidis, Aristoteles; Büsche, Guntram; Hofmann, Winfried; Kreipe, Hans Heinrich; Fenaux, Pierre; Hellström-Lindberg, Eva; Schlegelberger, Brigitte

    2011-01-01

    In patients with low and intermediate risk myelodysplastic syndrome and deletion 5q (del(5q)) treated with lenalidomide, monitoring of cytogenetic response is mandatory, since patients without cytogenetic response have a significantly increased risk of progression. Therefore, we have reviewed cytogenetic data of 302 patients. Patients were analyzed by karyotyping and fluorescence in situ hybridization. In 85 patients, del(5q) was only detected by karyotyping. In 8 patients undergoing karyotypic evolution, the del(5q) and additional chromosomal aberrations were only detected by karyotyping. In 3 patients, del(5q) was only detected by fluorescence in situ hybridization, but not by karyotyping due to a low number of metaphases. Karyotyping was significantly more sensitive than fluorescence in situ hybridization in detecting the del(5q) clone. In conclusion, to optimize therapy control of myelodysplastic syndrome patients with del(5q) treated with lenalidomide and to identify cytogenetic non-response or progression as early as possible, fluorescence in situ hybridization alone is inadequate for evaluation. Karyotyping must be performed to optimally evaluate response. (clinicaltrials.gov identifier: NCT01099267 and NCT00179621) PMID:21109690

  8. Allogeneic stem cell transplantation in chronic lymphocytic leukemia patients with 17p deletion: consult-transplant v consult-no-transplant analysis

    PubMed Central

    Poon, Michelle L.; Fox, Patricia S.; Samuels, Barry I.; O’Brien, Susan; Jabbour, Elias; Hsu, Yvonne; Gulbis, Alison; Korbling, Martin; Champlin, Richard; Abruzzo, Lynne V.; Bassett, Roland L.; Khouri, Issa F.

    2015-01-01

    Allogeneic stem cell transplantation (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred 17p- CLL patients for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL, who were referred to the transplant service from 2007 to 2010, were identified. Of these patients, 32 (62%) patients did not undergo alloSCT, mainly because of treatment- or disease-related complications (n=15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in 17p- CLL patients, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure. PMID:24913509

  9. Delineation of the clinically recognizable 17q22 contiguous gene deletion syndrome in a patient carrying the smallest microdeletion known to date.

    PubMed

    Martínez-Fernández, María Luisa; Fernández-Toral, Joaquin; Llano-Rivas, Isabel; Bermejo-Sánchez, Eva; MacDonald, Alexandra; Martínez-Frías, María Luisa

    2015-09-01

    We describe a patient with a 1.34 Mb microdeletion at chromosome band 17q22, which is also present in his affected mother. To better delineate this microdeletion syndrome, we compare the clinical and molecular characteristics of 10 previously reported cases and our patient. Of these, the present patient has the smallest deletion which includes five genes: MMD, TMEM100, PCTP, ANKFN1, and NOG. We compare the clinical manifestations described in relation to NOG, since this is the only gene whose loss is shared by our patient and the other eight patients. Previously, the clinical patterns associated with NOG mutations have been included under the general term "NOG-related symphalangism spectrum disorder (NOG-SSD)." Based on our analyses, and considering that there is a clinical correlation observed in cases with a "17q22 microdeletion including NOG" of which the main characteristics can be contributed to loss of this gene, we propose that the clinical patterns observed in these patients should be named as NOG-spectrum disorder-contiguous gene syndrome (NOGSD-CGS). This designation is important for clinicians because when a patient has defects concordant with alterations of NOG but also presents other anomalies not related to this gene, they would be able to suspect the existence of a microdeletion affecting 17q22, therefore, allowing an early diagnosis. This will also enable the clinician to provide the family with adequate information about the prognosis and the risk of reoccurrence in future potential offspring.

  10. Novel mitochondrial tRNA Leu(CUN) transition and D4Z4 partial deletion in a patient with a facioscapulohumeral phenotype.

    PubMed

    Filosto, Massimiliano; Tonin, Paola; Scarpelli, Mauro; Savio, Chiara; Greco, Francesca; Mancuso, Michelangelo; Vattemi, Gaetano; Govoni, Vittorio; Rizzuto, Nicolò; Tupler, Rossella; Tomelleri, Giuliano

    2008-03-01

    Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the T Psi C stem of the tRNA(Leu(CUN)) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) "double trouble". PMID:18343111

  11. High frequency of exon 15 deletion in the FANCA gene in Tunisian patients affected with Fanconi anemia disease: implication for diagnosis

    PubMed Central

    Amouri, Ahlem; Talmoudi, Faten; Messaoud, Olfa; d'Enghien, Catherine D; Rekaya, Mariem B; Allegui, Ines; Azaiez, Héla; Kefi, Rym; Abdelhak, Ahlem; Meseddi, Sondes H; Torjemane, Lamia; Ouederni, Monia; Mellouli, Fethi; Abid, Héla B; Aissaoui, Lamia; Bejaoui, Mohamed; Othmen, Tarek B; Lyonnet, Dominique S; Soulier, Jean; Hachicha, Mongia; Dellagi, Koussay; Abdelhak, Sonia; Fanconi, Tunisian

    2014-01-01

    Tunisian population is characterized by its heterogeneous ethnic background and high rate of consanguinity. In consequence, there is an increase in the frequency of recessive genetic disorders including Fanconi anemia (FA). The aim of this study was to confirm the existence of a founder haplotype among FA Tunisian patients and to identify the associated mutation in order to develop a simple tool for FA diagnosis. Seventy-four unrelated families with a total of 95 FA patients were investigated. All available family members were genotyped with four microsatellite markers flanking FANCA gene. Haplotype analysis and homozygosity mapping assigned 83 patients belonging to 62 families to the FA-A group. A common haplotype was shared by 42 patients from 26 families at a homozygous state while five patients from five families were heterozygous. Among them, 85% were from southern Tunisia suggesting a founder effect. Using multiplex ligation-dependent probe amplification (MLPA) technique, we have also demonstrated that this haplotype is associated with a total deletion of exon 15 in FANCA gene. Identification of a founder mutation allowed genetic counseling in relatives of these families, better bone marrow graft donor selection and prenatal diagnosis. This mutation should be investigated in priority for patients originating from North Africa and Middle East. PMID:24689079

  12. Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications.

    PubMed

    Starr, Lois J; Truemper, Edward J; Pickering, Diane L; Sanger, Warren G; Olney, Ann Haskins

    2014-08-01

    Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.12-13.33, as well as an 886 kb deletion of 20p13 at 18,580-904,299 bp. This anomaly occurred as the recombinant product of a paternal pericentric inversion. There have been 23 reported clinical cases involving 20qter duplications; however, to our knowledge this is only the second reported patient with a paternal pericentric inversion resulting in 46,XY,rec(20)dup(20q). This patient shares many characteristics with previously described patients with 20qter duplications, including microphthalmia, anteverted nares, long ears, cleft palate, small chin, dimpled chin, cardiac malformations, and normal intrauterine growth. While there is variable morbidity in patients with terminal duplications of 20q, a review of previously reported patients and comparison to our patient's findings shows significant phenotypic similarity.

  13. Dental developmental abnormalities in a patient with subtelomeric 7q36 deletion syndrome may confirm a novel role for the SHH gene☆

    PubMed Central

    Linhares, Natália D.; Svartman, Marta; Salgado, Mauro Ivan; Rodrigues, Tatiane C.; da Costa, Silvia S.; Rosenberg, Carla; Valadares, Eugênia R.

    2013-01-01

    Studies in mice demonstrated that the Shh gene is crucial for normal development of both incisors and molars, causing a severe retardation in tooth growth, which leads to abnormal placement of the tooth in the jaw and disrupted tooth morphogenesis. In humans the SHH gene is located on chromosome 7q36. Defects in its protein or signaling pathway may cause holoprosencephaly spectrum, a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres and that can be manifested in microforms such as single maxillary central incisor. A novel role for this gene in the developing human primary dentition was recently demonstrated. We report a 12-year old boy with a de novo 7q36.1-qter deletion characterized by high-resolution karyotyping, oligonucleotide aCGH and FISH. His phenotype includes intellectual disability, non-verbal communication, hypospadia, partial sacral agenesis and absence of coccyx, which are distinctive features of the syndrome and mainly correlated with the MNX1, HTR5A and EN2 genes. No microforms of holoprosencephaly spectrum were observed; but the patient had diastema and dental developmental abnormalities, such as conical, asymmetric and tapered inferior central incisors. The dental anomalies are reported herein for the first time in subtelomeric 7q36 deletion syndrome and may confirm clinically a novel role for the SHH gene in dental development. PMID:25606385

  14. Dental developmental abnormalities in a patient with subtelomeric 7q36 deletion syndrome may confirm a novel role for the SHH gene.

    PubMed

    Linhares, Natália D; Svartman, Marta; Salgado, Mauro Ivan; Rodrigues, Tatiane C; da Costa, Silvia S; Rosenberg, Carla; Valadares, Eugênia R

    2014-12-01

    Studies in mice demonstrated that the Shh gene is crucial for normal development of both incisors and molars, causing a severe retardation in tooth growth, which leads to abnormal placement of the tooth in the jaw and disrupted tooth morphogenesis. In humans the SHH gene is located on chromosome 7q36. Defects in its protein or signaling pathway may cause holoprosencephaly spectrum, a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres and that can be manifested in microforms such as single maxillary central incisor. A novel role for this gene in the developing human primary dentition was recently demonstrated. We report a 12-year old boy with a de novo 7q36.1-qter deletion characterized by high-resolution karyotyping, oligonucleotide aCGH and FISH. His phenotype includes intellectual disability, non-verbal communication, hypospadia, partial sacral agenesis and absence of coccyx, which are distinctive features of the syndrome and mainly correlated with the MNX1, HTR5A and EN2 genes. No microforms of holoprosencephaly spectrum were observed; but the patient had diastema and dental developmental abnormalities, such as conical, asymmetric and tapered inferior central incisors. The dental anomalies are reported herein for the first time in subtelomeric 7q36 deletion syndrome and may confirm clinically a novel role for the SHH gene in dental development.

  15. Cloning and characterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy

    SciTech Connect

    Laporte, J.; Hu, Ling-Jia; Kretz, C.

    1997-05-01

    We have identified a novel human gene that is entirely deleted in two boys with abnormal genital development and myotubular myopathy (MTM1). The gene, F18, is located in proximal Xq28, approximately 80 kb centromeric to the recently isolated MTM1 gene. Northern analysis of mRNA showed a ubiquitous pattern and suggested high levels of expression in skeletal muscle, brain, and heart. A transcript of 4.6 kb was detected in a range of tissues, and additional alternate forms of 3.8 and 2.6 kb were present in placenta and pancreas, respectively. The gene extends over 100 kb and is composed of at least seven exons, of which two are non-coding. Sequence analysis of a 4.6-kb cDNA contig revealed two overlapping open reading frames (ORFs) that encode putative proteins of 701 and 424 amino acids, respectively. Two alternative spliced transcripts affecting the large open reading frame were identified that, together with the Northern blot results, suggest that distinct proteins are derived from the gene. No significant homology to other known proteins was detected, but segments of the first ORF encode polyglutamine tracts and proline-rich domains, which are frequently observed in DNA-binding proteins. The F18 gene is a strong candidate for being implicated in the intersexual genitalia present in the two MTM1-deleted patients. The gene also serves as a candidate for other disorders that map to proximal Xq28. 15 refs., 3 figs., 1 tab.

  16. Hypoparathyroidism associated with aneurysm of the left subclavian artery (Kommerell's diverticulum) in an adult patient with a chromosome 22q11.2 deletion.

    PubMed

    Trombetti, A; Bottani, A; George, F; Rizzoli, R

    2001-10-01

    Hypoparathyroidism may either be acquired or of congenital origin. From the latter group, which represents a minority of cases, agenesis or hypoplasia of the parathyroid glands resulting in symptomatic hypocalcemia in the newborn or infant frequently is caused by a microdeletion of chromosome 22q11.2. We describe a man in whom hypoparathyroidism was first diagnosed at the age of 59 years. The endocrine disorder was found to be associated with this chromosome imbalance and also with an aneurysm of the left subclavian artery (Kommerell's diverticulum) compressing the esophagus and trachea. Given the potential implication for genetic counseling, a 22q11.2 deletion should be considered in the differential diagnosis of adult patients with hypoparathyroidism of unknown origin and should be searched for by appropriate molecular cytogenetic technique.

  17. A patient presenting a 22q13 deletion associated with an apparently balanced translocation t(16;22): An illustrative case in the investigation of patients with low ARSA activity

    PubMed Central

    Artigalás, Osvaldo; Paskulin, Giorgio; Riegel, Mariluce; Burin, Maira; Saraiva-Pereira, Maria Luiza; Maluf, Sharbel; Kiss, Andrea; Schwartz, Ida Vanessa D.

    2012-01-01

    A 10-year-old speechless, mentally deficient male, with low arylsulfatase A (ARSA) activity, and presumably, methachromatic leukodystrophy, underwent genetic evaluation. As the clinical picture was not compatible with this diagnosisan ARSA gene and chromosome analysis were performed, showing the presence of a pseudodeficiency ARSA allele and a de novo apparently balanced t(16;22)(p11.2;q13) translocation. A deletion on the long arm of chromosome 22 encompassing the ARSA gene, as shown by FISH and array-CGH, indicated a 22q13 deletion syndrome. This case illustrates the importance of detailed cytogenetic investigation in patients presenting low arylsulfatase A activity and atypical/unspecific clinical features. PMID:22888290

  18. Monoclonal antibodies against the muscle-specific N-terminus of dystrophin: Characterization of dystrophin in a muscular dystrophy patient with a frameshift deletion of Exons 3-7

    SciTech Connect

    Thanh, L. T.; Man, N. thi; Morris, G.E. ); Love, D.R.; Davies, K.E. ); Helliwell, T.R. )

    1993-07-01

    The first three exons of the human muscle dystrophin gene were expressed as a [beta]-galactosidase fusion protein. 1-his protein was then used to prepare two monoclonal antibodies (mAbs) which react with native dystrophin on frozen muscle sections and with denatured dystrophin on western blots but which do not cross-react with the distrophin-related protein, utrophin. Both mAbs recognized dystrophin in muscular dystrophy (MD) patients with deletions of exon 3, and further mapping with 11 overlapping synthetic peptides showed that they both recognize an epitope encoded by the muscle-specific exon 1. Neither mAb recognizes the brain dystrophin isoform, confirming the prediction from mRNA data that this has a different N-terminus. One Becker MD patient with a frameshift deletion of exons 3-7 is shown to produce dystrophin which reacts with the N-terminal mAbs, as well as with mAbs which bind on the C-terminal side of the deletion. The data suggest that transcription begins at the normal muscle dystrophin promoter and that the normal reading frame is restored after the deletion. A number of mechanisms have been proposed for restoration of the reading frame after deletion of exons 3-7, but those which predict dystrophin with an abnormal N-terminus do not appear to be major mechanisms in this patient. 27 refs., 6 figs.

  19. Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.

    PubMed

    Duru, Adil Doganay; Sutlu, Tolga; Wallblom, Ann; Uttervall, Katarina; Lund, Johan; Stellan, Birgitta; Gahrton, Gösta; Nahi, Hareth; Alici, Evren

    2015-01-01

    Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21). PMID:26378933

  20. Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.

    PubMed

    Duru, Adil Doganay; Sutlu, Tolga; Wallblom, Ann; Uttervall, Katarina; Lund, Johan; Stellan, Birgitta; Gahrton, Gösta; Nahi, Hareth; Alici, Evren

    2015-01-01

    Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).

  1. Co-segregation of a homozygous SMN1 deletion and a heterozygous PMP22 duplication in a patient.

    PubMed

    Fernández, Raquel M; Peciña, Ana; Muñoz-Cabello, Beatriz; Antiñolo, Guillermo; Borrego, Salud

    2016-09-01

    Despite co-segregation of two different genetic neurological disorders within a family is rare, clinicians should take into consideration this possibility in patients presenting with unusual complex phenotypes or with unexpected electrophysiological findings. Here, we report a Spanish 11-month-old patient with spinal muscular atrophy type 2 and Charcot-Marie-Tooth 1A. PMID:27648268

  2. Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.

    PubMed

    Herman, Sean B; Guo, Tingwei; McGinn, Donna M McDonald; Blonska, Anna; Shanske, Alan L; Bassett, Anne S; Chow, Eva W C; Bowser, Mark; Sheridan, Molly; Beemer, Frits; Devriendt, Koen; Swillen, Ann; Breckpot, Jeroen; Digilio, M Cristina; Marino, Bruno; Dallapiccola, Bruno; Carpenter, Courtney; Zheng, Xin; Johnson, Jacob; Chung, Jonathan; Higgins, Anne Marie; Philip, Nicole; Simon, Tony; Coleman, Karlene; Heine-Suner, Damian; Rosell, Jordi; Kates, Wendy; Devoto, Marcella; Zackai, Elaine; Wang, Tao; Shprintzen, Robert; Emanuel, Beverly S; Morrow, Bernice E

    2012-11-01

    Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n = 360) and genotyping data (n = 737) with respect to presence (n = 54) or absence (n = 683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant.

  3. A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation

    PubMed Central

    Pickard, Ben S; Hollox, Edward J; Malloy, M Pat; Porteous, David J; Blackwood, Douglas HR; Armour, John AL; Muir, Walter J

    2004-01-01

    Background Cryptic structural abnormalities within the subtelomeric regions of chromosomes have been the focus of much recent research because of their discovery in a percentage of people with mental retardation (UK terminology: learning disability). These studies focused on subjects (largely children) with various severities of intellectual impairment with or without additional physical clinical features such as dysmorphisms. However it is well established that prevalence of schizophrenia is around three times greater in those with mild mental retardation. The rates of bipolar disorder and major depressive disorder have also been reported as increased in people with mental retardation. We describe here a screen for telomeric abnormalities in a cohort of 69 patients in which mental retardation co-exists with severe psychiatric illness. Methods We have applied two techniques, subtelomeric fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) to detect abnormalities in the patient group. Results A subtelomeric deletion was discovered involving loss of 4q in a patient with co-morbid schizoaffective disorder and mental retardation. Conclusion The precise region of loss has been defined allowing us to identify genes that may contribute to the clinical phenotype through hemizygosity. Interestingly, the region of 4q loss exactly matches that linked to bipolar affective disorder in a large multiply affected Australian kindred. PMID:15310400

  4. Submicroscopic deletion of chromosome region 16p13.3 in a Japanese patient with Rubinstein-Taybi syndrome

    SciTech Connect

    Masuno, Mitsuo; Imaizumi, Kiyoshi; Kurosawa, Kenji; Makita, Yoshio; Kuroki, Yoshikazu; Petrij, F.; Dauwerse, H.G.; Breuning, M.H.

    1994-12-01

    In a series of 25 Japanese patients with Rubinstein-Taybi syndrome, we screened, by high-resolution GTG banding and fluorescence in situ hybridization of a cosmid probe (RT1, D16S237), for microdeletions associated with this syndrome. In one patient, a microdeletion was demonstrated by in situ hybridization, but none were detected by high-resolution banding. 11 refs., 2 figs.

  5. Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems.

    PubMed

    D'Angelo, Carla S; Da Paz, José A; Kim, Chong A; Bertola, Débora R; Castro, Claudia I E; Varela, Monica C; Koiffmann, Célia P

    2006-01-01

    Monosomy 1p36 is one of the most commonly observed mental retardation (MR) syndromes that results in a clinically recognizable phenotype including delayed psychomotor development and/or MR, hypotonia, epilepsy, hearing loss, growth delay, microcephaly, deep-set eyes, flat nasal bridge and pointed chin. Besides, a Prader-Willi syndrome (PWS)-like phenotype has been described in patients with 1p36 monosomy. Forty-one patients presenting hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who tested negative for PWS were investigated by FISH and/or microsatellite markers. Twenty-six were analyzed with a 1p-specific subtelomeric probe, and one terminal deletion was identified. Thirty patients (15 of which also studied by FISH) were investigated by microsatellite markers, and no interstitial 1p36 deletion was found. Our patient presenting the 1p36 deletion did not have the striking features of this monosomy, but her clinical and behavioral features were quite similar to those observed in patients with PWS, except for the presence of normal sucking at birth. The extent of the deletion could be limited to the most terminal 2.5 Mb of 1p36, within the chromosomal region 1p36.33-1p36.32, that is smaller than usually seen in monosomy 1p36 patients. Therefore, chromosome 1p36.33 deletion should be investigated in patients with hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who test negative for PWS.

  6. Selection of nitrogen-fixing deficient Burkholderia vietnamiensis strains by cystic fibrosis patients: involvement of nif gene deletions and auxotrophic mutations.

    PubMed

    Menard, Aymeric; Monnez, Claire; Estrada de Los Santos, Paulina; Segonds, Christine; Caballero-Mellado, Jesus; Lipuma, John J; Chabanon, Gerard; Cournoyer, Benoit

    2007-05-01

    Burkholderia vietnamiensis is the third most prevalent species of the Burkholderia cepacia complex (Bcc) found in cystic fibrosis (CF) patients. Its ability at fixing nitrogen makes it one of the main Bcc species showing strong filiations with environmental reservoirs. In this study, 83% (29 over 35) of the B. vietnamiensis CF isolates and 100% of the environmental ones (over 29) were found expressing the dinitrogenase complex (encoded by the nif cluster) which is essential in N(2) fixation. Among the deficient strains, two were found growing with ammonium chloride suggesting that they were defective in N(2) fixation, and four with amino acids supplements suggesting that they were harbouring auxotrophic mutations. To get insights about the genetic events that led to the emergence of the N(2)-fixing defective strains, a genetic analysis of B. vietnamiensis nitrogen-fixing property was undertaken. A 40-kb-long nif cluster and nif regulatory genes were identified within the B. vietnamiensis strain G4 genome sequence, and analysed. Transposon mutagenesis and nifH genetic marker exchanges showed the nif cluster and several other genes like gltB (encoding a subunit of the glutamate synthase) to play a key role in B. vietnamiensis ability at growing in nitrogen-free media. nif cluster DNA probings of restricted genomic DNA blots showed a full deletion of the nif cluster for one of the N(2)-fixing defective strain while the other one showed a genetic organization similar to the one of the G4 strain. For 17% of B. vietnamiensis clinical strains, CF lungs appeared to have favoured the selection of mutations or deletions leading to N(2)-fixing deficiencies.

  7. Deletions of the elastin gene in Williams Syndrome

    SciTech Connect

    Greenberg, F.; Nickerson, E.; McCaskill, C.

    1994-09-01

    To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

  8. Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome

    PubMed Central

    Bedeschi, M.F.; Colombo, L.; Mari, F.; Hofmann, K.; Rauch, A.; Gentilin, B.; Renieri, A.; Clerici, D.

    2011-01-01

    Van den Ende-Gupta syndrome (VDEGS) is a congenital condition characterized by craniofacial and skeletal manifestations, specifically blepharophimosis, malar and maxillary hypoplasia, distinctive nose, arachnocamptodactyly, and long slender bones of the hands and feet. To date, only 24 patients have been described. It is generally thought that the syndrome is transmitted by an autosomal recessive mode of inheritance, although evidence for genetic heterogeneity has recently been presented. We report on a girl followed from birth up to 3 years of life with a set of peculiar minor anomalies, arachnocamptodactyly of hands and feet, characteristic of VDEGS in association with a 22q11.12 deletion. Recently, the VDEGS gene was mapped to the DiGeorge syndrome region on 22q11.2, and homozygous mutations in the SCARF2 gene were identified. We now report the first patient with VDEGS due to compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 splice site mutation. PMID:22140376

  9. Clinical presentation of two β-thalassemic Indian patients with 1p36 deletion syndrome: Case report.

    PubMed

    De, Puspal; Chatterjee, Tridip; Chakravarty, Sudipa; Chakravarty, Amit

    2014-09-01

    Here, we present two thalassemic patients (one male and one female), having unusual clinical phenotypes. Both had mental retardation in which one was associated with microcephaly and other had congenital cataract. They were referred to our institute for clinical evaluation and cytogenetic testing. Both patients were tested for presence of abnormal hemoglobin by high performance liquid chromatography and found to be thalassemic. Their β-globin mutation was also determined by amplification refractory mutation system-polymerase chain reaction. The male patient was found to have intervening sequence 1-5 (G-C)/+, indicating β-thalassemia trait and the female was found to have Cod 26 (G-A)/IVS 1-5 (G-C), indicating hemoglobin E-β thalassemia. Their cytogenetic analysis of blood lymphocytes were studied with high-resolution GTG-banding analysis by using chromosome profiling (Cyto-vision software 3.6) on their chromosomes. Results revealed 46,XY,del(1)(p36.21) in the male and 46,XX,del(1)(p36.3) in the female. Their genotype variation showed (based on genome browser) significant gene loss which probably leads to marked phenotype variation. We believe, thalassemia with mental retardation associated with microcephaly and congenital cataract, both having loss in chromosome 1, p36 position, is reported probably first time from India. This report will definitely enlighten all concerns and add to the information in growing literature.

  10. Clinical presentation of two β-thalassemic Indian patients with 1p36 deletion syndrome: Case report

    PubMed Central

    De, Puspal; Chatterjee, Tridip; Chakravarty, Sudipa; Chakravarty, Amit

    2014-01-01

    Here, we present two thalassemic patients (one male and one female), having unusual clinical phenotypes. Both had mental retardation in which one was associated with microcephaly and other had congenital cataract. They were referred to our institute for clinical evaluation and cytogenetic testing. Both patients were tested for presence of abnormal hemoglobin by high performance liquid chromatography and found to be thalassemic. Their β-globin mutation was also determined by amplification refractory mutation system-polymerase chain reaction. The male patient was found to have intervening sequence 1-5 (G-C)/+, indicating β-thalassemia trait and the female was found to have Cod 26 (G-A)/IVS 1-5 (G-C), indicating hemoglobin E-β thalassemia. Their cytogenetic analysis of blood lymphocytes were studied with high-resolution GTG-banding analysis by using chromosome profiling (Cyto-vision software 3.6) on their chromosomes. Results revealed 46,XY,del(1)(p36.21) in the male and 46,XX,del(1)(p36.3) in the female. Their genotype variation showed (based on genome browser) significant gene loss which probably leads to marked phenotype variation. We believe, thalassemia with mental retardation associated with microcephaly and congenital cataract, both having loss in chromosome 1, p36 position, is reported probably first time from India. This report will definitely enlighten all concerns and add to the information in growing literature. PMID:27625875

  11. Clinical presentation of two β-thalassemic Indian patients with 1p36 deletion syndrome: Case report.

    PubMed

    De, Puspal; Chatterjee, Tridip; Chakravarty, Sudipa; Chakravarty, Amit

    2014-09-01

    Here, we present two thalassemic patients (one male and one female), having unusual clinical phenotypes. Both had mental retardation in which one was associated with microcephaly and other had congenital cataract. They were referred to our institute for clinical evaluation and cytogenetic testing. Both patients were tested for presence of abnormal hemoglobin by high performance liquid chromatography and found to be thalassemic. Their β-globin mutation was also determined by amplification refractory mutation system-polymerase chain reaction. The male patient was found to have intervening sequence 1-5 (G-C)/+, indicating β-thalassemia trait and the female was found to have Cod 26 (G-A)/IVS 1-5 (G-C), indicating hemoglobin E-β thalassemia. Their cytogenetic analysis of blood lymphocytes were studied with high-resolution GTG-banding analysis by using chromosome profiling (Cyto-vision software 3.6) on their chromosomes. Results revealed 46,XY,del(1)(p36.21) in the male and 46,XX,del(1)(p36.3) in the female. Their genotype variation showed (based on genome browser) significant gene loss which probably leads to marked phenotype variation. We believe, thalassemia with mental retardation associated with microcephaly and congenital cataract, both having loss in chromosome 1, p36 position, is reported probably first time from India. This report will definitely enlighten all concerns and add to the information in growing literature. PMID:27625875

  12. Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: a comparison between maternal uniparental disomy and deletion cases.

    PubMed

    Ogata, Hiroyuki; Ihara, Hiroshi; Murakami, Nobuyuki; Gito, Masao; Kido, Yasuhiro; Nagai, Toshiro

    2014-09-01

    This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader-Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P = 0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P = 0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P = 0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P = 0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood. PMID:24850752

  13. Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: a comparison between maternal uniparental disomy and deletion cases.

    PubMed

    Ogata, Hiroyuki; Ihara, Hiroshi; Murakami, Nobuyuki; Gito, Masao; Kido, Yasuhiro; Nagai, Toshiro

    2014-09-01

    This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader-Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P = 0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P = 0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P = 0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P = 0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood.

  14. De Novo 13q13.3-21.31 deletion involving RB1 gene in a patient with hemangioendothelioma of the liver

    PubMed Central

    2014-01-01

    Interstitial deletions of the long arm of chromosome 13 (13q) are related with variable phenotypes, according to the size and the location of the deleted region. The main clinical features are moderate/severe mental and growth retardation, cranio-facial dysmorphism, variable congenital defects and increased susceptibility to tumors. Here we report a 3-year-old girl carrying a de novo 13q13.3-21.32 interstitial deletion. She showed developmental delay, growth retardation and mild dysmorphism including curly hair, high forehead, short nose, thin upper lip and long philtrum. An abnormal mass was surgically removed from her liver resulting in a hemangioendothelioma. Array analysis allowed us to define a deleted region of about 27.87 Mb, which includes the RB1 gene. This is the first report of a 13q deletion associated with infantile hemangioendothelioma of the liver. PMID:24433316

  15. Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q-syndrome: Delineation of the critical region on 5q and identification of a 5q-breakout

    SciTech Connect

    Boultwood, J.; Fidler, C.; Lewis, S.; Littlewood, T.J.; Wainscoat, J.S.; Buckle, V.J. ); Kelly, S. ); Sheridan, H. )

    1994-02-01

    Molecular mapping techniques have defined the region of gene loss in two patients with the 5q-syndrome and uncharacteristically small 5q deletions (5q31-q33). The allelic loss of 10 genes localized to 5q23-qter (centromere-CSF2-EGR1-FGFA-GRL-ADRB2-CSF1R-SPARC-GLUH1-NKSF1-FLT4-telomere) was investigated in peripheral blood cell fractions. Gene dosage experiments demonstrated that CSF2, EGR1, NKSF1, and FLT4 were retained on the 5q-chromosome in both patients and that FGFA was retained in one patient, thus placing these genes outside the critical region. GRL, ADRB2, CSF1R, SPARC, and GLUH1 were shown to be deleted in both patients. The proximal breakpoint is localized between EGR1 and FGFA in one patient and between FGFA and ADRB2 in the other, and the distal breakpoint is localized between GLUH1 and NKSF1 in both patients. Pulsed-field gel electrophoresis was used to map the 5q deletion breakpoints, and breakpoint-specific fragments were detected with FGFA in the granulocyte but not the lymphocyte fraction of one patient. This study has established the critical region of gene loss of the 5q-chromosome in the 5q-syndrome, giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between FGFA and NKSF1. 54 refs., 3 figs., 2 tabs.

  16. Amelioration of the typical cognitive phenotype in a patient with the 5pter deletion associated with Cri-du-chat syndrome in addition to a partial duplication of CTNND2.

    PubMed

    Sardina, Jennifer M; Walters, Allyson R; Singh, Kathryn E; Owen, Renius X; Kimonis, Virginia E

    2014-07-01

    Cri-du-chat is a rare congenital syndrome characterized by intellectual disability, severe speech/developmental delay, dysmorphic features, and additional syndromic findings. The etiology of this disorder is well known, and is attributed to a large deletion on chromosome 5 that typically ranges from band 5p15.2 to the short arm terminus. This region contains CTNND2, a gene encoding a neuronal-specific protein, delta-catenin, which plays a critical role in cellular motility and brain function. The exact involvement of CTNND2 in the cognitive functionality of individuals with Cri-du-chat has not been fully deciphered, but it is thought to be significant. This report describes an 8-year-old African-American female with a complex chromosome 5 abnormality and a relatively mild case of cri-du-chat syndrome. Because of the surprisingly mild cognitive phenotype, although a karyotype had confirmed the 5p deletion at birth, an oligo-SNP microarray was obtained to further characterize her deletion. The array revealed a complex rearrangement, including a breakpoint in the middle of CTNND2, which resulted in a partial deletion and partial duplication of that gene. The array also verified the expected 5p terminal deletion. Although the patient has a significant deletion in CTNND2, half of the gene (including the promoter region) is not only preserved, but is duplicated. The patient's milder cognitive and behavioral presentation, in conjunction with her atypical 5p alteration, provides additional evidence for the role of CTNND2 in the cognitive phenotype of individuals with Cri-du-chat. PMID:24677774

  17. Serum Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3) Is Increased in Patients with Multiple Sclerosis and Is a Strong Independent Indicator of Disease Severity; 6.7kbp LILRA3 Gene Deletion Is Not Associated with Diseases Susceptibility

    PubMed Central

    An, Hongyan; Lim, Chai; Guillemin, Gilles J.; Vollmer-Conna, Ute; Rawlinson, William; Bryant, Katherine; Tedla, Nicodemus

    2016-01-01

    Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble immune regulatory molecule primarily expressed by monocytes and macrophages. A homozygous 6.7kbp LILRA3 gene deletion that removes the first seven of its eight exons is predicted to lead to lack of LILRA3 protein, although this has not been experimentally confirmed. Moreover, there are conflicting results with regards to the link between the LILRA3 homozygous genetic deletion and susceptibility to multiple sclerosis (MS) in different European populations. The aim of this study was to investigate whether LILRA3 gene deletion is associated with MS susceptibility in a North American cohort of European ancestry and assess if serum LILRA3 protein level is a marker of clinical subtype and/or disease severity in MS. A total of 456 patients with MS and 99 unrelated healthy controls were genotyped for the 6.7kbp LILRA3 gene deletion and levels of LILRA3 protein in sera determined by in-house sandwich ELISA. We showed that LILRA3 gene deletion was not associated with MS susceptibility and did not affect the age of disease onset, clinical subtype or disease severity. However, we discovered for the first time that homozygous LILRA3 gene deletion results in lack of production of LILRA3 protein. Importantly, LILRA3 protein level was significantly increased in sera of patients with MS when compared with control subjects, particularly in more severe type primary progressive MS. Multiple regression analysis showed that LILRA3 level in serum was one of the strongest independent markers of disease severity in MS, which potentially can be used as a diagnostic marker. PMID:26871720

  18. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

    PubMed

    Varela, Monica Castro; Kok, Fernando; Otto, Paulo Alberto; Koiffmann, Celia Priszkulnik

    2004-12-01

    Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

  19. SU-E-T-396: Dosimetric Accuracy of Proton Therapy for Patients with Metal Implants in CT Scans Using Metal Deletion Technique (MDT) Artifacts Reduction

    SciTech Connect

    Li, X; Kantor, M; Zhu, X; Frank, S; Sahoo, N; Li, H

    2014-06-01

    Purpose: To evaluate the dosimetric accuracy for proton therapy patients with metal implants in CT using metal deletion technique (MDT) artifacts reduction. Methods: Proton dose accuracies under CT metal artifacts were first evaluated using a water phantom with cylindrical inserts of different materials (titanium and steel). Ranges and dose profiles along different beam angles were calculated using treatment planning system (Eclipse version 8.9) on uncorrected CT, MDT CT, and manually-corrected CT, where true Hounsfield units (water) were assigned to the streak artifacts. In patient studies, the treatment plans were developed on manually-corrected CTs, then recalculated on MDT and uncorrected CTs. DVH indices were compared between the dose distributions on all the CTs. Results: For water phantom study with 1/2 inch titanium insert, the proton range differences estimated by MDT CT were with 1% for all beam angles, while the range error can be up to 2.6% for uncorrected CT. For the study with 1 inch stainless steel insert, the maximum range error calculated by MDT CT was 1.09% among all the beam angles compared with maximum range error with 4.7% for uncorrected CT. The dose profiles calculated on MDT CTs for both titanium and steel inserts showed very good agreements with the ones calculated on manually-corrected CTs, while large dose discrepancies calculated using uncorrected CTs were observed in the distal end region of the proton beam. The patient study showed similar dose distribution and DVHs for organs near the metal artifacts recalculated on MDT CT compared with the ones calculated on manually-corrected CT, while the differences between uncorrected and corrected CTs were much pronounced. Conclusion: In proton therapy, large dose error could occur due to metal artifact. The MDT CT can be used for proton dose calculation to achieve similar dose accuracy as the current clinical practice using manual correction.

  20. Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa.

    PubMed

    Vidal, F; Baudoin, C; Miquel, C; Galliano, M F; Christiano, A M; Uitto, J; Ortonne, J P; Meneguzzi, G

    1995-11-20

    Laminin 5 and laminin 6 are basement membrane proteins synthesized by the basal cells of stratifying squamous epithelia. Altered expression of laminin 5 has been associated with Herlitz junctional epidermolysis bullosa (H-JEB), a severe epidermal blistering disorder inherited as an autosomal recessive disease. We have isolated cDNA clones encoding the alpha 3 chain of laminin 5 and searched for mutations in the LAMA3 gene in H-JEB patients. In one H-JEB family, an affected individual exhibited drastically reduced immunoreactivity to antibodies directed against the alpha 3 chain of laminin 5 and an impaired expression of the corresponding mRNA transcripts. RT-PCR analysis of mRNA extracted from the proband's keratinocytes identified a homozygous single basepair deletion in the transcripts encoding the laminin alpha 3A and alpha 3B isoforms. The mutation causes a frameshift and premature termination codon in both alleles of the LAMA3 gene. Inheritance of the clinical H-JEB phenotype was consistent with the segregation of the mutated allele in the family. We also report the identity of the alpha chains of laminin 5 and epiligrin and provide evidence that LAMA3 transcripts are distinct from the laminin 6 alpha chain mRNA. PMID:8586427

  1. Cloning of the laminin {alpha}3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa

    SciTech Connect

    Vidal, F.; Ortonne, J.P. |; Galliano, M.F.

    1995-11-20

    Laminin 5 and laminin 6 are basement membrane proteins synthesized by the basal cells of stratifying squamous epithelia. Altered expression of laminin 5 has been associated with Herlitz junctional epidermolysis bullosa (H-JEB), a severe epidermal blistering disorder inherited as an autosomal recessive disease. We have isolated cDNA clones encoding the {alpha}3 chain of laminin 5 and searched for mutations in the LAMA3 gene in H-JEB patients. In one H-JEB family, an affected individual exhibited drastically reduced immunoreactivity to antibodies directed against the {alpha}3 chain of laminin 5 and an impaired expression of the corresponding mRNA transcripts. RT-PCR analysis of mRNA extracted from the proband`s keratinocytes identified a homozygous single basepair deletion in the transcripts encoding the laminin {alpha}3A and {alpha}3B isoforms. The mutation causes a frameshift and premature termination codon in both alleles of the LAMA3 gene. Inheritance of the clinical H-JEB phenotype was consistent with the segregation of the mutated allele in the family. We also report the identity of the {alpha} chains of laminin 5 and epiligrin and provide evidence that LAMA3 transcripts are distinct from the laminin 6 {alpha} chain mRNA. 35 refs., 5 figs., 1 tab.

  2. Epidermal growth factor receptor‐tyrosine kinase inhibitor therapy is especially beneficial to patients with exon 19 deletion compared with exon 21 L858R mutation in non‐small‐cell lung cancer: Systematic review and meta analysis

    PubMed Central

    Liu, Yinghui; Ren, Zuen; Wang, Jinghui

    2016-01-01

    Abstract Background The correlation between epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) and EGFR sensitive mutation subtypes in advanced or metastatic non‐small cell lung cancer (NSCLC) remains uncertain. We performed this meta‐analysis to determine different clinical outcomes between patients with exon 19 deletion accepting EGFR‐TKI therapy compared with those with exon 21 L858R mutation. Methods PubMed and Web of Science were analyzed for eligible trials. Raw data were extracted to give pooled estimates of the effect of EGFR‐TKI therapy on objective response rate (ORR), one‐year progression‐free survival (PFS), and two‐year overall survival (OS). Results We identified 13 eligible trials involving 912 patients. Prospective meta‐analysis demonstrated that the ORR of the 19 deletion group was significantly higher than the 21 L858R mutation group (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.18–3.33; P = 0.01), but no statistical significance between the one‐year PFS rate of the 19 deletion and 21 L858R groups (OR 1.44, 95% CI 0.96–2.18; P = 0.08) was found. However, retrospective meta‐analysis demonstrated that a significantly higher one‐year PFS rate was associated with the 19 deletion group (OR 1.73, 95% CI 1.17–2.56; P = 0.006). The two‐year survival rate of the 19 deletion group was significantly higher than the 21 L858R group (OR 5.27, 95 % CI 1.76–15.71; P = 0.003). Conclusions In advanced NSCLC patients, an exon 19 deleton may provide superior ORR, PFS, and OS after EGFR‐TKI treatment compared with an exon 21 L858R mutation. PMID:27385982

  3. Application of FISH 7q in MDS patients without monosomy 7 or 7q deletion by conventional G-banding cytogenetics: does -7/7q- detection by FISH have prognostic value?

    PubMed

    Ademà, Vera; Hernández, Jesús María; Abáigar, María; Lumbreras, Eva; Such, Esperanza; Calull, Anna; Dominguez, Esther; Arenillas, Leonor; Mallo, Mar; Cervera, José; Marugán, Isabel; Tormo, Mar; García, Francisca; González, Teresa; Luño, Elisa; Sanzo, Carmen; Martín, María Luisa; Fernández, Manuela; Costa, Dolors; Blázquez, Beatriz; Barreña, Beatriz; Marco, Fernando; Batlle, Ana; Buño, Ismael; Martínez-Laperche, Carolina; Noriega, Víctor; Collado, Rosa; Ivars, David; Carbonell, Félix; Vallcorba, Isabel; Melero, Josefa; Delgado, Elena; Vargas, María Teresa; Grau, Javier; Salido, Marta; Espinet, Blanca; Melero, Carme; Florensa, Lourdes; Pedro, Carmen; Solé, Francesc

    2013-04-01

    Chromosomal abnormalities are detected in 40-60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without evidence of monosomy 7 (-7) or 7q deletion (7q-) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected -7/7q- in 5.2% of patients. Presence of -7/7q- was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of -7/7q- by CC.

  4. The effect of hypocalcemia in early childhood on autism-related social and communication skills in patients with 22q11 deletion syndrome

    PubMed Central

    Muldoon, Meghan; Ousley, Opal Y.; Kobrynski, Lisa J.; Patel, Sheena; Oster, Matthew E.; Fernandez-Carriba, Samuel; Cubells, Joseph F.; Coleman, Karlene; Pearce, Bradley D.

    2014-01-01

    22q11 deletion syndrome (22qDS), also known as DiGeorge Syndrome, is a copy number variant disorder that has a diverse clinical presentation including hypocalcaemia, learning disabilities, and psychiatric disorders. Many patients with 22q11DS present with signs that overlap with autism spectrum disorder (ASD) yet the possible physiological mechanisms that link 22q11DS with ASD are unknown. We hypothesized that early childhood hypocalcemia influences the neurobehavioral phenotype of 22q11DS. Drawing on a longitudinal cohort of 22q11DS patients, we abstracted albumin-adjusted serum calcium levels from 151 participants ranging in age from newborn to 19.5 years (mean 2.5 years). We then examined a subset of 20 infants and toddlers from this group for the association between the lowest calcium level on record and scores on the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC). The mean (SD) age at calcium testing was 6.2 (8.5) months whereas the mean (SD) age at the CSBS-DP ITC assessment was 14.7 (3.8) months. Lower calcium was associated with significantly greater impairment in the CSBS-DP ITC Social (p<0.05), Speech (p<0.01), and Symbolic domains (p<0.05), in regression models adjusted for sex, age at blood draw, and age at the psychological assessment. Nevertheless, these findings are limited by the small sample size of children with combined data on calcium and CSBS-DP ITC, and hence will require replication in a larger cohort with longitudinal assessments. Considering the role of calcium regulation in neurodevelopment and neuroplasticity, low calcium during early brain development could be a risk factor for adverse neurobehavioral outcomes. PMID:25267002

  5. [Novel large deletion c.22-1320_633+1224del in the CYB5R3 gene from patients with hereditary methemoglobinemia].

    PubMed

    Galeeva, N M; Nenasheva, S A; Kleĭmenova, I S; Poliakov, A V

    2012-11-01

    Hereditary types I and II methemoglobinemia is a rare autosomal recessive disease due to a deficiency of either soluble or soluble and membrane-bound forms of the enzyme NADH-cytochrome b5 reductase. The molecular genetic bases of both types of the disease consist in changes in the CYB5R3 gene. In this study, the novel and, to date, only large deletion in this gene is described, discovered in two unrelated families with types I and II methemoglobinemia. The common founder haplotype on the chromosomes carrying this mutation was identified. A universal approach for searching for the deletion boundaries was developed, and the c.22-1320_633+1224del deletion breakpoints were determined. In addition, a system for identifying the deletion in heterozygous and homozygous states was designed. PMID:23297489

  6. Chromosome deletion of 14q32.33 detected by array comparative genomic hybridization in a patient with features of dubowitz syndrome.

    PubMed

    Darcy, Diana C; Rosenthal, Scott; Wallerstein, Robert J

    2011-01-01

    We report a 4-year-old girl of Mexican origins with a clinical diagnosis of Dubowitz syndrome who carries a de novo terminal deletion at the 14q32.33 locus identified by array comparative genomic hybridization (aCGH). Dubowitz syndrome is a rare condition characterized by a constellation of features including growth retardation, short stature, microcephaly, micrognathia, eczema, telecanthus, blepharophimosis, ptosis, epicanthal folds, broad nasal bridge, round-tipped nose, mild to moderate developmental delay, and high-pitched hoarse voice. This syndrome is thought to be autosomal recessive; however, the etiology has not been determined. This is the first report of this deletion in association with this phenotype; it is possible that this deletion may be causal for a Dubowitz phenocopy.

  7. Chemokine receptor V Δ32 deletion in multiple sclerosis patients in Csongrád County in Hungary and the North-Bácska region in Serbia.

    PubMed

    Török, Nóra; Molnár, Kinga; Füvesi, Judit; Karácsony, Mária; Zsiros, Viktória; Fejes-Szabó, Annamária; Fiatal, Szilvia; Ádány, Róza; Somogyvári, Ferenc; Stojiljković, Olivera; Vécsei, László; Bencsik, Krisztina

    2015-01-01

    The roles of chemokine receptor V (CCR5) and its polymorphism, rs333 in multiple sclerosis (MS) are controversial. We investigated the receptor and its deletion in a large MS (428) and a numerous control (831) population in Csongrád County (Hungary) and North-Bácska (Serbia). Taqman probes firstly were used for the allele discrimination. There was no significant difference in genotype (OR=1.092, 95% CI=0.807-1.478, p=0.568 for wt/wt (wt=wild type allele) vs wt/Δ32, Δ32/Δ32 (Δ32=Δ32 base pair deletion allele)) or allele frequency (OR=0.914, 95% CI=0.692-1.207, p=0.525). Neither the deletion nor the wt allele affected the Expanded Disability Status Scale score or the age at onset. Our results indicate no association between the CCR5 Δ32 allele and MS.

  8. Clinical, cytogenetic, and molecular outcomes in a series of 66 patients with Pierre Robin sequence and literature review: 22q11.2 deletion is less common than other chromosomal anomalies.

    PubMed

    Gomez-Ospina, Natalia; Bernstein, Jonathan A

    2016-04-01

    Pierre Robin sequence (PRS) is an important craniofacial anomaly that can be seen as an isolated finding or manifestation of multiple syndromes. 22q11.2 deletion and Stickler syndrome are cited as the two most common conditions associated with PRS, but their frequencies are debated. We performed a retrospective study of 66 patients with PRS and reviewed their genetic testing, diagnoses, and clinical findings. The case series is complemented by a comprehensive literature review of the nature and frequency of genetic diagnosis in PRS. In our cohort 65% of patients had associated anomalies; of these, a genetic diagnosis was established in 56%. Stickler syndrome was the most common diagnosis, comprising approximately 11% of all cases, followed by Treacher Collins syndrome (9%). The frequency of 22q11.2 deletion was 1.5%. Chromosome arrays, performed for 72% of idiopathic PRS with associated anomalies, revealed two cases of 18q22→qter deletion, a region not previously reported in association with PRS. A review of the cytogenetic anomalies identified in this population supports an association between the 4q33-qter, 17q24.3, 2q33.1, and 11q23 chromosomal loci and PRS. We found a low frequency of 22q11.2 deletion in PRS, suggesting it is less commonly implicated in this malformation. Our data also indicate a higher frequency of cytogenetic anomalies in PRS patients with associated anomalies, and a potential new link with the 18q22→qter locus. The present findings underscore the utility of chromosomal microarrays in cases of PRS with associated anomalies and suggest that delaying testing for apparently isolated cases should be considered.

  9. Phenotypic characterization of rare interstitial deletion of chromosome 4

    PubMed Central

    Ismail, Samira; Helmy, Nivine A.; Mahmoud, Wael M.; El-Ruby, Mona O.

    2012-01-01

    Interstitial deletion of the long arm of chromosome 4 is rare. Patients with interstitial deletion of the long arm of chromosome 4 differ from those with terminal deletions. Phenotypes may be variable, depending upon the specific length and location of the deleted portion. Here, we report on a boy exhibiting most of the congenital malformations encountered in terminal 4q syndrome. The conventional karyotyping and Fluorescence in-situ hybridization revealed a de novo interstitial del (4)(q31q32). The current report is a further document highlighting that deletion of segment q31 could be contributing to the expression of most of the phenotype of 4q deletion syndrome. Using array comparative genome hybridization methodology is recommended for investigating further cases with similar segmental interstitial deletions to support and delineate findings and to define genes implicated in the pathogenesis of the disorder.

  10. Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature.

    PubMed

    Sivasankaran, Aswini; Kanakavalli, Murthy K; Anuradha, Deenadayalu; Samuel, Chandra R; Kandukuri, Lakshmi R

    2016-01-01

    Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY,-9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed.

  11. Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature.

    PubMed

    Sivasankaran, Aswini; Kanakavalli, Murthy K; Anuradha, Deenadayalu; Samuel, Chandra R; Kandukuri, Lakshmi R

    2016-01-01

    Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY,-9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed. PMID:27222354

  12. Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion.

    PubMed

    Neubert, Gerda; von Au, Katja; Drossel, Katrin; Tzschach, Andreas; Horn, Denise; Nickel, Renate; Kaindl, Angela M

    2013-01-10

    Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.

  13. Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions

    SciTech Connect

    Lindsay, E.A.; Goldberg, R.; Jurecic, V.

    1995-07-03

    Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.

  14. FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax.

    PubMed

    Ding, Yibing; Zhu, Chengchu; Zou, Wei; Ma, Dehua; Min, Haiyan; Chen, Baofu; Ye, Minhua; Pan, Yanqing; Cao, Lei; Wan, Yueming; Zhang, Wenwen; Meng, Lulu; Mei, Yuna; Yang, Chi; Chen, Shilin; Gao, Qian; Yi, Long

    2015-05-01

    Primary spontaneous pneumothorax (PSP) is a significant clinical problem, affecting tens of thousands patients annually. Germline mutations in the FLCN gene have been implicated in etiology of familial PSP (FPSP). Most of the currently identified FLCN mutations are small indels or point mutations that detected by Sanger sequencing. The aim of this study was to determine large FLCN deletions in PSP families that having no FLCN sequence-mutations. Multiplex ligation-dependent probe amplification (MLPA) assays and breakpoint analyses were used to detect and characterize the deletions. Three heterozygous FLCN intragenic deletions were identified in nine unrelated Chinese families including the exons 1-3 deletion in two families, the exons 9-14 deletion in five families and the exon 14 deletion in two families. All deletion breakpoints are located in Alu repeats. A 5.5 Mb disease haplotype shared in the five families with exons 9-14 deletion may date the appearance of this deletion back to approximately 16 generations ago. Evidences for founder effects of the other two deletions were also observed. This report documents the first identification of founder mutations in FLCN, as well as expands mutation spectrum of the gene. Our findings strengthen the view that MLPA analysis for intragenic deletions/duplications, as an important genetic testing complementary to DNA sequencing, should be used for clinical molecular diagnosis in FPSP.

  15. Case history and genome-wide scans for copy number variants in a family with patient having 15q11.1-q11.2 duplication and 22q11.2 deletion, and schizophrenia.

    PubMed

    Takahashi, Sakae; Suzuki, Takahiro; Nakamura-Tomizuka, Sakura; Osaki, Koichi; Sotome, Yuta; Sagawa, Tomoaki; Uchiyama, Makoto

    2015-06-01

    Many studies have indicated that chromosomes 15q11 and 22q11 may be associated with the genetic etiologies of schizophrenia. We have followed an adult schizophrenia case with 15q11.1-q11.2 duplication and 22q11.2 deletion. Here we report his clinical history, and copy number variants (CNVs) identified by microarray and real-time PCR in the patient and his parents. This is the first report describing a detailed phenotype of an adult schizophrenic case with both 15q11 and 22q11 CNVs as revealed by novel and trustworthy technologies. Subjects were a 33-year-old male patient with 15q11 and 22q11 CNVs, and his normal parents. He fulfilled the DSM-IV criteria for schizophrenia at age 18 years. He was also diagnosed with 22q11.2 deletion syndrome by fluorescence in situ hybridization (FISH) at age 18 years. To search for CNVs in more detail, whole-genome array-CGH analyses including ∼ 420,000 probes were carried out in the patient and his parents. For validations of the CNVs detected by array-CGH, real-time PCR analyses of these CNVs were performed. The patient had two disease-specific CNVs, 15q11.1-q11.2 duplication (∼ 2.7 Mb) and 22q11.21 deletion (∼ 2.9 Mb). These two regions are important for the development of schizophrenia, and this patient had shown symptoms of schizophrenia. Thus, the two areas may contain causal genes for schizophrenia.

  16. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment

    PubMed Central

    2012-01-01

    Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone

  17. Somatic mosaicism for a DMD gene deletion

    SciTech Connect

    Saito, Kayoko; Ikeya, Kiyoko; Kondo, Eri

    1995-03-13

    Mosaicism is a mixed state, with two cell populations of different genetic origins caused by a cell mutation occurring after fertilization. In the present case, DNA analysis of lymphocytes led to a DMD diagnosis before death. Postmortem immunocytochemical and DNA analysis showed somatic mosaicism. At age 18 years, blood lymphocyte DNA analysis showed a DMD gene deletion, upstream from exon 7 to the 5{prime} end containing both muscle and brain promoters. As the patient`s mother and elder sister had no deletions, he was considered to have a new mutation. Immunocytochemical studies of postmortem tissues showed that dystrophin was absent from the tongue, deltoid, intercostal, psoas and rectus femoris muscles, but there was a mix of dystrophin-positive and negative fibers in the rectus abdominis, cardiac, temporalis and sternocleidomastoid muscles. All diaphragm cells were dystrophin positive. Polymerase chain reaction (PCR) amplification from all tissues except the temporalis and sternocleidomastoid muscles, diaphragm and kidney, in which no deletion was found, showed the deletion from at least exon 6 to the 5{prime} end containing both muscle and brain promoters. In this case, a genomic deletion of the DMD gene contributed to the formation of tissues derived from both ectoderm and endoderm, and cells of mesodermal origin showed genotypic and phenotypic heterogeneity. Our results indicate a mutation of the present case may have occurred just before the period of germ layer formation. 34 refs., 7 figs.

  18. Application of FISH 7q in MDS patients without monosomy 7 or 7q deletion by conventional G-banding cytogenetics: does -7/7q- detection by FISH have prognostic value?

    PubMed

    Ademà, Vera; Hernández, Jesús María; Abáigar, María; Lumbreras, Eva; Such, Esperanza; Calull, Anna; Dominguez, Esther; Arenillas, Leonor; Mallo, Mar; Cervera, José; Marugán, Isabel; Tormo, Mar; García, Francisca; González, Teresa; Luño, Elisa; Sanzo, Carmen; Martín, María Luisa; Fernández, Manuela; Costa, Dolors; Blázquez, Beatriz; Barreña, Beatriz; Marco, Fernando; Batlle, Ana; Buño, Ismael; Martínez-Laperche, Carolina; Noriega, Víctor; Collado, Rosa; Ivars, David; Carbonell, Félix; Vallcorba, Isabel; Melero, Josefa; Delgado, Elena; Vargas, María Teresa; Grau, Javier; Salido, Marta; Espinet, Blanca; Melero, Carme; Florensa, Lourdes; Pedro, Carmen; Solé, Francesc

    2013-04-01

    Chromosomal abnormalities are detected in 40-60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without evidence of monosomy 7 (-7) or 7q deletion (7q-) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected -7/7q- in 5.2% of patients. Presence of -7/7q- was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of -7/7q- by CC. PMID:23337401

  19. Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region

    PubMed Central

    Egger, Jos I M; Verhoeven, Willem M A; Verbeeck, Wim; de Leeuw, Nicole

    2014-01-01

    The 16p11.2 microdeletion syndrome is characterized by a wide range of phenotypic expressions and is frequently associated with developmental delay, symptoms from the autism spectrum, epilepsy, congenital anomalies, and obesity. These phenotypes are often related to a proximal 16p11.2 deletion of approximately 600 kb (BP4–BP5) that includes the SH2B1 gene that is reported to be causative for morbid obesity. This more centromeric deletion is most strongly related to autism spectrum susceptibility and is functionally different from the more distal 16p12.2p11.2 region, which includes the so-called atypical 16p11.2 BP2–BP3 deletion (approximately 220 kb) presenting with developmental delay, behavioral problems and mild facial dysmorphisms. Here, an adult male with a long history of maladaptive behaviors is described who was referred for diagnostic assessment of his amotivational features. Extensive neuropsychological examination demonstrated rigid thinking, anxious beliefs, and ideas of reference in the presence of normal intelligence. Microarray analysis demonstrated a de novo 970 kb 16p11.2 BP1–BP4 microdeletion that can be regarded as explanatory for his behavioral profile. It is concluded that microdeletion syndromes are not exclusively related to intellectual disabilities and genetic testing is of putative relevance for the understanding of neuropsychiatric and neuropsychological phenomena. PMID:24707176

  20. A maternally inherited 16p13.11-p12.3 duplication concomitant with a de novo SOX5 deletion in a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features.

    PubMed

    Quintela, Ines; Barros, Francisco; Lago-Leston, Ramon; Castro-Gago, Manuel; Carracedo, Angel; Eiris, Jesus

    2015-06-01

    We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant.

  1. A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures.

    PubMed

    Smyk, Marta; Roeder, Elizabeth; Cheung, Sau Wai; Szafranski, Przemyslaw; Stankiewicz, Paweł

    2015-08-01

    Defects of long-range regulatory elements of dosage-sensitive genes represent an under-recognized mechanism underlying genetic diseases. Haploinsufficiency of SOX9, the gene essential for development of testes and differentiation of chondrocytes, results in campomelic dysplasia, a skeletal malformation syndrome often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and disrupting its distant cis-regulatory elements, have been described in patients with milder forms of campomelic dysplasia, Pierre Robin sequence, and sex reversal. We present an ∼1.58 Mb deletion mapping ∼1.28 Mb upstream to SOX9 that encompasses its putative long-range cis-regulatory element(s) and MAP2K6 in a patient with Pierre Robin sequence and osteopenia with multiple fractures. Low bone mass panel testing using massively parallel sequencing of 23 nuclear genes, including COL1A1 and COL1A2 was negative. Based on the previous mouse model of Map2k6, suggesting that Sox9 is likely a downstream target of the p38 MAPK pathway, and our previous chromosome conformation capture-on-chip (4C) data showing potential interactions between SOX9 promoter and MAP2K6, we hypothesize that deletion of MAP2K6 might have affected SOX9 expression and contributed to our patient's phenotype.

  2. Mild Phenotype in a Patient with a De Novo 6.3 Mb Distal Deletion at 10q26.2q26.3

    PubMed Central

    Tanteles, George A.; Nikolaou, Elpiniki; Christou, Yiolanda; Alexandrou, Angelos; Evangelidou, Paola; Christophidou-Anastasiadou, Violetta; Sismani, Carolina; Papacostas, Savvas S.

    2015-01-01

    We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes. PMID:26294985

  3. Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes

    PubMed Central

    Sadikovic, Bekim; Wang, Jing; El-Hattab, Ayman; Landsverk, Megan; Douglas, Ganka; Brundage, Ellen K.; Craigen, William J.; Schmitt, Eric S.; Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and

  4. Glu-47, which forms a salt bridge between neurophysin-II and arginine vasopressin, is deleted in patients with familial central diabetes insipidus

    SciTech Connect

    Yuasa, Hiromitsu; Ito, Masafumi; Nagasaki, Hiroshi; Oiso, Yutaka; Saito, Hidehiko ); Miyamoto, S.; Sasaki, N. )

    1993-09-01

    The arginine vasopressin (AVP) gene was sequenced in a pedigree with familial central diabetes insipidus (DI). When polymerase chain reaction-amplified DNAs from affected subjects were subjected to polyacrylamide gel electrophoresis, fragments including exon 2 displayed two additional, slower migrating bands. These extra bands represented DNA heteroduplexes, indicating that there was a deletion or insertion mutation in exon 2. As the region with such a mutation was identified by direct sequence analysis, polymerase chain reaction-amplified fragments including the region were subcloned and sequenced. A 3-basepair deletion (AGG) out of two consecutive AGG sequences (nucleotides 1824-1829) was identified in one of two alleles. The cosegregation of the mutation with the DI phenotype in the family was confirmed by restriction enzyme analyses. This mutation should yield an abnormal AVP precursor lacking Glu[sup 47] in its neurophysin-II (NP) moiety. Since Glu[sup 47] is essential for NP molecules to form a salt bridge with AVP, it is very likely that the function of NP as a carrier protein for AVP would be impaired. The authors suggest that AVP would undergo accelerated proteolytic degradation, and this mechanism would be involved in the pathogenesis of DI in this pedigree. 34 refs., 4 figs., 2 tabs.

  5. Angelman syndrome: Validation of molecular cytogenetic analysis of chromosome 15q11-q13 for deletion detection

    SciTech Connect

    White, L.; Knoll, J.H.M.

    1995-03-13

    In a series of 18 individuals comprising parents of Angelman syndrome (AS) patients and AS patients with large deletions, microdeletions, and no deletions, we utilized fluorescence in situ hybridization (FISH) with genomic phage clones for loci D15S63 and GABRB3 for deletion detection of chromosome 15q11-q13. Utilization of probes at these loci allows detection of common large deletions and permits discrimination of less common small deletions. In all individuals the molecular cytogenetic data were concordant with the DNA deletion analyses. FISH provides an accurate method of deletion detection for chromosome 15q11-q13. 23 refs., 2 figs., 1 tab.

  6. Deletion of GPIHBP1 causing severe chylomicronemia.

    PubMed

    Rios, Jonathan J; Shastry, Savitha; Jasso, Juan; Hauser, Natalie; Garg, Abhimanyu; Bensadoun, André; Cohen, Jonathan C; Hobbs, Helen H

    2012-05-01

    Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1. PMID:22008945

  7. Ectrodactyly and proximal/intermediate interstitial deletion 7q

    SciTech Connect

    McElveen, C.; Carvajal, M.V.; Moscatello, D.

    1995-03-13

    We report on an individual with severe mental retardation, seizures, microcephaly, unusual face, scoliosis, and cleft feet and cleft right hand. The chromosomal study showed a proximal interstitial deletion 7q (q11.23q22). From our review of the literature, 11 patients have been reported with ectrodactyly (split hand/split foot malformation) and proximal/intermediate interstitial deletions or rearrangements of 7q. The critical segment for ectrodactyly seems to be located between 7q21.2 and 7q22.1. This malformation is present in 41% of the patients whose deletion involves the critical segment. 37 refs., 3 figs., 1 tab.

  8. De novo proximal interstitial deletions of 14q: Cytogenetic and molecular investigations

    SciTech Connect

    Shapira, S.K.; Anderson, K.L.; Orr-Urtregar, A.; Craigen, W.J.; Lupski, J.R.; Shaffer, L.G.

    1994-08-01

    We report on 2 unrelated patients who had chromosome analysis performed because of psychomotor delay, failure to thrive, and minor anomalies. Each patient had a novel proximal 14q deletion (q11.2 to q21.1 in patient 737 and q12 to q22 in patient 777). Polymorphic (C-A){sub n} microsatellite markers distributed along the length of chromosome 14q were examined in both patients and their parents in order to determine which marker loci were deleted. The deletion in patient 737 was found to be paternal in origin, based on the analysis of 2 marker loci (D14S54 and D14S70), thus assigning these loci to the deleted interval q11.2 q21.1. Furthermore, 3 loci were not deleted (TCRD, D14S50, and D14S80), suggesting that they are within or proximal to 14q11.2. In the other family (patient 777), none of the markers were fully informative, but the deleted chromosome was determined to be paternally derived based on cytogenetic heteromorphisms. Despite having overlapping proximal 14q deletions, these 2 patients shared few phenotypic similarities except for failure to thrive, micrognathia, and hypoplasia of the corpus callosum. Therefore, a distinct proximal 14q deletion syndrome is not yet apparent. However, the molecular analyses facilitated the localization of several 14q DNA markers to the deletion regions in these 2 patients, while excluding other markers from each deletion. 24 refs., 4 figs.

  9. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

    PubMed

    Aoyama, Yuka; Yamamoto, Toshiyuki; Sakaguchi, Naomi; Ishige, Mika; Tanaka, Toju; Ichihara, Tomoko; Ohara, Katsuaki; Kouzan, Hiroko; Kinosada, Yasutomi; Fukao, Toshiyuki

    2015-06-01

    Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the present study, we initially used PCR with genomic followed by direct sequencing to investigate the molecular genetic basis of HMGCL deficiency in two patients clinically diagnosed with the condition. Although we identified a mutation in each patient, the inheritance patterns of these mutations were not consistent with disease causation. Therefore, we investigated HMGCL using multiplex ligation-dependent probe amplification (MLPA) to determine the copy numbers of all exons. A heterozygous deletion that included exons 2-4 was identified in one of the patients. MLPA revealed that the other patient had two copies for all HMGCL exons. Paternal uniparental isodisomy of chromosome 1 was confirmed in this patient by microarray analysis. These findings indicate that MLPA is useful for the identification of genomic aberrations and mutations other than small-scale nucleotide alterations. To the best of our knowledge, this is the first study describing HMGCL deficiency caused by uniparental disomy. PMID:25872961

  10. Duplication/deletion of chromosome 8p

    SciTech Connect

    Priest, J.H.

    1995-09-11

    The article by Guo et al. provides evidence for deletion of D8S596 loci (assigned to 8p23) in at least some patients with inverted duplications of 8p. Cytogenetic break points forming the inverted duplication are remarkably similar among most of their patients and those reported previously, suggesting a common mechanism for this interesting rearrangement. Why should similar breaks occur in 8p and why is a FISH signal absent in the distal short arm when the ONCOR digoxigenin-labeled probe for loci D8S596 is used? Other studies also indicate that duplication for the region 8p12-p22 is associated with a deletion distal to the duplication itself. 4 refs.

  11. Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene

    SciTech Connect

    Canning, S.; Dryja, T.P. )

    1989-07-01

    The authors found deletions involving the retinoblastoma gene in 12 of 49 tumors from patients with retinoblastoma or osteosarcoma. After mapping the deletion breakpoints, they found that no two breakpoints coincided. Thus, the data do not support the conclusions of others regarding the existence of a hotspot for deletion breakpoints in this gene. In 4 of the tumors, they sequenced 200 base pairs surrounding each deletion breakpoint. Three deletions had termini within pairs of short, direct repeats ranging in size from 4 to 7 base pairs. These results indicate that the slipped mispairing mechanism may predominate in the generation of deletions at this locus. The review of deletion breakpoints at other genetic loci reveals that the nature of the sequences present at deletion breakpoints (short, direct repeats versus middle repetitive elements) varies according to the genetic locus under study.

  12. Constitutional Ip36 deletion in a child with neuroblastoma

    SciTech Connect

    Biegel, J.A.; Zackai, E.H.; Scher, C.D.; Emanuel, B.S. Univ. of Pennsylvania, Philadelphia ); White, P.S.; Marshall, H.N.; Fujimori, Minoru; Brodeur, G.M. )

    1993-01-01

    The authors describe a child with dysmorphic features, as well as developmental and growth delay, who developed neuroblastoma at 5 mo of age. Cytogenetic analysis of blood lymphocytes revealed an interstitial deletion of 1p36.1 [r arrow] 1p36.2, which was apparent only with high-resolution banding. Molecular analysis with a collection of polymorphic DNA probes for 1p confirmed an interstitial deletion involving subbands of 1p36. Deletions of this region are a common finding in neuroblastoma cells from patients with advanced stages of disease. Therefore, these results (a) suggest that constitutional deletion of this region predisposed the patient to the development of neuroblastoma and (b) support the localization of a neuroblastoma tumor-suppressor locus to 1p36. 48 refs., 2 figs.

  13. Genotype-phenotype correlation of 16p13.3 terminal duplication and 22q13.33 deletion: Natural history of a patient and review of the literature.

    PubMed

    Fontes, Marshall I B; Santos, Ana P; Molck, Miriam C; Simioni, Milena; Nascimento, Diogo L L; Andrade, Ana K M; Rosenberg, Carla; Krepischi, Ana C V; Appenzeller, Simone; Monlleó, Isabella L; Gil-da-Silva-Lopes, Vera Lúcia

    2016-03-01

    This article reports a patient with a de novo ∼ 9.32 Mb duplication at 16p13.3 and a ∼ 71 Kb deletion at 22q13.33. The patient was followed from 1 month old to 3 years and 8 months of age and presented typical features of the 16p13.3 duplication syndrome. In addition, the patient presents a portal cavernoma, an alteration rarely reported in this condition. Renal agenesis was detected as additional developmental defect. After genomic array and FISH analysis, the karyotype was 46,XX,ins(22;16)(q13;p13.2p13.3). ish ins(22;16)(RP11-35P16+, RP11-27M24+). arr16p13.2p13.3(85,880-9,413,353)×3 dn arr22q13.33 (51,140,789-51,197,838)×1 dn. The authors provide a comprehensive review of the literature. This approach shed light on the genotype-phenotype correlation.

  14. Deletion of chromosomal region 13q14.3 in childhood acute lymphoblastic leukemia.

    PubMed

    Cavé, H; Avet-Loiseau, H; Devaux, I; Rondeau, G; Boutard, P; Lebrun, E; Méchinaud, F; Vilmer, E; Grandchamp, B

    2001-03-01

    Deletion of the 13q14 chromosomal region is frequent in B cell chronic lymphocytic leukemia (B-CLL) and is believed to inactivate a tumor supressor gene (TSG) next to RB1. We studied microsatellite markers spanning the 13q14 chromosomal region in 138 children with acute lymphoblastic leukemia (ALL). Allelic loss was demonstrated in six cases (4.3%). Deletion did not include RB1 in two cases. In five patients, the deleted region overlapped that described in B-CLL. A sixth patient harbored a smaller deletion, slightly more telomeric than minimal deleted regions reported in B-CLL. Apparent differences in the delineation of the minimal deleted region could be due to the fact that the putative TSG is a very large gene, with some deletions affecting only a part of it. Our present findings suggest that at least some of its exons lie within a region of less than 100 kb more telomeric that previously thought.

  15. Intragenic MBD5 familial deletion variant does not negatively impact MBD5 mRNA expression.

    PubMed

    Mullegama, Sureni V; Elsea, Sarah H

    2014-01-01

    2q23.1 deletion syndrome is characterized by intellectual disability, speech impairment, seizures, disturbed sleep pattern, behavioral problems, and hypotonia. Core features of this syndrome are due to haploinsufficiency of MBD5. Deletions that include coding and noncoding exons show reduced MBD5 mRNA expression. We report a patient with a neurological and behavioral phenotype similar to 2q23.1 deletion syndrome with an inherited intronic deletion in the 5-prime untranslated region of MBD5. Our data show that this patient has normal MBD5 mRNA expression; therefore, this deletion is likely not causative for 2q23.1 deletion syndrome. Overall, it is important to validate intronic deletions for pathogenicity.

  16. Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening: investigation of the effect of the mutant allele.

    PubMed

    Bross, Peter; Frederiksen, Jane B; Bie, Anne S; Hansen, Jakob; Palmfeldt, Johan; Nielsen, Marit N; Duno, Morten; Lund, Allan M; Christensen, Ernst

    2012-09-01

    A patient with suspected glutaric aciduria type 1 (GA-1) was detected by newborn screening. GA-1 is known as an autosomal recessively inherited disease due to defects in the gene coding for glutaryl-CoA dehydrogenase (GCDH), a mitochondrial enzyme involved in the catabolism of the amino acids hydroxylysine, lysine and tryptophan. DNA and cDNA sequencing revealed a 18 bp deletion (c.553_570del18) resulting in deletion of six amino acids (p.Gly185_Ser190del) in one allele and no sequence changes in the other allele. Confirmatory biochemical analysis of blood, urine and cultured fibroblasts from the proband were consistent with a mild biochemical GA-1 phenotype. Recombinant expression of the mutant variant in E. coli showed that the GCDH-(p.Gly185_Ser190del) protein displayed severely decreased assembly into tetramers and enzyme activity. To discover a potential dominant negative effect of the mutant protein, we engineered a prokaryotic expression system in which expression of a wild type and a mutant GCDH allele is controlled by separately inducible promoters. These cells displayed decreased levels of GCDH tetramer and enzyme activity when expressing both the wild type and the mutant GCDH variant protein compared to the situation when only the wild type allele was expressed. Further experiments suggest that the major impact of the GCDH-(p.Gly185_Ser190del) protein in heterozygous cells consists of hampering the assembly of wild type GCDH into tetramers. Our experimental data are consistent with the hypothesis that heterozygosity for this mutation confers a dominant negative effect resulting in a GCDH enzyme activity that is significantly lower than the expected 50%.

  17. Xp22. 3 deletions in isolated familial Kallmann's syndrome

    SciTech Connect

    Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. ); Young, J.; Pholsena, M.; Schaison, G. ); Kirk, J.; Bouloux, P. )

    1993-04-01

    Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

  18. Clinical and cytogenetic aspects of X-chromosome deletions.

    PubMed

    Goldman, B; Polani, P E; Daker, M G; Angell, R R

    1982-01-01

    Karyotype/phenotype correlations in six non-mosaic patients with dysgenetic ovaries and partial deletions of the X-chromosome (three patients with short arm, and three with long arm deletions) are presented and the pertinent literature is analysed. It would appear that functioning ovarian tissue is present more often in patients with a short arm deletion than in those with a deleted long arm. This may represent a difference in the strength of two sets of controlling factors, but it can also be related to break point position. This in turn may be misinterpreted due to the difficulty in distinguishing between terminal and interstitial deletions in the long arm. Stature may be a heterochromatic effect, but if specific genetic factors influencing stature exist, then they would appear to be situated mostly on the short arm of the X-chromosome, although some 'statural determinants' occur also on the long arm and could be located rather close to the centromere. Deletions of the short arm of the X-chromosome were almost always associated with some features of the Turner phenotype, and could possibly be related to a gene dosage effect.

  19. Two 22q telomere deletions serendipitously detected by FISH.

    PubMed

    Precht, K S; Lese, C M; Spiro, R P; Huttenlocher, P R; Johnston, K M; Baker, J C; Christian, S L; Kittikamron, K; Ledbetter, D H

    1998-11-01

    Cryptic telomere deletions have been proposed to be a significant cause of idiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (approximately 2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currently documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use of telomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantly higher detection rate of subtelomeric rearrangements.

  20. Nine de novo duplications affecting both maternal and paternal chromosomes and an inherited 15q11.2 deletion, in a patient with developmental delay

    PubMed Central

    Tayeh, Marwan K; Rocco, Tracy; Ackley, Todd; Ernst, Leslie; Glover, Thomas; Innis, Jeffrey W

    2015-01-01

    Key Clinical Message A patient with developmental delay and nine, de novo, tandem duplications affecting eight different chromosomes that arose on both maternal and paternal chromosomes indicating a vulnerable zygotic or early postzygotic period of development for these errors, potentially affected by genetic and nongenetic factors. PMID:26185636

  1. Uveitis in DiGeorge syndrome: a case of autoimmune ocular inflammation in a patient with deletion 22q11.2

    PubMed Central

    Gottlieb, Chloe; Li, Zhuqing; Uzel, Gulbu; Nussenblatt, Robert B; Sen, H Nida

    2010-01-01

    Purpose Del22q11.2, also known as DiGeorge syndrome, has a spectrum of ocular, facial and systemic features. Despite features of T cell dysfunction, infection and autoimmunity (including juvenile idiopathic arthritis), uveitis has not been described in patients with DiGeorge syndrome. Methods We describe a case of a 25-year-old male with bilateral granulomatous panuveitis who after initial investigation and treatment for an infectious cause was determined to have autoimmune-related uveitis with evidence on clinical, laboratory and imaging assessments suggestive of ocular sarcoidosis. Results The patient was found to have a normal T cell count and T cell proliferative response that was compared to a control patient, and phenotypes determined by flow cytometry were normal. However, the CD4/CD8 ratio in this patient was slightly lower than normal and the number of CD28 negative T cells, in both CD4 and CD8 populations, were significantly higher than a control. Conclusions The significance of these T cell abnormalities is unknown in the context of this patient’s uveitis but is suggestive of a role in autoimmunity, which is a known phenomenon in del22q11.2 syndrome, although autoimmune-related uveitis is not a previously described feature. PMID:20141355

  2. More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

    SciTech Connect

    1995-11-06

    This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

  3. Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region

    SciTech Connect

    Michaelis, R.C.; Skinner, S.A.; Lethco, B.A.

    1995-01-02

    Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and The D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. 28 refs., 6 figs.

  4. Clinicopathological and Targeted Exome Gene Features of a Patient with Metastatic Acinic Cell Carcinoma of the Parotid Gland Harboring an ARID2 Nonsense Mutation and CDKN2A/B Deletion

    PubMed Central

    Warner, Wayne A.; Wong, Deborah J.; Palma-Diaz, Fernando; Shibuya, Terry Y.; Momand, Jamil

    2015-01-01

    We describe the presentation, treatment, clinical outcome, and targeted genome analysis of a metastatic salivary acinic cell carcinoma (AciCC). A 71-year-old male presented with a 3 cm right tail of a parotid lesion, first detected as a nodule by the patient seven months earlier. He had a right total parotidectomy with cranial nerve VII resection, right facial nerve resection and grafting, resection of the right conchal cartilage, and right modified radical neck dissection. The primary tumor revealed AciCC with two distinct areas: a well-differentiated component with glandular architecture and a dedifferentiated component with infiltrative growth pattern associated with prominent stromal response, necrosis, perineural invasion, and cellular pleomorphism. Tumor staging was pT4 N0 MX. Immunohistochemistry staining showed pankeratin (+), CD56 (−), and a Ki67 proliferation index of 15%. Upon microscopic inspection, 49 local lymph nodes resected during parotidectomy were negative for cancer cells. Targeted sequencing of the primary tumor revealed deletions of CDKN2A and CDKN2B, a nonsense mutation in ARID2, and single missense mutations of unknown significance in nine other genes. Despite postoperative localized radiation treatment, follow-up whole body PET/CT scan showed lung, soft tissue, bone, and liver metastases. The patient expired 9 months after resection of the primary tumor. PMID:26634163

  5. Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy

    SciTech Connect

    Bianchi, Marzia; Rizza, Teresa; Verrigni, Daniela; Martinelli, Diego; Tozzi, Giulia; Torraco, Alessandra; Piemonte, Fiorella; Dionisi-Vici, Carlo; Nobili, Valerio; Francalanci, Paola; Boldrini, Renata; Callea, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; and others

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Expanded array of mtDNA deletions. Black-Right-Pointing-Pointer Pearson syndrome with prominent hepatopathy associated with single mtDNA deletions. Black-Right-Pointing-Pointer Detection of deletions in fibroblasts and blood avoids muscle and liver biopsy. Black-Right-Pointing-Pointer Look for mtDNA deletions before to study nuclear genes related to mtDNA depletion. -- Abstract: Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.

  6. Characterization of a lymphoblastoid line deleted for lambda immunoglobulin genes

    SciTech Connect

    Hough, C.A., White, B.N., Holden, J.A.

    1995-04-01

    While characterizing the cat eye syndrome (CES) supernumerary chromosome for the presence of {lambda} immunoglobulin gene region sequences, a lymphoblastoid cell line from one CES patient was identified in which there was selection of cells deleted from some IGLC and IGLV genes. Two distinct deletions, one on each chromosome 22, were identified, presumably arising from independent somatic recombination events occurring during B-lymphocyte differentiation. The extent of the deleted regions was determined using probes from the various IGLV subgroups and they each covered at least 82 kilobases. The precise definition of the deletions was not possible because of conservation of some restriction sites in the IGLV region. The cell line was used to map putative IGLV genes within the recombinant phage {lambda}V{lambda}135 to the distal part of the IGLV gene region. 35 refs., 4 figs.

  7. Interstitial deletion of 13q associated with polymicrogyria.

    PubMed

    Kogan, Jillene M; Egelhoff, John C; Saal, Howard M

    2008-04-01

    Interstitial deletion of the long arm of chromosome 13 is a rare condition characterized by multiple clinical findings. We report a male dizygotic twin with an interstitial deletion of 13q and failure to thrive, hypotonia, polymicrogyria, bilateral foci of retinoblastoma, hearing loss, bilateral inguinal hernias, submucous cleft palate, and dysmorphic features including a triangular shaped face, broad forehead, small chin, prominent eyes, downslanting palpebral fissures, and a downturned mouth. Chromosome analysis showed an interstitial deletion of chromosome 13 which was confirmed by fluorescence in situ hybridization analysis to include the Rb locus, but spare the 13q subtelomeric region. The karyotype was 46,XY,del(13)(q14.1q31.2).ish del(13)(RB1-,D13S327+) de novo. Breakpoints were further characterized by SNP-based microarray. Retinoblastoma tumors are a well-known complication of deletion of the retinoblastoma susceptibility gene, located at chromosome 13q14.2. Growth retardation is another common feature that has been described in other patients with a deletion of 13q. Additionally, this patient had brain findings on MRI consistent with bilateral polymicrogyria with predominance of the frontal lobes, as well as prominent infratentorial and supratentorial vasculature. There are a variety of polymicrogyria syndromes that are distinguished by the cortical location of the abnormal folding. Several of the subtypes have known genetic loci associated with them. To our knowledge, this is the only report of polymicrogyria in association with a deletion of chromosome 13.

  8. Mitochondrial DNA deletions serve as biomarkers of aging in the skin, but are typically absent in nonmelanoma skin cancers.

    PubMed

    Eshaghian, Alex; Vleugels, Ruth A; Canter, Jeffrey A; McDonald, Michel A; Stasko, Thomas; Sligh, James E

    2006-02-01

    The potential role of mitochondrial DNA (mtDNA) deletions in nonmelanoma skin cancer (NMSC) and in cutaneous photoaging was explored using a genetic approach. Tumors and photodamaged tumor-free "margin" skin were obtained from NMSC patients undergoing excision and the mtDNA from these specimens was screened for the presence of deletions using long extension PCR. mtDNA deletions were abundant in margin tissue specimens from older patients and their number correlated with the patient age. There was a statistically significant difference between the number of mtDNA deletions in tumors and margins. Fewer deletions were detected in the tumors than the margins and the tumors often had no deletions, implying a potential selection for full-length mtDNA or perhaps a protective role for mtDNA deletions in the process of tumorigenesis. The observed mtDNA deletions from skin were often unreported (19 of 21 deletions), but typically shared structural features with mtDNA deletions reported in other tissues. Some mtDNA deletions were detected from the skin of multiple individuals, including 3,715 and 6,278-base pair (bp) deletions, whose frequencies approached that of the previously well-characterized 4977-bp "common" deletion. These data support the use of mtDNA mutations as biomarkers of photoaging in the skin.

  9. Deletion pattern in the dystrophin gene in Turks and a comparison with Europeans and Indians.

    PubMed

    Onengüt, S; Kavaslar, G N; Battaloğlu, E; Serdaroğlu, P; Deymeer, F; Ozdemir, C; Calafell, F; Tolun, A

    2000-01-01

    Patterns of dystrophin gene deletions in DMD/BMD patients were compared in four populations: Turks (n = 146 deletions), Europeans (n = 838), North Indians (n = 89), and Indians from all over India (n = 103). Statistical tests revealed that there are differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the four populations are not significantly different. The variations strongly suggest that sequence differences exist in the introns, and the differences are in agreement with genetic distances among populations. The similarities suggest that some intronic sequences have been conserved and that those will trigger recurrent deletions, since it is unlikely that gene flow would disperse the deleted chromosomes, which vanish from the gene pool in a few generations.

  10. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.

    PubMed

    Clappier, E; Grardel, N; Bakkus, M; Rapion, J; De Moerloose, B; Kastner, P; Caye, A; Vivent, J; Costa, V; Ferster, A; Lutz, P; Mazingue, F; Millot, F; Plantaz, D; Plat, G; Plouvier, E; Poirée, M; Sirvent, N; Uyttebroeck, A; Yakouben, K; Girard, S; Dastugue, N; Suciu, S; Benoit, Y; Bertrand, Y; Cavé, H

    2015-11-01

    The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.

  11. Anal atresia, coloboma, microphthalmia, and nasal skin tag in a female patient with 3.5 Mb deletion of 3q26 encompassing SOX2.

    PubMed

    Salem, Nabeel J M; Hempel, Maja; Heiliger, Katrin-Janine; Hosie, Stuart; Meitinger, Thomas; Oexle, Konrad

    2013-06-01

    A full term female newborn presented with prominent forehead, bilateral microphthalmia, iris coloboma and cataract, wide intercanthal distance, large, low-set and protruding ears, skin tag at the left nasal nostril, imperforate anus with rectovestibular fistula, and postnatal growth delay with brachymicrocephaly. A marker chromosome was not detectable and the copy number of 22q11 was normal. However, array CGH revealed a 3.5 Mb microdeletion of chromosome region 3q26.32-3q26.33 (chr. 3: 178,598,162-182,114,483; hg19) which comprised the SOX2 gene. While SOX2 haploinsufficiency is known to cause microphthalmia and coloboma, it has not been described before in patients with anal atresia.

  12. Prevalence of β(S)-globin gene haplotypes, α-thalassemia (3.7 kb deletion) and redox status in patients with sickle cell anemia in the state of Paraná, Brazil.

    PubMed

    Shimauti, Eliana LitsukoTomimatsu; Silva, Danilo Grunig Humberto; de Souza, Eniuce Menezes; de Almeida, Eduardo Alves; Leal, Francismar Prestes; Bonini-Domingos, Claudia Regina

    2015-01-01

    The aim of this study was to determine the frequency of beta S-globin gene (β(S) globin) haplotypes and alpha thalassemia with 3.7 kb deletion (-α(3.7kb) thalassemia) in the northwest region of Paraná state, and to investigate the oxidative and clinical-hematological profile of β(S) globin carriers in this population. Of the 77 samples analyzed, 17 were Hb SS, 30 were Hb AS and 30 were Hb AA. The β(S)globin haplotypes and -α(3.7kb) thalassemia were identified using polymerase chain reaction.Trolox equivalent antioxidant capacity (TEAC) and lipid peroxidation (LPO) were assessed spectophotometrically. Serum melatonin levels were determined using high-performance liquid chromatography coupled to coulometric electrochemical detection. The haplotype frequencies in the SS individuals were as follows: Bantu- 21 (62%), Benin - 11 (32%) and Atypical- 2 (6%). Bantu/Benin was the most frequent genotype. Of the 47 SS and AS individuals assessed, 17% (n = 8) had the -α(3.7kb) mutation. Clinical manifestations, as well as serum melatonin, TEAC and LPO levels did not differ between Bantu/Bantu and Bantu/Benin individuals (p > 0.05). Both genotypes were associated with high LPO and TEAC levels and decreased melatonin concentration. These data suggest that the level of oxidative stress in patients with Bantu/Bantu and Bantu/Benin genotypes may overload the antioxidant capacity. PMID:26500435

  13. Transmitted deletions of medial 5p and learning difficulties; does the cadherin cluster only become penetrant when flanking genes are deleted?

    PubMed

    Barber, John C K; Huang, Shuwen; Bateman, Mark S; Collins, Amanda L

    2011-11-01

    The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family. PMID:21965044

  14. Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome

    SciTech Connect

    Gandelman, K.Y.; Gibson, L.; Meyn, M.S.; Yang-Feng, T.L. )

    1992-09-01

    Wolf-Hirschhorn syndrome (WHS), associated with a deletion of chromosome 4p, is characterized by mental and growth retardation and typical dysmorphism. A girl with clinical features of WHS was found to carry a subtle deletion of chromosome 4p. Initially suggested by high-resolution chromosome analysis, her deletion was confirmed by fluorescence in situ hybridization (FISH) with cosmid probes, E13, and Y2, of D4S113. To delineate this 4p deletion, the authors performed a series of FISH and pulsed-field gel electrophoresis analysis by using probes from 4p16.3. A deletion of [approximately]2.5 Mb with the breakpoint at [approximately]80 kb distal to D4S43 was defined in this patient and appears to be the smallest WHS deletion so far identified. To further refine the WHS critical region, they have studied three unrelated patients with presumptive 4p deletions, two resulting from unbalanced segregations of parental chromosomal translocations and one resulting from an apparently de novo unbalanced translocation. Larger deletions were identified in two patients with WHS. One patient who did not clinically present with WHS had a smaller deletion that thus eliminates the distal 100-300 kb from the telomere as being part of the WHS region. This study has localized the WHS region to [approximately]2 MB between D4S43 and D4S142. 37 refs., 4 figs., 1 tab.

  15. Deletion of small nuclear ribonucleoprotein polypeptide N (SNRPN) in Prader-Willi syndrome detected by fluorescence in situ hybridization: Two sibs with the typical phenotype without a cytogenetic deletion in chromosome 15q

    SciTech Connect

    Ishikawa, Tatsuya; Kibe, Tetsuya; Wada, Yoshiro

    1996-04-24

    The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene is regarded as one of the candidates for Prader-Willi syndrome (PWS). We describe two sibs with typical PWS presenting deletion of SNRPN detected by fluorescence in situ hybridization (FISH). Neither a cytogenetically detectable 15q12 deletion nor a deletion for the D15S11, D15S10, and GABRB3 cosmid probes were found in either patient. This implies a smaller deletion limited to the PWS critical region. FISH with a SNRPN probe will permit analysis of PWS patients with limited deletions not detectable with other probes. 22 refs., 1 fig.

  16. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

    PubMed Central

    Fernández, Luis; Nevado, Julián; Santos, Fernando; Heine-Suñer, Damià; Martinez-Glez, Victor; García-Miñaur, Sixto; Palomo, Rebeca; Delicado, Alicia; Pajares, Isidora López; Palomares, María; García-Guereta, Luis; Valverde, Eva; Hawkins, Federico; Lapunzina, Pablo

    2009-01-01

    Background Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date. Methods We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents. Results Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping. Conclusion The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors. PMID

  17. Mosaic 7q31 deletion involving FOXP2 gene associated with language impairment.

    PubMed

    Palka, Chiara; Alfonsi, Melissa; Mohn, Angelika; Cerbo, Renato; Guanciali Franchi, Paolo; Fantasia, Donatella; Morizio, Elisena; Stuppia, Liborio; Calabrese, Giuseppe; Zori, Roberto; Chiarelli, Francesco; Palka, Giandomenico

    2012-01-01

    We report on a 10-year-old patient with childhood apraxia of speech (CAS) and mild dysmorphic features. Although multiple karyotypes were reported as normal, a bacterial artificial chromosome array comparative genomic hybridization revealed the presence of a de novo 14.8-Mb mosaic deletion of chromosome 7q31. The deleted region involved several genes, including FOXP2, which has been associated with CAS. Interestingly, the deletion reported here was observed in about 50% of cells, which is the first case of mosaicism in a 7q31 deletion. Despite the presence of the deletion in only 50% of cells, the phenotype of the patient was not milder than other published cases. To date, 6 cases with a deletion of 9.1-20 Mb involving the FOXP2 gene have been reported, suggesting a new contiguous gene deletion syndrome characterized mainly by CAS caused by haploinsufficiency of the genes encompassed in the 7q critical region. This report suggests that children found with a deletion involving the FOXP2 region should be evaluated for CAS and that analysis of the FOXP2 gene including array comparative genomic hybridization should be considered in selected patients with CAS. Mosaic deletions in this area may also be considered as causative of CAS.

  18. De novo interstitial deletion q16.2q21 on chromosome 6

    SciTech Connect

    Villa, A.; Urioste, M.; Luisa, M.

    1995-01-30

    A de novo interstitial deletion of 6q16.2q21 was observed in a 23-month-old boy with mental and psychomotor delay, obese appearance, minor craniofacial anomalies, and brain anomalies. We compare clinical manifestations of this patient with those observed in previously reported cases with similar 6q interstitial deletions. It is interesting to note the clinical similarities between some patients with interstitial deletions of 6q16 or q21 bands and patients with Prader-Willi syndrome (PWS) and it may help to keep in mind cytogenetic studies of patients with some PWS findings. 24 refs., 3 figs., 2 tabs.

  19. DPY19L2 Deletion as a Major Cause of Globozoospermia

    PubMed Central

    Koscinski, Isabelle; ElInati, Elias; Fossard, Camille; Redin, Claire; Muller, Jean; Velez de la Calle, Juan; Schmitt, Françoise; Ben Khelifa, Mariem; Ray, Pierre; Kilani, Zaid; Barratt, Christopher L.R.; Viville, Stéphane

    2011-01-01

    Globozoospermia, characterized by round-headed spermatozoa, is a rare (< 0.1% in male infertile patients) and severe teratozoospermia consisting primarily of spermatozoa lacking an acrosome. Studying a Jordanian consanguineous family in which five brothers were diagnosed with complete globozoospermia, we showed that the four out of five analyzed infertile brothers carried a homozygous deletion of 200 kb on chromosome 12 encompassing only DPY19L2. Very similar deletions were found in three additional unrelated patients, suggesting that DPY19L2 deletion is a major cause of globozoospermia, given that 19% (4 of 21) of the analyzed patients had such deletion. The deletion is most probably due to a nonallelic homologous recombination (NAHR), because the gene is surrounded by two low copy repeats (LCRs). We found DPY19L2 deletion in patients from three different origins and two different breakpoints, strongly suggesting that the deletion results from recurrent events linked to the specific architectural feature of this locus rather than from a founder effect, without fully excluding a recent founder effect. DPY19L2 is associated with a complete form of globozoospermia, as is the case for the first two genes found to be associated with globozoospermia, SPATA16 or PICK1. However, in contrast to SPATA16, for which no pregnancy was reported, pregnancies were achieved, via intracytoplasmic sperm injection, for two patients with DPY19L2 deletion, who then fathered three children. PMID:21397063

  20. Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting.

    PubMed

    Williams, C A; Zori, R T; Stone, J W; Gray, B A; Cantu, E S; Ostrer, H

    1990-03-01

    Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.

  1. Novel mutation-deletion in the PHOX2B gene of the patient diagnosed with Neuroblastoma, Hirschsprung’s Disease, and Congenital Central Hypoventilation Syndrome (NB-HSCR-CCHS) Cluster

    PubMed Central

    Szymońska, Izabela; Borgenvik, Thore Langfeldt; Karlsvik, Tina Margrethe; Halsen, Anders; Malecki, Bianka Kathryn; Saetre, Sindre Ervik; Jagła, Mateusz; Kruczek, Piotr; Talowska, Anna Madetko; Drabik, Grażyna; Zasada, Magdalena; Malecki, Marek

    2015-01-01

    Introduction Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, are genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12. Specific Aim The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster. Patient A one day old male patient presented to the Jagiellonian University Medical College (JUMC), American Children Hospital, neonatal Intensive Care Unit (ICU) due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child’s parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient’s Guardian Informed Consent and the approval from the Institutional Review Board. Genetic/Genomic Methods Karyotyping was analyzed based upon Giemsa banding. The patient’s genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests. Results G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides: c.699–706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product. Conclusion Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCR-CCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of

  2. Genetics Home Reference: 18q deletion syndrome

    MedlinePlus

    ... Veltman JA, van Ravenswaaij-Arts CM. Genotype-phenotype mapping of chromosome 18q deletions by high-resolution array ... L, Pihko H. 18q deletions: clinical, molecular, and brain MRI findings of 14 individuals. Am J Med ...

  3. Schizophrenia in an Adult With 6p25 Deletion Syndrome

    PubMed Central

    Caluseriu, O.; Mirza, G.; Ragoussis, J.; Chow, E.W.C.; MacCrimmon, D.; Bassett, A.S.

    2011-01-01

    Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld–Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation. PMID:16642507

  4. Genetic Counseling for the 22q11.2 Deletion

    ERIC Educational Resources Information Center

    McDonald-McGinn, Donna M.; Zackai, Elaine H.

    2008-01-01

    Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

  5. [Multiplex PCR for detecting genotypes of deletional alpha-thalassemia].

    PubMed

    Wu, Jie-Ying; Liao, Can; Li, Jian; Huang, Yi-Ning

    2004-08-01

    To investigate the clinical application of multiplex PCR in detecting genotypes of deletional alpha-thalassemia in South China and observe the distribution frequency of alpha-globin gene deletion, 145 patients with silent carrier, alpha thalassemia trait or HbH were identified by M-PCR and 1.2% agarose gel electrophoresis. There are 1.3, 1.6, 1.8 and 2.0 kb bands which indicate --(SEA), -alpha(4.2), alphaalpha and -alpha(3.7), respectively. The results showed that among 145 patients, 100 patients with --(SEA)/alphaalpha (68.9%), 15 with -alpha(3.7)/alphaalpha (10.3%), 8 with -alpha(4.2)/alphaalpha (5.52%), 2 with -alpha(3.7)/-alpha(4.2) (1.38%), 1 with -alpha(3.7)/-alpha(3.7) (0.69%), 1 with -alpha(4.2)/-alpha(4.2) (0.69%), 14 with --(SEA)/-alpha(3.7) (9.65%), 2 with --(SEA)/-alpha(4.2) (1.38%) were found. Two patients prenatal diagnosed were confirmed with Bart's hydrops fetuses. In conclusion, M-PCR analysis is a simple, rapid and accurate method for detection of alpha-thalassemia gene deletion. This technique is helpful in screening, carrier identification and prenatal diagnosis of deletional alpha-thalassemia.

  6. Compound heterozygous PMP22 deletion mutations causing severe Charcot-Marie-Tooth disease type 1.

    PubMed

    Abe, Akiko; Nakamura, Kazuyuki; Kato, Mitsuhiro; Numakura, Chikahiko; Honma, Tomomi; Seiwa, Chizuru; Shirahata, Emi; Itoh, Aiko; Kishikawa, Yumiko; Hayasaka, Kiyoshi

    2010-11-01

    We present a 3⅓-year-old girl with severe Charcot-Marie-Tooth disease type 1 (Dejerine-Sottas disease), who was a compound heterozygote carrying a deletion of the whole peripheral myelin protein 22 (PMP22) and a deletion of exon 5 in the other PMP22 allele. Haplotype analyses and sequence determination revealed a 11.2 kb deletion spanning from intron 4 to 3'-region of PMP22, which was likely generated by nonhomologous end joining. Severely affected patients carrying a PMP22 deletion must be analyzed for the mutations of the other copy of PMP22. PMID:20739940

  7. Mucopolysaccharidosis type IVA: Common double deletion in the N-Acetylgalactosamine-6-sulfatase gene (GALNS)

    SciTech Connect

    Hori, Toshinori; Tomatsu, Shunji; Fukuda, Seiji

    1995-04-10

    Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase (GALNS). We found two separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene, including some exons. There are Alu repetitive elements near the breakpoints of the 8.0-kb deletion, and this deletion resulted from an Alu-Alu recombination. The other 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at deletion breakpoints. The same rearrangement has been observed in a heteroallelic state in four unrelated patients. This is the first documentation of a common double deletion a gene that is not a member of a gene cluster. 39 refs., 5 figs.

  8. Cardiac Defects and Results of Cardiac Surgery in 22q11.2 Deletion Syndrome

    ERIC Educational Resources Information Center

    Carotti, Adriano; Digilio, Maria Cristina; Piacentini, Gerardo; Saffirio, Claudia; Di Donato, Roberto M.; Marino, Bruno

    2008-01-01

    Specific types and subtypes of cardiac defects have been described in children with 22q11.2 deletion syndrome as well as in other genetic syndromes. The conotruncal heart defects occurring in patients with 22q11.2 deletion syndrome include tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus, interrupted aortic…

  9. A de novo interstitial deletion of chromosome 6 (q22.2q23.1).

    PubMed

    Park, J P; Graham, J M; Berg, S Z; Wurster-Hill, D H

    1988-02-01

    A unique interstitial deletion of the long arm of chromosome 6 involving bands q22.2 and q23.1 was observed in a patient referred for craniostenosis and developmental delay. The associated phenotypic anomalies are compared with other reported cases of deletion 6q involving adjacent regions.

  10. Interstitial deletion of long arm of chromosome 13.

    PubMed

    Carnevale, A; Frias, S; Alcantar, R

    1984-01-01

    The case is presented of a patient with the karyotype 46,XX,del(13q)(pter----q22::q32----qter) confirmed by densitometry and a phenotype of mental and growth deficiency, hypotonia, hypertelorism, ptosis, broad nasal bridge, protruding upper incisors, short neck, dislocation of the hip, hypoplasia of the thumbs, fusion of fourth and fifth metacarpal bones and syndactyly of toes. The findings are compared with those of well documented cases with a similar deleted segment of the long arm of chromosome 13. Although it seems obvious that a clinical syndrome for the distal deletion 13q appears to exist more studies with banded chromosomes are needed. PMID:6609673

  11. 78 FR 46927 - Procurement List; Proposed Deletions

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  16. Somatic mutation analysis of KRAS, BRAF, HER2 and PTEN in EGFR mutation-negative non-small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel deletion in HER2 gene from Indian patients.

    PubMed

    Bhaumik, Sangeet; Ahmad, Firoz; Das, Bibhu Ranjan

    2016-10-01

    Somatic mutations of KRAS, BRAF, HER2, PTEN genes are the most important molecular markers after the EGFR gene mutation. The current study evaluated the frequency and distribution pattern of KRAS, BRAF, HER2, PTEN mutation in Indian non-small cell lung carcinoma patients. The frequency of KRAS, BRAF, HER2, PTEN mutations was 6.4 % (14/204), 1.5 % (3/204), 1.5 % (3/204), 0 % (0/204), respectively. KRAS, BRAF, HER2 mutations were more prevalent in males than in females. KRAS and HER2 showed a trend of a higher frequency of mutation in the age group of <60 years, whereas BRAF mutations were more frequent in the age group of ≥60 years. Sequencing analysis of KRAS gene revealed c.34G>T (G12C) (n = 8), c.35G>A (G12D) (n = 3), c.35G>T (G12 V) (n = 1) and c.34G>T (G12C)/c.41T>C (V14A) (n = 2) mutations. Three different BRAF mutations (L584P: n = 1, V600E: n = 1, K601E: n = 1) were detected. Two cases harboured c.2324_2325ins12 (ATACGTGATGGC duplication) in HER2 gene, and one case was positive for NG_007503.2 (NM_001005862.2):c.2218-4del. It is less certain, but still quite possible that this mutation will affect splicing as the deletion of one C actually brings in one additional purine into the region. In conclusion, the present study demonstrates an instance of diverse nature of KRAS, BRAF, HER2 and PTEN gene in Indian patients and confirms that the frequency of these gene mutations varies globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS, BRAF, HER2 and PTEN gene mutations.

  17. Somatic mutation analysis of KRAS, BRAF, HER2 and PTEN in EGFR mutation-negative non-small cell lung carcinoma: determination of frequency, distribution pattern and identification of novel deletion in HER2 gene from Indian patients.

    PubMed

    Bhaumik, Sangeet; Ahmad, Firoz; Das, Bibhu Ranjan

    2016-10-01

    Somatic mutations of KRAS, BRAF, HER2, PTEN genes are the most important molecular markers after the EGFR gene mutation. The current study evaluated the frequency and distribution pattern of KRAS, BRAF, HER2, PTEN mutation in Indian non-small cell lung carcinoma patients. The frequency of KRAS, BRAF, HER2, PTEN mutations was 6.4 % (14/204), 1.5 % (3/204), 1.5 % (3/204), 0 % (0/204), respectively. KRAS, BRAF, HER2 mutations were more prevalent in males than in females. KRAS and HER2 showed a trend of a higher frequency of mutation in the age group of <60 years, whereas BRAF mutations were more frequent in the age group of ≥60 years. Sequencing analysis of KRAS gene revealed c.34G>T (G12C) (n = 8), c.35G>A (G12D) (n = 3), c.35G>T (G12 V) (n = 1) and c.34G>T (G12C)/c.41T>C (V14A) (n = 2) mutations. Three different BRAF mutations (L584P: n = 1, V600E: n = 1, K601E: n = 1) were detected. Two cases harboured c.2324_2325ins12 (ATACGTGATGGC duplication) in HER2 gene, and one case was positive for NG_007503.2 (NM_001005862.2):c.2218-4del. It is less certain, but still quite possible that this mutation will affect splicing as the deletion of one C actually brings in one additional purine into the region. In conclusion, the present study demonstrates an instance of diverse nature of KRAS, BRAF, HER2 and PTEN gene in Indian patients and confirms that the frequency of these gene mutations varies globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS, BRAF, HER2 and PTEN gene mutations. PMID:27637917

  18. Molecular dissection of the 5q deletion in myelodysplastic syndrome

    PubMed Central

    Ebert, Benjamin L.

    2011-01-01

    The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of Chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haploinsufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q- syndrome. The megakaryocytic and platelet phenotype of the 5q- syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of Chromosome 5q is due to haploinsufficiency of multiple genes. PMID:21943668

  19. 5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease.

    PubMed

    Ilari, Rita; Agosta, Guillermo; Bacino, Carlos

    2016-03-01

    We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder.

  20. Deletion mapping indicates that MTS1 is the target of frequent deletions at chromosome 9p21 in paediatric acute lymphoblastic leukaemias.

    PubMed

    Guidal-Giroux, C; Gérard, B; Cavé, H; Duval, M; Rohrlich, P; Elion, J; Vilmer, E; Grandchamp, B

    1996-02-01

    Recent reports have indicated a high frequency of deletions of MTS1 (CDKN2, p16ink4, CDKI4) in acute lymphoblastic leukaemias (ALLs). This gene is located at chromosome 9p21 and encodes an inhibitor of cyclin D-dependent kinases. In contrast with the observations in some other malignancies, no inactivation of MTS1 by intragenic mutation was demonstrated in leukaemias. A contribution of MTS1 alterations to leukaemogenesis therefore remains questionable. In order to test for the implication of MTS1 as a tumour suppressor gene in paediatric ALLs we have explored the 9p21 chromosomal region of 46 children with this disease. The copy number of the MTS1 gene in blasts from the patients was determined using a quantitative PCR assay enabling us to precisely detect mono- and bi-allelic deletions. Rearrangements of the gene were sought by Southern blot analysis. The extent of the deletions was studied using microsatellite markers spanning the 9p21 chromosomal region. Point mutations were sought in exon 1 and exon 2 of the MTS1 gene in patients with a mono-allelic deletion in addition, exon 2 of MTS1, which contains two-thirds of the coding region, was sequenced in all patients who had no deletion of the gene. Altogether, our data are consistent with the view that MTS1 is the target of 9p21 deletions. Either one or two alleles of the gene were deleted in 36% of non-selected children with B-lineage ALL and both alleles were deleted in all seven patients we studied with T-lineage ALL. The absence of any point mutation implies that the major mechanism of inactivation of MTS1 in ALLs is deletional.

  1. Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: Multiple-exon skipping as a secondary effect of the mutations

    SciTech Connect

    Fisher, C.W.; Fisher, C.R.; Chuang, J.L.; Lau, K.S.; Chuang, D.T.; Cox, R.P. )

    1993-02-01

    The authors have identified two novel mutant alleles in the transacylase (E2) gene of the human branched-chain [alpha]-keto acid dehydrogenase (BCKAD) complex in 6 of 38 patients with maple syrup urine disease (MSUD). One mutation, a 2-bp (AT) deletion in exon 2 of the E2 gene, causes a frameshift downstream of residue ([minus]26) in the mitochondrial targeting presequence. The second mutation, a G-to-T transversion in exon 6 of the E2 gene, produces a premature stop codon at Glu-163 (E163*). Transfection of constructs harboring the E163* mutation into an E2-deficient MSUD cell line produced a truncated E2 subunit. However, this mutant E2 chain is unable to assemble into a 24-mer cubic structure and is degraded in the cell. The 2-bp (AT) deletion and the E163* mutant alleles occur in either the homozygous or compound-heterozygous state in the 6 of 38 unrelated MSUD patients studied. Moreover, an array of precise single- and multiple-exon deletions were observed in many amplified E2 mutant cDNAs. The latter results appear to represent secondary effects on RNA processing that are associated with the MSUD mutations at the E2 locus. 30 refs., 8 figs.

  2. Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia

    PubMed Central

    Deeb, Kristin K.; Smonskey, Matthew T.; DeFedericis, HanChun; Deeb, George; Sait, Sheila N.J.; Wetzler, Meir; Wang, Eunice S.; Starostik, Petr

    2014-01-01

    In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations. PMID:25379410

  3. Mini-Review: Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes.

    PubMed

    Rocha, C F; Vasques, R B; Santos, S R; Paiva, C L A

    2016-01-01

    The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of this study was to review the cases of 1p36 deletion that was reported between 1999 and 2014, in order to identify a possible correlation between the size of the 1p36-deleted segment and the clinical phenotype of the disease. Scientific articles published in the (National Center for Biotechnology Information; NCBI http://www.ncbi.nlm.nih.gov/pubmed) and Scientific Electronic Library Online (www.scielo.com.br) databases were searched using key word combinations, such as "1p36 deletion", "monosomy 1p36 deletion", and "1p36 deletion syndrome". Articles in English or Spanish reporting the correlation between deletion sizes and the respective clinical phenotypes were retrieved, while letters, reviews, guidelines, and studies with mouse models were excluded. Among the 746 retrieved articles, only 17 (12 case reports and 5 series of cases), comprising 29 patients (9 males and 20 females, aged 0 months (neonate) to 22 years) bearing the 1p36 deletions and whose clinical phenotypes were described, met the inclusion criteria. The genotype-phenotype correlation in monosomy 1p36 is a challenge because of the variability in the size of the deleted segment, as well as in the clinical manifestations of similar size deletions. Therefore, the severity of the clinical features was not always associated with the deletion size, possibly because of the other influences, such as stochastic factors, epigenetic events, or reduced penetration of the deleted genes.

  4. Interstitial deletions 4q21.1q25 and 4q25q27: Phenotypic variability and relation to Rieger anomaly

    SciTech Connect

    Kulharya, A.S.; Schneider, N.R.; Tonk, V.

    1995-01-16

    We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region. 15 refs., 4 figs., 1 tab.

  5. Further delineation of the chromosome 14q terminal deletion syndrome.

    PubMed

    van Karnebeek, Clara D M; Quik, Safira; Sluijter, Sigrid; Hulsbeek, Miriam M F; Hoovers, Jan M N; Hennekam, Raoul C M

    2002-06-01

    A patient with hypotonia, blepharophimosis, ptosis, a bulbous nose, a long philtrum, upturned corners of the mouth, and mild developmental delay was found to have a small subtelomeric deletion of the long arm of chromosome 14 (q32.31-qter). In comparing her phenotype with previously reported patients with similar 14q deletions, due to either a linear deletion or to a ring chromosome 14, a clinically recognizable terminal 14q microdeletion syndrome was evident. Due to the limited number of cases reported, it was not possible to assign specific features to specific regions of terminal 14q. The comparison of features in cases with a linear deletion of 14qter (n = 19) to those in cases with a deletion due to a ring chromosome 14 (n = 23), both with the same breakpoint in 14q, showed that seizures and retinitis pigmentosa have been found only in patients with ring chromosomes. Several hypotheses are put forward to explain this difference: mitotic instability of ring chromosomes; a telomere position effect in ring chromosomes in which the 14p telomere silences nearby gene(s) on the q-arm; and dose-dependent gene(s) involved in seizures and retinitis pigmentosa located on the short arm of chromosome 14. In our opinion, only seizures may be explained by the mitotic instability of ring chromosomes, while both seizures and retinitis pigmentosa may be explained by silencing of gene(s) on 14q by the 14p telomere; the third hypothesis seems unlikely to explain either symptom.

  6. Investigation of TBX1 gene deletion in Iranian children with 22q11.2 deletion syndrome: correlation with conotruncal heart defects

    PubMed Central

    Ganji, Hamid; Salehi, Mansoor; Sedghi, Maryam; Abdali, Hossein; Nouri, Nayereh; Sadri, Leyli; Hosseinzadeh, Majid; Vakili, Bahareh; Lotfi, Mahdi

    2013-01-01

    Background DiGeorge syndrome (DGS) is the result of a microdeletion in chromosome 22q11.2 in over 90% of cases. DGS is the second most frequent syndrome after Down syndrome and has an incidence of 1/4000 births. Unequal crossover between low-copy repeats, on the proximal part of the long arm of chromosome 22, usually results in a 3 Mb deletion in one of the chromosome 22 and a reciprocal and similarly sized duplication on the other one. Several studies have indicated that TBX1 (T-box 1) haploinsufficiency is responsible for many of the phenotypic traits of 22q11.2 deletion syndrome. Conotruncal heart defects (CTDs) are present in 75–85% of patients with 22q11.2 deletion syndrome in Western countries. Methods Among 78 patients fulfilling the criteria for DGS diagnosed by the fluorescence in situ hybridisation test, 24 had 22q11.2 deletion. Screening for TBX1 gene deletion was performed by multiplex ligation-dependent probe amplification (MLPA). Results Our results revealed that of 24 patients with TBX1 gene deletion, 12 had CTDs while 12 did not show any heart defects. Conclusions Our findings indicate that other genes or gene interactions may play a role in penetrance or the severity of heart disease among patients with DGS. PMID:27326128

  7. Distinct phenotype of PHF6 deletions in females.

    PubMed

    Di Donato, N; Isidor, B; Lopez Cazaux, S; Le Caignec, C; Klink, B; Kraus, C; Schrock, E; Hackmann, K

    2014-02-01

    We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation.

  8. L1CAM whole gene deletion in a child with L1 syndrome.

    PubMed

    Chidsey, Brandalyn A; Baldwin, Erin E; Toydemir, Reha; Ahles, Lauren; Hanson, Heather; Stevenson, David A

    2014-06-01

    L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2. PMID:24668863

  9. Comparison of female and male interstitial deletions in the distal Xq

    SciTech Connect

    Schmidt, M.

    1996-07-12

    We reviewed female interstitial deletions in the distal Xq and compared them to those reported in males. Most of the deletions were common to females and males, and they were scattered within Xq27 and proximal Xq. Six females had large deletions of 1-10 Mb which formed a contig covering {approximately}13 Mb within Xq27.1{r_arrow}proximal Xq28. In 3 of these patients the deleted X chromosome was preferentially active, and the phenotype was abnormal (mental retardation in the patient of Schmidt et al.; mental retardation and Hunter syndrome in the patient of Clarke et al.; and mental retardation and myotubular myopathy in the patient of Dahl et al.) All three deletions occurred de novo. Our previous analysis of these deletions showed no abnormalities in the methylation and replication patterns of the region distal to the deletion, and in the corresponding area on the normal X chromosome. Thus, there is no evidence that the skewed inactivation pattern in these cases resulted from the cell selection driven by anomalies of X inactivation. 33 refs., 1 fig.

  10. A summary of 7q interstitial deletions and exclusion mapping of the gene for beta-glucuronidase.

    PubMed Central

    Fagan, K; Gill, A; Henry, R; Wilkinson, I; Carey, B

    1989-01-01

    Three patients are described with different phenotypes and differing de novo interstitial deletions of the long arm of a chromosome 7. The first patient has a deletion with loss of the proximal 7q11.23 band. Only three other cases have been reported with this particular deletion. Our second case shows mild dysmorphism similar to the other four patients reported with deletion of bands 7q21.12----21.3. Our third patient has a deletion of the 7q22.1----32.2 segment and has many of the phenotypic features of the other reported cases of del 7q22----32. GUSB, the gene for beta-glucuronidase, has been localised to the 7cen----q22 region. Analysis of beta-glucuronidase levels in blood leucocytes of our patients has helped more precisely to assign this gene locus to 7q21.11 or 7q22.1. Images PMID:2486209

  11. A 1.1Mb deletion in distal 13q deletion syndrome region with congenital heart defect and postaxial polydactyly: additional support for a CHD locus at distal 13q34 region.

    PubMed

    Yang, Yi-Feng; Ai, Qi; Huang, Can; Chen, Jin-Lan; Wang, Jian; Xie, Li; Zhang, Wei-Zhi; Yang, Jin-Fu; Tan, Zhi-Ping

    2013-10-01

    13q deletion syndrome is a rare genetic disorder, especially for group 3 deletion (13q33-q34 deletion). Previously we described a patient with congenital heart defect and mental retardation and proposed that a distal 6Mb region might contain the causative gene of congenital heart defect. Here we present a new patient with congenital heart defects (CHD), hand and foot anomalies and mild mental retardation. We identified a 1.1Mb deletion at chromosome 13q34 with high resolution SNP-array BeadChips (HumanOmni1-Quad, Illumina, USA). This chromosome region contains ten annotated genes, including GRK1, TFDP1, RASA3 and GAS6. To our knowledge, this represents the smallest 13q34 deletion identified to date. Our study provides additional support that distal 13q34 deletion region might contain key gene(s) responsible for cardiac development.

  12. Novel approach to identifying the hepatitis B virus pre-S deletions associated with hepatocellular carcinoma

    PubMed Central

    Zhao, Zhi-Mei; Jin, Yan; Gan, Yu; Zhu, Yu; Chen, Tao-Yang; Wang, Jin-Bing; Sun, Yan; Cao, Zhi-Gang; Qian, Geng-Sun; Tu, Hong

    2014-01-01

    AIM: To develop a novel non-sequencing method for the detection of hepatitis B virus (HBV) pre-S deletion mutants in HBV carriers. METHODS: The entire region of HBV pre-S1 and pre-S2 was amplified by polymerase chain reaction (PCR). The size of PCR products was subsequently determined by capillary gel electrophoresis (CGE). CGE were carried out in a PACE-MDQ instrument equipped with a UV detector set at 254 nm. The samples were separated in 50 μm ID eCAP Neutral Coated Capillaries using a voltage of 6 kV for 30 min. Data acquisition and analysis were performed using the 32 Karat Software. A total of 114 DNA clones containing different sizes of the HBV pre-S gene were used to determine the accuracy of the CGE method. One hundred and fifty seven hepatocellular carcinoma (HCC) and 160 non-HCC patients were recruited into the study to assess the association between HBV pre-S deletion and HCC by using the newly-established CGE method. Nine HCC cases with HBV pre-S deletion at the diagnosis year were selected to conduct a longitudinal observation using serial serum samples collected 2-9 years prior to HCC diagnosis. RESULTS: CGE allowed the separation of PCR products differing in size > 3 bp and was able to identify 10% of the deleted DNA in a background of wild-type DNA. The accuracy rate of CGE-based analysis was 99.1% compared with the clone sequencing results. Using this assay, pre-S deletion was more frequently found in HCC patients than in non-HCC controls (47.1% vs 28.1%, P < 0.001). Interestingly, the increased risk of HCC was mainly contributed by the short deletion of pre-S. While the deletion ≤ 99 bp was associated with a 2.971-fold increased risk of HCC (95%CI: 1.723-5.122, P < 0.001), large deletion (> 99 bp) did not show any association with HCC (P = 0.918, OR = 0.966, 95%CI: 0.501-1.863). Of the 9 patients who carried pre-S deletions at the stage of HCC, 88.9% (8/9) had deletions 2-5 years prior to HCC, while only 44.4%4 (4/9) contained such deletions 6

  13. Gene Deletion by Synthesis in Yeast.

    PubMed

    Kim, Jinsil; Kim, Dong-Uk; Hoe, Kwang-Lae

    2017-01-01

    Targeted gene deletion is a useful tool for understanding the function of a gene and its protein product. We have developed an efficient and robust gene deletion approach in yeast that employs oligonucleotide-based gene synthesis. This approach requires a deletion cassette composed of three modules: a central 1397-bp KanMX4 selection marker module and two 366-bp gene-specific flanking modules. The invariable KanMX4 module can be used in combination with different pairs of flanking modules targeting different genes. The two flanking modules consist of both sequences unique to each cassette (chromosomal homologous regions and barcodes) and those common to all deletion constructs (artificial linkers and restriction enzyme sites). Oligonucleotides for each module and junction regions are designed using the BatchBlock2Oligo program and are synthesized on a 96-well basis. The oligonucleotides are ligated into a single deletion cassette by ligase chain reaction, which is then amplified through two rounds of nested PCR to obtain sufficient quantities for yeast transformation. After removal of the artificial linkers, the deletion cassettes are transformed into wild-type diploid fission yeast SP286 cells. Verification of correct clone and gene deletion is achieved by performing check PCR and tetrad analysis. This method with proven effectiveness, as evidenced by a high success rate of gene deletion, can be potentially applicable to create systematic gene deletion libraries in a variety of yeast species. PMID:27671940

  14. Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1.

    PubMed Central

    Devriendt, K; Matthijs, G; Van Dael, R; Gewillig, M; Eyskens, B; Hjalgrim, H; Dolmer, B; McGaughran, J; Bröndum-Nielsen, K; Marynen, P; Fryns, J P; Vermeesch, J R

    1999-01-01

    Deletions in the distal region of chromosome 8p (del8p) are associated with congenital heart malformations. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive, impulsive behavior. We studied genotype-phenotype correlations in nine unrelated patients with a de novo del8p, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. With the exception of one large terminal deletion, all deletions were interstitial. In five patients, a commonly deleted region of approximately 6 Mb was present, with breakpoints clustering in the same regions. One patient without a heart defect or microcephaly but with mild mental retardation and characteristic behavior had a smaller deletion within this commonly deleted region. Two patients without a heart defect had a more proximal interstitial deletion that did not overlap with the commonly deleted region. Taken together, these data allowed us to define the critical deletion regions for the major features of a del8p. PMID:10090897

  15. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia

    PubMed Central

    Ouillette, Peter; Collins, Roxane; Shakhan, Sajid; Li, Jinghui; Li, Cheng; Shedden, Kerby; Malek, Sami N.

    2011-01-01

    Purpose To further our understanding of the biology and prognostic significance of various chromosomal 13q14 deletions in CLL. Experimental Design We have analyzed data from SNP 6.0 arrays to define the anatomy of various 13q14 deletions in a cohort of 255 CLL patients and have correlated two subsets of 13q14 deletions (type I: exclusive of RB1 and type II: inclusive of RB1) with patient survival. Further, we have measured the expression of the 13q14-resident microRNAs by Q-PCR in 242 CLL patients and subsequently assessed their prognostic significance. We have sequenced all coding exons of RB1 in patients with monoallelic Rb1 deletion and have sequenced the 13q14-resident miR locus in all patients. Results Large 13q14 (type II) deletions were detected in ~20% of all CLL patients and were associated with shortened survival. A strong association between 13q14 type II deletions and elevated genomic complexity, as measured through CLL-FISH or SNP 6.0 array profiling, was identified, suggesting that these lesions may contribute to CLL disease evolution through genomic destabilization. Sequence and copy number analysis of the RB1 gene identified a small CLL subset that is RB1 null. Finally, neither the expression levels of the 13q14-resident microRNAs nor the degree of 13q14 deletion, as measured through SNP 6.0 array-based copy number analysis, had significant prognostic importance. Conclusions Our data suggest that the clinical course of CLL is accelerated in patients with large (type II) 13q14 deletions that span the RB1 gene, therefore justifying routine identification of 13q14 subtypes in CLL management. PMID:21890456

  16. Deletion at chromosome 16p13. 3 as a cause of Rubinstein-Taybi syndrome: Clinical aspects

    SciTech Connect

    Hennekam, R.C.M.; Tilanus, M.; Boogaard, M.J.H. van den ); Hamel, B.C.J.; Voshart-van Heeren, H.; Mariman, E.C.M.; Beersum, S.E.C. van ); Breuning, M.H. )

    1993-02-01

    In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16p13.3 is described. The authors investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental disomy plays a role in etiology, and (c) to compare clinical features in patients with a deletion to those in individuals in whom deletions were not detectable. Molecular studies showed a copy of chromosome 16 from each parent in all 19 patients. Uniparental disomy was also excluded for five other chromosome arms known to be imprinted in mice. None of the probes used for determining the origin of the deleted chromosome proved to be informative. The clinical features were essentially the same in patients with and without visible deletion, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces. A small deletion at 16p13.3 may be found in some patients with Rubinstein-Taybi syndrome. Cytogenetically undetectable deletions, point mutations, mosaicism, heterogeneity, or phenocopy by a nongenetic cause are the most probable explanations for the absence of cytogenetic or molecular abnormalities in other patients with Rubinstein-Taybi syndrome. 26 refs., 3 tabs., 2 figs.

  17. Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes

    PubMed Central

    Doco-Fenzy, Martine; Leroy, Camille; Schneider, Anouck; Petit, Florence; Delrue, Marie-Ange; Andrieux, Joris; Perrin-Sabourin, Laurence; Landais, Emilie; Aboura, Azzedine; Puechberty, Jacques; Girard, Manon; Tournaire, Magali; Sanchez, Elodie; Rooryck, Caroline; Ameil, Agnès; Goossens, Michel; Jonveaux, Philippe; Lefort, Geneviève; Taine, Laurence; Cailley, Dorothée; Gaillard, Dominique; Leheup, Bruno; Sarda, Pierre; Geneviève, David

    2014-01-01

    Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader–Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion. PMID:24129437

  18. Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes.

    PubMed

    Doco-Fenzy, Martine; Leroy, Camille; Schneider, Anouck; Petit, Florence; Delrue, Marie-Ange; Andrieux, Joris; Perrin-Sabourin, Laurence; Landais, Emilie; Aboura, Azzedine; Puechberty, Jacques; Girard, Manon; Tournaire, Magali; Sanchez, Elodie; Rooryck, Caroline; Ameil, Agnès; Goossens, Michel; Jonveaux, Philippe; Lefort, Geneviève; Taine, Laurence; Cailley, Dorothée; Gaillard, Dominique; Leheup, Bruno; Sarda, Pierre; Geneviève, David

    2014-04-01

    Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

  19. Mosaic 18q21.2 deletions including the TCF4 gene: a clinical report.

    PubMed

    Rossi, Massimiliano; Labalme, Audrey; Cordier, Marie-Pierre; Till, Marianne; Blanchard, Gaëlle; Dubois, Remi; Guibaud, Laurent; Heissat, Sophie; Javouhey, Etienne; Lachaux, Alain; Mure, Pierre-Yves; Ville, Dorothée; Edery, Patrick; Sanlaville, Damien

    2012-12-01

    Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial dysmorphism, profound intellectual disability, and the possible occurrence of epilepsy and breathing anomalies. It is caused by haploinsufficiency of the TCF4 gene. No significant difference in clinical severity has been reported to date between PTHS patients carrying 18q21 deletions including the TCF4 gene, and those harboring TCF4 point mutations, suggesting a lack of genotype/phenotype correlation. Moreover, the size of 18q21 deletions including the TCF4 gene does not appear to have a significant effect on the phenotypic severity, suggesting that TCF4 haploinsufficiency is the most important prognostic factor in 18q deletions. We describe two unrelated patients presenting with clinical features reminiscent of PTHS and carrying mosaic interstitial 18q21 deletions characterized by array comparative genomic hybridization. One of the patients presented the lowest level of mosaic 18q21 deletion reported to date (5-10%). Our report and a review of the literature show that the mosaic status does not appear to have a significant effect on the clinical severity of 18q21 deletions, which are associated with a poor neurological outcome, whereas a mosaic TCF4 point mutation can result in a significantly milder phenotype. Malformations of internal organs are currently considered to be rare in PTHS. The patients described here had visceral anomalies, suggesting that a full morphological assessment, including heart and abdominal ultrasound scans, should be performed systematically in PTHS patients. PMID:23165966

  20. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

    PubMed Central

    El Khattabi, Laïla; Guimiot, Fabien; Pipiras, Eva; Andrieux, Joris; Baumann, Clarisse; Bouquillon, Sonia; Delezoide, Anne-Lise; Delobel, Bruno; Demurger, Florence; Dessuant, Hélène; Drunat, Séverine; Dubourg, Christelle; Dupont, Céline; Faivre, Laurence; Holder-Espinasse, Muriel; Jaillard, Sylvie; Journel, Hubert; Lyonnet, Stanislas; Malan, Valérie; Masurel, Alice; Marle, Nathalie; Missirian, Chantal; Moerman, Alexandre; Moncla, Anne; Odent, Sylvie; Palumbo, Orazio; Palumbo, Pietro; Ravel, Aimé; Romana, Serge; Tabet, Anne-Claude; Valduga, Mylène; Vermelle, Marie; Carella, Massimo; Dupont, Jean-Michel; Verloes, Alain; Benzacken, Brigitte; Delahaye, Andrée

    2015-01-01

    6q16 deletions have been described in patients with a Prader–Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype–phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed. PMID:25351778

  1. 78 FR 56679 - Procurement List; Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-13

    ... 8/2/2013 (78 FR 46927-46928), the Committee for Purchase From People Who Are Blind or Severely... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Deletions from the Procurement List. SUMMARY:...

  2. Alagille syndrome and deletion of 20p.

    PubMed Central

    Anad, F; Burn, J; Matthews, D; Cross, I; Davison, B C; Mueller, R; Sands, M; Lillington, D M; Eastham, E

    1990-01-01

    We add five cases of 20p deletion to the 10 cases already published. Four had craniofacial, vertebral, ocular, and cardiovascular features of Alagille syndrome, which adds weight to the assignment of this disorder to the short arm of chromosome 20. Included in our series is the first report of familial transmission of a 20p deletion. Images PMID:2074558

  3. 22.5 MB DELETION OF 13q31.1-q34 ASSOCIATED WITH HPE, DWM, AND HSCR: A CASE REPORT AND REDEFINING THE SMALLEST DELETED REGIONS.

    PubMed

    Alp, M Y; Çebi, A H; Seyhan, S; Cansu, A; Aydin, H; Ikbal, M

    2016-01-01

    Partial deletion of the long arm of the chromosome 13, 13q deletion syndrome is a rare chromosomal disorder characterized by severe growth and mental retardation, microcephaly, facial dysmorphism, brain malformations (holoprosencephaly, Dandy-Walker malformation), distal limb defects, eye anomalies, genitourinary and gastrointestinal tract malformations (Hirschsprung's disease). Approximately 1.2 Mb region in 13q32 was suggested as minimal critical region which is responsible for severe mental and growth retardation and brain anomalies. Here we described a male patient with de novo interstitial deletion of 13q31.1-q34 associated with short stature, microcephaly, facial dysmorphism, clinodactyly, cryptorchidism, micropenis, epilepsy, HPE, DWM, and HSCR. According to the literature review, present case indicated that smallest deleted region associated with DWM and HPE might be located at the 13q32.3, limb defects 13q34, anogenital malformations 13q33.3-34, and HSCR 13q31.1-32.1. PMID:27192891

  4. A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.

    PubMed

    Viñas-Jornet, Marina; Esteba-Castillo, Susanna; Gabau, Elisabeth; Ribas-Vidal, Núria; Baena, Neus; San, Joan; Ruiz, Anna; Coll, Maria Dolors; Novell, Ramon; Guitart, Miriam

    2014-11-01

    Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.

  5. FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes

    SciTech Connect

    Teshima, I.; Chadwick, D.; Chitayat, D.

    1996-03-29

    We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered. 41 refs., 4 figs., 2 tabs.

  6. A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion

    PubMed Central

    Viñas-Jornet, Marina; Esteba-Castillo, Susanna; Gabau, Elisabeth; Ribas-Vidal, Núria; Baena, Neus; San, Joan; Ruiz, Anna; Coll, Maria Dolors; Novell, Ramon; Guitart, Miriam

    2014-01-01

    Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance. PMID:25614873

  7. NF1 Microdeletion Syndrome: Refined FISH Characterization of Sporadic and Familial Deletions with Locus-Specific Probes

    PubMed Central

    Riva, Paola; Corrado, Lucia; Natacci, Federica; Castorina, Pierangela; Wu, Bai-Li; Schneider, Gretchen H.; Clementi, Maurizio; Tenconi, Romano; Korf, Bruce R.; Larizza, Lidia

    2000-01-01

    Summary Two familial and seven sporadic patients with neurofibromatosis 1—who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene—were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the ∼0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes—BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS—were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8–3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions. PMID:10631140

  8. Type I oculocutaneous albinism (OCA1) associated with a large deletion of the tyrosinase (TYR) gene

    SciTech Connect

    Spritz, R.A.; Wick, P.A.; Holmes, S.A.; Schnur, R.E. |

    1994-09-01

    OCA1 is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes, due to deficient enzymatic activity of tyrosinase. TYR consists of 5 exons spanning over 65 kb at 11q14-q21. Analyses of TYR in >400 unrelated patients with OCA1 have identified more than 50 different point mutations; however, no large deletions have been detected. Here we report a large deletion of TYR in a Caucasian boy with OCA1B. Simultaneous SSCP/heteroduplex screening and DNA sequence analysis indicated that the patient was apparently homozygous for a previously described TYR mutation, adjacent to the 3` splice site of IVS2 (-7, t{r_arrow}a). To distinguish between possible gene deletion vs. maternal uniparental isodisomy, we characterized several chromosome 11 polymorphisms. Maternal uniparental isodisomy was excluded by the patient`s heterozygosity for alleles at D11S35 (11q21-122) and HBG2 (11p15.5). In addition, the patient failed to inherit paternal alleles at an MboI RFLP in exon 1 of TYR and at a TaqI RFLP in the promoter region of the gene. To detect a possible submicroscopic deletion, we performed quantitative Southern blot hybridization using a full length TYR cDNA. Compared with controls, both the patient and his father appeared deleted for two or three TYR-derived PstI fragments; the two TYRL-derived fragments appeared normal. These data indicate that the patient and his father have a partial TYR deletion, including at least exons 1, 2, and IVS2. Based on the organization of the gene, this deletion is at least 50 kb in size. The patient is thus hemizygous for the maternally-inherited mutation in IVS2, accounting for his OCA1B phenotype.

  9. Deletion affecting band 7q36 not associated with holoprosencephaly

    SciTech Connect

    Ebrahim, S.A.D.; Krivchenia, E.; Mohamed, A.N.

    1994-09-01

    Although the appearance of 7q36 aberrations have been postulated to be responsible for holoprosencephaly (HPE), the presence of a de novo 7q36 deletion in fetus without HPE has not been reported. We report the first case of a fetus with 7q36 deletion but lacking HPE. Ultrasound examination of a 25-year-old G3P1 Caucasian female showed small head circumference with microcephaly at 28 weeks. Decreased amniotic fluid volume, bilateral renal dilatation and abnormal facial features were also noted. Chromosome analysis after cordocentesis showed an abnormal female karyotype with a deletion involving the chromosome band 7q36, 46,XX,del(7)(q36). Chromosome studies on the biological parents were normal. In view of the chromosome finding and after extensive counseling, the couple elected to terminate the pregnancy. The chromosome findings were confirmed by fetal blood chromosome analysis at termination. Post-mortem examination confirmed dysmorphic features including a depressed nasal bridge and large flat ears with no lobules, but no cleft lip or palate was noted. Internal abnormalities included a bicuspid pulmonary valve and abnormally located lungs. The brain weighed 190g (249 {plus_minus} 64g expected) and had symmetric cerebral hemispheres without evidence of HPE or other gross or microscopic malformation, except focal cerebellar cortical dysplasia. In summary, our patient showed a deletion of the same chromosomal band implicated in HPE but lacked HPE. This finding indicates that 7q36 deletion may be seen in the absence of HPE and suggests that other genetic mechanisms may be responsible for HPE in this setting.

  10. Preliminary phenotypic map of chromosome 4p16 based on 4p deletions

    SciTech Connect

    Estabrooks, L.L.; Rao, K.W.; Aylsworth, A.S.

    1995-07-17

    We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients` deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies. 12 refs., 2 figs., 1 tab.

  11. Genotype-phenotype correlation in 13q13.3-q21.3 deletion.

    PubMed

    Tosca, Lucie; Brisset, Sophie; Petit, François M; Metay, Corinne; Latour, Stéphanie; Lautier, Benoît; Lebas, Axel; Druart, Luc; Picone, Olivier; Mas, Anne-Elisabeth; Prévot, Sophie; Tardieu, Marc; Goossens, Michel; Tachdjian, Gérard

    2011-01-01

    Pure interstitial deletions of the long arm of chromosome 13 are correlated with variable phenotypes according to the size and the location of the deleted region. Deletions involving the 13q13q21 region are rare. In order to establish interstitial 13q genotype-phenotype correlation, we used high resolution 244K oligonucleotide array in addition to conventional karyotype and molecular (fluorescent in situ hybridization, microsatellite markers analysis) techniques in two independent probands carrying a deletion 13q13 to 13q21. First patient was a 3-year-old girl with mental retardation and dysmorphy carrying a 13q13.3q21.31 de novo deletion diagnosed post-natally. The second one was a fetus with de novo del(13)(q14q21.2) associated with first trimester increased nuchal translucency. We showed that specific dysmorphic features (macrocephaly, high forehead, hypertelorism, large nose, large and malformed ears and retrognathia) were correlated to the common 13q14q21 chromosomal segment. Physical examination revealed overgrowth with global measurement up to the 95th percentile in both probands. This is the second description of overgrowth in patients carrying a 13q deletion. Haploinsufficiency of common candidates genes such as CKAP2, SUGT1, LECT1, DCLK1 and SMAD9, involved in cell division and bone development, is a possible mechanism that could explain overgrowth in both patients. This study underlines also that cytogenetic analysis could be performed in patients with overgrowth.

  12. Comparison of phenotype in uniparental disomy and deletion Prader-Willi syndrome: Sex specific differences

    SciTech Connect

    Mitchell, J.; Langlois, S.; Robinson, W.P.

    1996-10-16

    Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P<.001) limited to the UPD group with a predominance (68%) of males. An equal number of males and females was observed in the deletion group. When analyzed by sex, several significant differences between the UPD and deletion groups were observed. Female UPD patients were found to be less severely affected than female deletion patients in terms of length of gavage feeding and a later onset of hyperphagia. Although these traits are likely to be influenced by external factors, they may reflect a milder presentation of female UPD patients which could explain the observed sex bias by causing under-ascertainment of female UPD. Alternatively, there may be an effect of sex on either early trisomy 15 survival or the probability of somatic loss of a chromosome from a trisomic conceptus. 26 refs., 1 tab.

  13. Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations

    PubMed Central

    2013-01-01

    Background RBFOX1 is an important splicing factor regulating developmental and tissue-specific alternative splicing in heart, muscle, and neuronal tissues. Constitutional genetic defects in RBFOX1 are implicated in multiple medical conditions. Results We identified 14 copy number variants (CNV) involving RBFOX1 from 2,124 consecutive pediatric patients referred for chromosomal microarray analysis (CMA), including 13 intragenic deletions and a single intragenic duplication. The clinical significances of the intragenic deletions of RBFOX1 were evaluated. Conclusions Our data strongly supports the associations of intragenic deletions of RBFOX1 with a diversity of neurodevelopmental and neuropsychiatric disorders, and possibly other clinical features. PMID:23822903

  14. Delineating the phenotype of 1p36 deletion in adolescents and adults.

    PubMed

    Brazil, Ashley; Stanford, Kevin; Smolarek, Teresa; Hopkin, Robert

    2014-10-01

    1p36 deletion is the most common telomeric deletion syndrome, with an incidence of 1/5,000-1/10,000. A variety of clinical complications have been reported including seizures, hypotonia, heart malformations, cardiomyopathy, vision problems, and hearing loss. Approximately 90% are reported to have severe to profound intellectual disability and 75% to have absent expressive language. Little is known about long-term outcomes. The current literature suggests a poor prognosis for most patients. This study attempted to assess medical conditions and function of adolescent and adult patients with 1p36 deletion. A survey was distributed through three support groups to identify patients >12 years of age to assess functional status and medical problems in older patients with 1p36 deletion syndrome. 40 patients were identified between 12 and 46 years old. Among our survey sample, medical complications including seizures, hypotonia, structural heart defects, hearing loss, and vision problems, were similar to previous reports. However, functional skills were better than anticipated, with an overwhelming majority reported to independently sit, walk, and receive the majority of nutrition orally. Forty-four percent were reported to use complex speech abilities. While medical problems in patients with 1p36 deletion were similar to those that have been previously reported, we also demonstrated these same concerns persist into adolescence and adulthood. Additionally, patients were reported to have better functional skills than anticipated. Thus, quality of life and level of function appear to be better than anticipated from previous studies. © 2014 Wiley Periodicals, Inc.

  15. Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

    PubMed Central

    2012-01-01

    Background The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. Results We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. Discussion This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement. PMID:22260333

  16. Molecular definition of deletions of different segments of distal 5p that result in distinct phenotypic features

    SciTech Connect

    Church, D.M.; Bengtsson, U.; Wasmuth, J.J.; Niebuhr, E.

    1995-05-01

    Cri du chat syndrome (CDC) is a segmental aneusomy associated with deletions of chromosome 5p15. In an effort to define regions that produce the phenotypes associated with CDC, we have analyzed deletions from 17 patients. The majority of these patients had atypical CDC features or were asymptomatic. Using these patients, we have mapped several phenotypes associated with deletions of 5p, including speech delay, catlike cry, newborn facial dysmorphism, and adult facial dysmorphism. This phenotypic map should provide a framework with which to begin identification of genes associated with various phenotypic features associated with deletions of distal 5p. We have also analyzed the parental origin of the de novo deletions, to determine if genomic imprinting could be occurring in this region. In addition, we have isolated cosmids that could be useful for both prenatal and postnatal assessments of del5(p) individuals. 25 refs., 4 figs., 3 tabs.

  17. Targeted chromosomal deletions and inversions in zebrafish.

    PubMed

    Gupta, Ankit; Hall, Victoria L; Kok, Fatma O; Shin, Masahiro; McNulty, Joseph C; Lawson, Nathan D; Wolfe, Scot A

    2013-06-01

    Zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) provide powerful platforms for genome editing in plants and animals. Typically, a single nuclease is sufficient to disrupt the function of protein-coding genes through the introduction of microdeletions or insertions that cause frameshifts within an early coding exon. However, interrogating the function of cis-regulatory modules or noncoding RNAs in many instances requires the excision of this element from the genome. In human cell lines and invertebrates, two nucleases targeting the same chromosome can promote the deletion of intervening genomic segments with modest efficiencies. We have examined the feasibility of using this approach to delete chromosomal segments within the zebrafish genome, which would facilitate the functional study of large noncoding sequences in a vertebrate model of development. Herein, we demonstrate that segmental deletions within the zebrafish genome can be generated at multiple loci and are efficiently transmitted through the germline. Using two nucleases, we have successfully generated deletions of up to 69 kb at rates sufficient for germline transmission (1%-15%) and have excised an entire lincRNA gene and enhancer element. Larger deletions (5.5 Mb) can be generated in somatic cells, but at lower frequency (0.7%). Segmental inversions have also been generated, but the efficiency of these events is lower than the corresponding deletions. The ability to efficiently delete genomic segments in a vertebrate developmental system will facilitate the study of functional noncoding elements on an organismic level.

  18. Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q

    SciTech Connect

    Koiffmann, C.P.; Vianna-Morgante, A.M.; Wajntal, A.

    1995-07-31

    Deletion 11q23{r_arrow}qter and duplication 12q23{r_arrow}qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23{r_arrow}24 in the cause of the neuroblastoma is discussed. 18 refs., 2 figs., 1 tab.

  19. Nasal dimple as part of the 22q11.2 deletion syndrome

    SciTech Connect

    Gripp, K.W.; Reed, L.A.; Emanuel, B.S. |

    1997-03-31

    The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia. 11 refs., 2 figs.

  20. 1p36 deletion syndrome: an update.

    PubMed

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

  1. 1p36 deletion syndrome: an update

    PubMed Central

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. PMID:26345236

  2. The use of two different MLPA kits in 22q11.2 deletion syndrome.

    PubMed

    Evers, L J M; Engelen, J J M; Houben, L M H; Curfs, L M G; van Amelsvoort, T A M J

    2016-04-01

    22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other "typical ones". We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis. PMID:26921528

  3. Novel features of 3q29 deletion syndrome: Results from the 3q29 registry

    PubMed Central

    Glassford, Megan R.; Rosenfeld, Jill A.; Freedman, Alexa A.; Zwick, Michael E.

    2016-01-01

    3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet‐based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction 13.9 oz (394 g), adjusted for gestational age and sex, P = 6.5e‐07). We further report on the frequency of heart defects, autism, recurrent ear infections, gastrointestinal phenotypes, and dental phenotypes, among others. We also report on the expected timing of delayed developmental milestones. This is the most comprehensive description of the 3q29 deletion phenotype to date. These results are clinically actionable toward improving patient care for 3q29 deletion carriers, and can guide the expectations of physicians and parents. These data also demonstrate the value of patient‐reported outcomes to reveal the full phenotypic spectrum of rare genomic disorders. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID:26738761

  4. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).

  5. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired). PMID:22224845

  6. Deletion of chromosome 21 in a girl with congenital hypothyroidism and mild mental retardation

    SciTech Connect

    Ahlbom, B.E.; Anneren, G.; Sidenvall, R.

    1996-08-23

    We report on a girl with a large interstitial deletion of the long arm of chromosome 21 and with mild mental retardation, congenital hypothyroidism, and hyperopia. The deletion [del(21)(q11.1-q22.1)] extends molecularly from marker D21S215 to D21S213. The distal breakpoint is not clearly defined but is situated between markers D21S213 and IFNAR. This patient has the largest deletion of chromosome 21 known without having severe mental retardation or malformations. The deletion does not involve the {open_quotes}Down syndrome chromosome{close_quotes} region, the region of chromosome 21 which in trisomy causes most of the manifestations of Down syndrome. Apparently, the proximal part of the long arm of chromosome 21 does not include genes that are responsible for severe clinical effects in the event of either deletion or duplication, since several reported patients with either trisomy or deletion of this region have mild phenotypic abnormalities. Congenital hypothyroidism is much more common in Down syndrome than in the average population. Thus, the congenital hypothyroidism of the present patient might indicate that there is one or several genes on the proximal part of chromosome 21, which might be of importance for the thyroid function. 24 refs., 4 figs., 2 tabs.

  7. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44

    PubMed Central

    Nagamani, Sandesh C Sreenath; Erez, Ayelet; Bay, Carolyn; Pettigrew, Anjana; Lalani, Seema R; Herman, Kristin; Graham, Brett H; Nowaczyk, Malgorzata JM; Proud, Monica; Craigen, William J; Hopkins, Bobbi; Kozel, Beth; Plunkett, Katie; Hixson, Patricia; Stankiewicz, Pawel; Patel, Ankita; Cheung, Sau Wai

    2012-01-01

    Submicroscopic deletions involving chromosome 1q43–q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43–q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion. PMID:21934713

  8. Interstitial deletion of the long arm of chromosome 3: case report, review, and definition of a phenotype.

    PubMed

    Alvarado, M; Bocian, M; Walker, A P

    1987-08-01

    Interstitial deletions of 3q have, to our knowledge, been reported in only four patients. We present an additional patient with interstitial deletion of 3q, with breakpoints at 3q23 and 3q25. The patient was small for gestational age and had a multiple congenital anomalies (MCA) syndrome including microcephaly; unusual facial appearance with bilateral microphthalmia, blepharophimosis, and ptosis; ventricular septal defect; and bilateral clubfeet. Comparison between the clinical and cytogenetic findings of the present case and those of previously reported cases suggests that a recognizable phenotype may be associated with deletions of 3q2.

  9. Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

    SciTech Connect

    Thanh, L.T.; Man, Nguyen Thi; Morris, G.E.

    1995-08-28

    We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.

  10. Syndrome of proximal interstitial deletion 4p15

    SciTech Connect

    Fryns, J.P.

    1995-09-11

    In this journal, Chitayat et al. reported on 2 boys and a girl with interstitial deletion in the short arm of chromosome 4, including p15.2p15.33. All 3 patients had a characteristic face distinct from that of Wolf-Hirschhorn syndrome and multiple minor congenital anomalies. One patient had a congenitally enlarged penis. The authors noted that all had normal growth, and all had moderate psychomotor retardation (patient 1, developmental age of 4-6 years at age 9 years; patient 2, mental age 6 years at age 25 years; and patient 3, global delay with hypotonia, difficulties in both gross and fine motor development, and persistent delay in language skills). 5 refs., 1 fig.

  11. Molecular investigations of mitochondrial deletions: evaluating the usefulness of different genetic tests.

    PubMed

    Tońska, Katarzyna; Piekutowska-Abramczuk, Dorota; Kaliszewska, Magdalena; Kowalski, Paweł; Tańska, Anna; Bartnik, Ewa; Pronicka, Ewa; Krajewska-Walasek, Małgorzata

    2012-09-10

    Deletions in mitochondrial DNA are a common cause of mitochondrial disorders. The molecular diagnosis of mtDNA deletions for years was based on Southern hybridization later replaced by PCR methods such as PCR with primers specific for a particular deletion (mainly the so-called common deletion of 4977 bp) and long PCR. In order to evaluate the usefulness of MLPA (Multiplex Ligation-dependent Probe Amplification) in molecular diagnosis of large scale mtDNA deletions we compare four diagnostic methods: Southern hybridization, PCR, long-PCR and MLPA in a group of 16 patients with suspected deletions. Analysis was performed on blood, muscle and in one case hepatic tissue DNA. The MLPA was not able to confirm all the deletions detected by PCR methods, but due to its relative ease of processing, minimal equipment, low costs and the additional possibility to detect frequent point mtDNA mutations in one assay it is worth considering as a screening method. We recommend to always confirm MLPA results by PCR methods.

  12. Case report: cytogenetic and molecular analysis of proximal interstitial deletion of 4p, review of the literature and comparison with wolf-hirschhorn syndrome.

    PubMed

    Bailey, Nathanael G; South, Sarah T; Hummel, Marybeth; Wenger, Sharon L

    2010-01-01

    We report on a two-year-old female with a de novo proximal interstitial deletion of the short arm of chromosome 4 and a tetralogy of Fallot malformation. The patient had a karyotype of 46,XX,del(4)(p14p15.33) that was further characterized by array comparative genomic hybridization (aCGH). Phenotypic abnormalities for our patient are compared with those of previously reported patients with similar proximal 4p deletions as well as more distal deletions. The functions of genes that are deleted within this segment are reviewed.

  13. Neuropathology of 16p13.11 Deletion in Epilepsy

    PubMed Central

    Liu, Joan Y. W.; Kasperavičiūtė, Dalia; Martinian, Lillian; Thom, Maria; Sisodiya, Sanjay M.

    2012-01-01

    16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets

  14. A Case of Concurrent Miller-Dieker Syndrome (17p13.3 Deletion) and 22q11.2 Deletion Syndrome.

    PubMed

    Atwal, Paldeep S; Macmurdo, C

    2015-12-01

    Features of Miller-Dieker syndrome (MDS, 17p13.3 deletion syndrome, LIS1-associated lissencephaly) include classic lissencephaly, microcephaly, cardiac malformations, growth restriction, and characteristic facial changes. Individuals with 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome) are known to have congenital cardiac malformations (in particular conotruncal defects), palatal abnormalities (especially velopharyngeal insufficiency), hypocalcemia, immune deficiency, learning disabilities, and characteristic facial features. This case report describes phenotypic characteristics of a patient with extremely rare instance of having both MDS and 22q11.2 deletion syndrome that is unique in the medical literature. Prognosis in this concurrent phenotype is poor with our patient suffering from several malformations seen in both conditions and expiring in the neonatal period.

  15. A Case of Concurrent Miller-Dieker Syndrome (17p13.3 Deletion) and 22q11.2 Deletion Syndrome.

    PubMed

    Atwal, Paldeep S; Macmurdo, C

    2015-12-01

    Features of Miller-Dieker syndrome (MDS, 17p13.3 deletion syndrome, LIS1-associated lissencephaly) include classic lissencephaly, microcephaly, cardiac malformations, growth restriction, and characteristic facial changes. Individuals with 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome) are known to have congenital cardiac malformations (in particular conotruncal defects), palatal abnormalities (especially velopharyngeal insufficiency), hypocalcemia, immune deficiency, learning disabilities, and characteristic facial features. This case report describes phenotypic characteristics of a patient with extremely rare instance of having both MDS and 22q11.2 deletion syndrome that is unique in the medical literature. Prognosis in this concurrent phenotype is poor with our patient suffering from several malformations seen in both conditions and expiring in the neonatal period. PMID:27617133

  16. Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

    PubMed Central

    Lone, Anna Mari; Leidl, Mathias; McFedries, Amanda K.; Horner, James W.; Creemers, John; Saghatelian, Alan

    2014-01-01

    Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL−/−) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL−/− mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL−/− pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL−/− mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease. PMID:24586561

  17. Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma.

    PubMed

    Wyatt, Alexander; Bakrania, Preeti; Bunyan, David J; Osborne, Robert J; Crolla, John A; Salt, Alison; Ayuso, Carmen; Newbury-Ecob, Ruth; Abou-Rayyah, Y; Collin, J Richard O; Robinson, David; Ragge, Nicola

    2008-11-01

    Severe ocular malformations, including anophthalmia-microphthalmia (AM), are responsible for around 25% of severe visual impairment in childhood. Recurrent interstitial deletions of 14q22-23 are associated with AM and a wide range of extra-ocular phenotypes including brain anomalies. The homeobox gene OTX2 is located at 14q22.3 and has recently been identified as mutated in AM patients. Eight human OTX2 mutations have been reported in subjects with severe eye malformations, including AM, and variable developmental delay. We screened a novel AM cohort for mutations and deletions in OTX2, and identified four new mutations in six individuals and two cases of whole gene deletions. Our data suggest that OTX2 mutations and deletions account for 2-3% of AM cases.

  18. A New Intergenic α-Globin Deletion (α-αΔ125) Found in a Kabyle Population.

    PubMed

    Singh, Amrathlal Rabbind; Lacan, Philippe; Cadet, Estelle; Bignet, Patricia; Dumesnil, Cécile; Vannier, Jean-Pierre; Joly, Philippe; Rochette, Jacques

    2016-01-01

    We have identified a deletion of 125 bp (α-α(Δ125)) (NG_000006.1: g.37040_37164del) in the α-globin gene cluster in a Kabyle population. A combination of singlex and multiplex polymerase chain reaction (PCR)-based assays have been used to identify the molecular defect. Sequencing of the abnormal PCR amplification product revealed a novel α1-globin promoter deletion. The endpoints of the deletion were characterized by sequencing the deletion junctions of the mutated allele. The observed deletion was located 378 bp upstream of the α1-globin gene transcription initiation site and leaves the α2 gene intact. In some patients, the α-α(Δ125) deletion was shown to segregate with Hb S (HBB: c.20A>T) and/or Hb C (HBB: c.19G>A) or a β-thalassemic allele. The α-α(Δ125) deletion has no discernible effect on red cell indices when inherited with no other abnormal globin genes. The family study demonstrated that the deletion is heritable. This is the only example of an intergenic α2-α1 non coding DNA deletion, leaving the α2-globin gene and the α1 coding part intact.

  19. Idiopathic thromobocytopenic purpura in two mothers of children with DiGeorge sequence: A new component manifestation of deletion 22q11?

    SciTech Connect

    Levy, A.; Philip, N.; Michel, G.

    1997-04-14

    The phenotypic spectrum caused by the microdeletion of chromosome 22q11 region is known to be variable. Nearly all patients with DiGeorge sequence (DGS) and approximately 60% of patients with velocardiofacial syndrome exhibit the deletion. Recent papers have reported various congenital defects in patients with 22q11 deletions. Conversely, some patients have minimal clinical expression. Ten to 25% of parents of patients with DGS exhibit the deletion and are nearly asymptomatic. Two female patients carrying a 22q11 microdeletion and presenting with idiopathic thrombocytopenic purpura are reported. Both had children with typical manifestations of DGS. 12 refs., 4 figs., 1 tab.

  20. Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15.

    PubMed

    Di Gregorio, Eleonora; Orsi, Laura; Godani, Massimiliano; Vaula, Giovanna; Jensen, Stella; Salmon, Eric; Ferrari, Giancarlo; Squadrone, Stefania; Abete, Maria Cesarina; Cagnoli, Claudia; Brussino, Alessandro; Brusco, Alfredo

    2010-03-01

    Spinocerebellar ataxia type15 (SCA15) is a pure ataxia characterized by very slow progression. Only seven families have been identified worldwide, in which partial deletions and a missense mutation of the inositol triphosphate receptor type I gene (ITPR1) have been reported. We examined a four-generation Italian family segregating an autosomal dominant cerebellar ataxia, in which linkage analysis was positive for the SCA15 locus. We performed a genomic real-time polymerase chain reaction to search for ITPR1 gene deletions in this family and in 60 SCA index cases negative for mutations in the SCA1-3, 6-8, 10, 12,and dentatorubral-pallidoluysian atrophy genes. The deleted segments were characterized using a custom array comparative genomic hybridization analysis. We have identified two families with an ITPR1 gene deletion: in one, the deletion involved ITPR1 only, while in the other both sulfatase-modifying factor 1 and ITPR1. Clinical data of ten patients and brain MRI (available for six) showed that the phenotype substantially overlapped known SCA15 cases,but we also noted buccolingual dyskinesias, facial myokymias,and pyramidal signs never reported in SCA15. ITPR1 expression analysis of two deleted cases showed a half dose. Our results further support ITPR1 gene as causative of SCA15. The families reported show that SCA15 is present in Italy and has a greater variability in the age at onset and clinical features than previously reported. We propose that the search for ITPR1 deletions is mandatory in the clinical hypothesis of SCA15 and that ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level.

  1. Molecular Definition of the 22q11 Deletions in Velo-Cardio-Facial Syndrome

    PubMed Central

    Morrow, Bernice; Goldberg, Rosalie; Carlson, Christine; Gupta, Ruchira Das; Sirotkin, Howard; Collins, John; Dunham, Ian; O'Donnell, Hilary; Scambler, Peter; Shprintzen, Robert; Kucherlapati, Raju

    1995-01-01

    Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers >9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation ImagesFigure 2Figure 3 PMID:7762562

  2. Phenotype-Genotype Discrepancy Due to a 5.5-kb Deletion in the GALT Gene.

    PubMed

    González-del Angel, Ariadna; Velázquez-Aragón, José; Alcántara-Ortigoza, Miguel A; Vela-Amieva, Marcela; Hernández-Martínez, Nancy

    2012-01-01

    Classical galactosemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT). More than 200 mutations have been described in the GALT gene. A 5.5-kb GALT deletion, first described in patients of Ashkenazi Jewish ancestry, may lead either to an erroneous genotype assignment of classical galactosemia or to discrepancies with parental genotypes and the expected biochemical phenotype. The presence of the 5.5-kb deletion was examined in 27 Mexican nonrelated families with at least one child with reduced GALT activity in erythrocytes and it was detected in the 5.5% (n=3) of the 54 alleles tested. The first molecular studies in three of our families showed that the genotypes of the parents were inconsistent with those of their children, which were considered initially as homozygous p.N314D-Duarte 2, but after analyzing for the presence of the 5.5-kb deletion, were reassigned as compound heterozygotes [5.5-kb deletion]+[p.N314D-Duarte 2]. Identification of the 5.5-kb deletion in Mexican patients suggests that this mutation might not be exclusive to a given ethnic group and should be tested in other populations, especially when there is a discrepancy between the genotypes of patients and parents or by incongruence between biochemical phenotype and GALT genotype. Establishing a genotype-phenotype correlation for the 5.5-kb GALT deletion and determining the appropriate management will require additional studies in patients with a G/G genotype bearing the 5.5-kb GALT deletion.

  3. Opitz GBBB syndrome and the 22q11.2 deletion

    SciTech Connect

    Lacassie, Y.; Arriaza, M.I.

    1996-03-29

    Recently, McDonald-McGinn et al. reported the presence of a deletion 22q11.2 in a family with autosomal dominant inheritance and in a sporadic case with the Opitz GBBB syndrome. The presence of a vascular ring in these patients prompted them to look for this deletion, since this anomaly may be associated with the 22q11.2 deletion. They reviewed the Opitz GBBB syndrome and the 22q11.2 microdeletion syndrome, finding considerable overlap of manifestations. They proposed that, in some patients, the Opitz GBBB syndrome may be due to a 22q11.2 deletion. We recently examined a newborn boy referred because of MCA. The cardinal findings in this patient (hypertelorism, hypospadias with descended testicles, characteristic nose and truncus arteriosus type I) were suggestive of the Opitz GBBB syndrome and of the velocardiofacial syndrome. The chromosomes were apparently normal (46,XY), but the FISH study showed a 22q11.2 deletion. The patient developed hypocalcemia with very low level of PTH and heart failure requiring surgery. His immunological status was normal except that CD4 cells were mildly low and natural killer cells were increased in number. The family history was noncontributory, but the full evaluation of the family is pending. The mother at first glance presents apparent hypertelorism. 3 refs.

  4. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome.

    PubMed

    Beygo, J; Buiting, K; Seland, S; Lüdecke, H-J; Hehr, U; Lich, C; Prager, B; Lohmann, D R; Wieczorek, D

    2012-01-01

    Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1.

  5. Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region.

    PubMed

    Strehle, Eugen-Matthias; Yu, Linbo; Rosenfeld, Jill A; Donkervoort, Sandra; Zhou, Yulin; Chen, Tian-Jian; Martinez, Jose E; Fan, Yao-Shan; Barbouth, Deborah; Zhu, Hongbo; Vaglio, Alicia; Smith, Rosemarie; Stevens, Cathy A; Curry, Cynthia J; Ladda, Roger L; Fan, Zheng Jane; Fox, Joyce E; Martin, Judith A; Abdel-Hamid, Hoda Z; McCracken, Elizabeth A; McGillivray, Barbara C; Masser-Frye, Diane; Huang, Taosheng

    2012-09-01

    Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

  6. 3-Hydroxy-3-methylglutaryl CoA lyase (HL): Mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients

    SciTech Connect

    Wang, S.P.; Robert, M.F.; Mitchell, G.A.

    1996-04-01

    3-hydroxy-3-methylglutaryl CoA lyase (HL, EC 4.1.3.4) catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetic acid and acetyl CoA, the final reaction of both ketogenesis and leucine catabolism. Autosomal-recessive HL deficiency in humans results in episodes of hypoketotic hypoglycemia and coma. Using a mouse HL cDNA as a probe, we isolated a clone containing the full-length mouse HL gene that spans about 15 kb of mouse chromosome 4 and contains nine exons. The promoter region of the mouse HL gene contains elements characteristic of a housekeeping gene: a CpG island containing multiple Sp1 binding sites surrounds exon 1, and neither a TATA nor a CAAT box are present. We identified multiple transcription start sites in the mouse HL gene, 35 to 9 bases upstream of the translation start codon. We also isolated two human HL genomic clones that include HL exons 2 to 9 within 18 kb. The mouse and human HL genes (HGMW-approved symbol HMGCL) are highly homologous, with identical locations of intron-exon junctions. By genomic Southern blot analysis and exonic PCR, was found 2 of 33 HL-deficient probands to be homozygous for large deletions in the HL gene. 26 refs., 4 figs., 2 tabs.

  7. 22q11.2 deletion syndrome

    PubMed Central

    McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A. S.; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

    2016-01-01

    22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population. PMID:27189754

  8. Exact break point of a 50 kb deletion 8 kb centromeric of the HLA-A locus with HLA-A*24:02: the same deletion observed in other A*24 alleles and A*23:01 allele.

    PubMed

    Mitsunaga, Shigeki; Okudaira, Yuko; Kunii, Nanae; Cui, Tailin; Hosomichi, Kazuyoshi; Oka, Akira; Suzuki, Yasuo; Homma, Yasuhiko; Sato, Shinji; Inoue, Ituro; Inoko, Hidetoshi

    2011-08-01

    In a structural aberration analysis of patients with arthritis mutilans, a 50 kb deletion near the HLA-A locus with HLA-A*24:02 allele was detected. It was previously reported that HLA-A*24:02 haplotype harbored a large-scale deletion telomeric of the HLA-A gene in healthy individuals. In order to confirm that the deletion are the same in patients with arthritis mutilans and in healthy individuals, and to identify the break point of this deletion, the boundary sequences across the deletion in A*24:02 was amplified by polymerase chain reaction (PCR) as a 3.7 kb genomic fragment and subjected to nucleotide sequence determination. A comparison of these genomic sequences with those of the non-A*24:02 haplotype revealed that the deleted genomic region spanning 50 kb was flanked by 3.7 kb repetitive element-rich segments homologous to each other on both sides in non-A*24. The nucleotide sequences of the PCR products were identical in patients with arthritis mutilans and in healthy individuals, revealing that the deletion linked to A*24:02 is irrelevant to the onset of arthritis mutilans. The deletion was detected in all other A*24 alleles so far examined but not in other HLA-A alleles, except A*23:01. This finding, along with the phylogenic tree of HLA-A alleles and the presence of the 3.7 kb highly homologous segments at the boundary of the deleted genomic region in A*03 and A*32, may suggest that this HLA-A*24:02-linked deletion was generated by homologous recombination within two 3.7 kb homologous segments situated 50 kb apart in the ancestral A*24 haplotype after divergence from the A*03 and A*32 haplotypes.

  9. R3-R4 deletion in the PRNP gene is associated with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Cervenakova, L.; Brown, P.; Nagle, J.

    1994-09-01

    There are conflicting reports on the association of deletions in the PRNP gene on chromosome 20 with CJD, a rapidly progressive fatal spongiform encephalopathy. We accumulated data suggesting that a deletion of R3-R4 type (parts of the third and fourth repeats are deleted from the area of four repeating 24 bp sequences in the 5{prime} region of the gene) is causing CJD. Screening of 129 unaffected control individuals demonstrated presence of a deletion of R2 type in four (1.55% of the studied chromosomes), but none of them had the R3-R4 type. Of 181 screened patients with spongiform encephalopathies, two had a deletion of R3-R4 type with no other mutations in the coding sequence. Both patients had a classical rapidly progressive dementing disease and diffuse spongiform degeneration, and both cases were apparently sporadic. The same R3-R4 type of deletion was detected in three additional neuropathologically confirmed spongiform encephalopathy patients, of which two had other known pathogenic mutations in the PRNP gene: at codon 178 on the methionine allele exhibiting the phenotype of fatal familial insomnia, and codon 200 causing CJD with severe dementia; the third was a patient with iatrogenic CJD who developed the disease after treatment with growth hormone extracted from cadaveric human pituitary glands. In all cases the deletion coincided with a variant sequence at position 129 coding for methionine.

  10. Interleukin 3 gene is located on human chromosome 5 and is deleted in myeloid leukemias with a deletion of 5q

    SciTech Connect

    Le Beau, M.M.; Epstein, N.D.; O'Brien, S.J.; Nienhuis, A.W.; Yang, Y.C.; Clark, S.C.; Rowley, J.D.

    1987-08-01

    The gene IL-3 encodes interleukin 3, a hematopoietic colony-stimulating factor (CSF) that is capable of supporting the proliferation of a broad range of hematopoietic cell types. By using somatic cell hybrids and in situ chromosomal hybridization, the authors localized this gene to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted (del(5q)) in patients with myeloid disorders. By in situ hybridization, IL-3 was found to be deleted in the 5q-chromosome of one patient with refractory anemia who had a del(5)(q15q33.3), of three patients with refractory anemia (two patients) or acute nonlymphocytic leukemia (ANLL) de novo who had a similar distal breakpoint (del(5)(q13q33.3)), and of a fifth patient, with therapy-related ANLL, who had a similar distal breakpoint in band q33(del(5)(q14q33.3)). Southern blot analysis of somatic cell hybrids retaining the normal or the deleted chromosome 5 from two patients with the refractory anemia 5q- syndrome indicated that IL-3 sequences were absent from the hybrids retaining the deleted chromosome 5 but not from hybrids that had a cytologically normal chromosome 5. Thus, a small segment of chromosome 5 contains IL-3, GM-CSF, CSF-1, and FMS. The findings and earlier results indicating that GM-CSF, CSF-1, and FMS were deleted in the 5q- chromosome, suggest that loss of IL-3 or of other CSF genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

  11. The interleukin 3 gene is located on human chromosome 5 and is deleted in myeloid leukemias with a deletion of 5q.

    PubMed Central

    Le Beau, M M; Epstein, N D; O'Brien, S J; Nienhuis, A W; Yang, Y C; Clark, S C; Rowley, J D

    1987-01-01

    The gene IL-3 encodes interleukin 3, a hematopoietic colony-stimulating factor (CSF) that is capable of supporting the proliferation of a broad range of hematopoietic cell types. By using somatic cell hybrids and in situ chromosomal hybridization, we localized this gene to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, IL-3 was found to be deleted in the 5q-chromosome of one patient with refractory anemia who had a del(5)(q15q33.3), of three patients with refractory anemia (two patients) or acute nonlymphocytic leukemia (ANLL) de novo who had a similar distal breakpoint [del(5)(q13q33.3)], and of a fifth patient, with therapy-related ANLL, who had a similar distal breakpoint in band q33 [del(5)(q14q33.3)]. Southern blot analysis of somatic cell hybrids retaining the normal or the deleted chromosome 5 from two patients with the refractory anemia 5q- syndrome indicated that IL-3 sequences were absent form the hybrids retaining the deleted chromosome 5 but not from hybrids that had a cytologically normal chromosome 5. Thus, a small segment of chromosome 5 contains IL-3, GM-CSF (the gene encoding granulocyte-macrophage-CSF), CSF-1 (the gene encoding macrophage-CSF), and FMS (the human c-fms protooncogene, which encodes the CSF-1 receptor). Our findings and earlier results indicating that GM-CSF, CSF-1, and FMS were deleted in the 5q-chromosome, suggest that loss of IL-3 or of other CSF genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q). Images PMID:3497400

  12. Parameterized Complexity of Eulerian Deletion Problems.

    PubMed

    Cygan, Marek; Marx, Dániel; Pilipczuk, Marcin; Pilipczuk, Michał; Schlotter, Ildikó

    2014-01-01

    We study a family of problems where the goal is to make a graph Eulerian, i.e., connected and with all the vertices having even degrees, by a minimum number of deletions. We completely classify the parameterized complexity of various versions: undirected or directed graphs, vertex or edge deletions, with or without the requirement of connectivity, etc. The collection of results shows an interesting contrast: while the node-deletion variants remain intractable, i.e., W[1]-hard for all the studied cases, edge-deletion problems are either fixed-parameter tractable or polynomial-time solvable. Of particular interest is a randomized FPT algorithm for making an undirected graph Eulerian by deleting the minimum number of edges, based on a novel application of the color coding technique. For versions that remain NP-complete but fixed-parameter tractable we consider also possibilities of polynomial kernelization; unfortunately, we prove that this is not possible unless NP⊆coNP/poly. PMID:24415818

  13. Levodopa response in Parkinsonism with multiple mitochondrial DNA deletions.

    PubMed

    Wilcox, Robert A; Churchyard, Andrew; Dahl, Henrik H; Hutchison, Wendy M; Kirby, Denise M; Thyagarajan, Dominic

    2007-05-15

    We report a patient with an autosomal dominant chronic progressive external ophthalmoplegia phenotype associated with multiple mtDNA deletions in muscle from a family in which linkage analysis excluded mutations in DNA polymerase gamma (POLG), adenine nucleotide translocase (ANT-1) or C10orf2 (Twinkle). She presented with prominent Parkinsonism characterized by prolonged benefit from levodopa (L-dopa) and the later development of L-dopa induced dyskinesias and motor fluctuations. Thus L-dopa responsiveness, L-dopa induced dyskinesias and motor fluctuations may also occur in atypical Parkinsonism of mitochondrial disease, just as they may in multiple system atrophy. PMID:17357142

  14. Homozygous deletions of a copy number change detected by array CGH: a new cause for mental retardation?

    PubMed

    Curry, Cynthia J; Mao, Rong; Aston, Emily; Mongia, Shella K; Treisman, Tamara; Procter, Melinda; Chou, Bob; Whitby, Heidi; South, Sarah T; Brothman, Arthur R

    2008-08-01

    We describe two unrelated patients with mental retardation and normal karyotypes found to have relatively large homozygous deletions (>150 kb) of different regions detected by array comparative genomic hybridization (aCGH). Patient 1 showed a 157-214 kb deletion at 8q24.2, containing BAC clone RP11-17M8. This patient was born to phenotypically normal parents and has microcephaly, distinctive craniofacial features, brachymetacarpia, brachymetatarsia and severe mental retardation. This BAC clone is listed as a copy number variant on the Database of Genomic Variants (http://projects.tcag.ca/variation/). Heterozygosity for the deletion was found in the mother (father is deceased) and uniparental disomy of chromosome 8 was excluded. Patient 2 showed a 812-902 kb deletion at 12q21.1, containing BAC clone RP11-89P15. This region was not listed in any public database as a known variant. This patient has mild craniofacial dysmorphic features, bifid uvula, peripheral pulmonic stenosis and developmental delay. Heterozygosity for this deletion was confirmed in the phenotypically normal parents and two normal siblings, but surprisingly, homozygosity for the deletion in an apparently normal younger sibling brings into question whether this large homozygous copy number change (CNC) is causal. Homozygous deletions of CNCs have not previously been reported in association with a phenotype or mental retardation. These cases represent homozygosity for presumably benign CNCs, and while causality for the phenotypes cannot be confirmed, similar deletions are bound to be identified more frequently as aCGH is used with increasing regularity. Such homozygous deletions should be viewed as potentially clinically relevant. PMID:18627067

  15. Genitourinary Defects Associated with Genomic Deletions in 2p15 Encompassing OTX1

    PubMed Central

    Jorgez, Carolina J.; Rosenfeld, Jill A.; Wilken, Nathan R.; Vangapandu, Hima V.; Sahin, Aysegul; Pham, Dung; Carvalho, Claudia M. B.; Bandholz, Anne; Miller, Amanda; Weaver, David D.; Burton, Barbara; Babu, Deepti; Bamforth, John S.; Wilks, Timothy; Flynn, Daniel P.; Roeder, Elizabeth; Patel, Ankita; Cheung, Sau W.; Lupski, James R.; Lamb, Dolores J.

    2014-01-01

    Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1–4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2–7 had large de novo CNVs (2.39–6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia. PMID:25203062

  16. Novel deletion and a new missense mutation (Glu 217 Lys) at the catalytic site in two adenosine deaminase alleles of a patient with neonatal onset adenosine deaminase severe combined immunodeficiency

    SciTech Connect

    Hirschhorn, R.; Nicknam, M.N.; Eng, F.; Yang, D.R.; Borkowsky, W. )

    1992-11-01

    Mutations at the adenosine deaminase (ADA) locus result in a spectrum of disorders, encompassing a fulminant neonatal onset severe combined immunodeficiency (SCID) and childhood onset immunodeficiency, as well as apparently normal immune function. The extent of accumulation of the toxic metabolite, deoxyATP, correlates directly with severity of disease. The authors have now determined the mutations on both alleles of a child with fulminant, neonatal onset ADA SCID and accumulation of extremely high concentrations of deoxyATP. The genotype was consistent with the severely affected phenotype. One allele carried a large deletion that arose by non-homologous recombination and included the first five exons and promoter region. The second allele carried a missense mutation (G[sup 649]A) resulting in replacement of Glu[sup 217], an amino acid involved in the catalytic site, by Lys and predicting a major alteration in charge. Expression of the mutant cDNA on Cos cells confirmed that the mutation abolished enzyme activity. The authors have previously reported that a missense mutation at the preceding codon is similarly associated with neonatal onset ADA SCID and accumulation of extremely high deoxyATP. These findings suggest that genotype-phenotype correlations may be apparent for ADA SCID, despite the role that random variation in exposure to environmental pathogens may play in the initial phenotype. Such genotype-phenotype correlations may be important to consider in evaluating results of ongoing trials of [open quotes]gene[close quotes] and enzyme replacement therapy. 50 refs., 5 figs., 2 tabs.

  17. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    2001-01-01

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment in the context of a cloning vector which contains an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment. Also disclosed is a method for producing single-stranded DNA probes utilizing the same cloning vector. An optimal vector, PZIP is described. Methods for introducing unidirectional deletions into a terminal location of a cloned DNA sequence which is inserted into the vector of the present invention are also disclosed. These methods are useful for introducing deletions into either or both ends of a cloned DNA insert, for high throughput sequencing of any DNA of interest.

  18. Frontonasal malformation with tetralogy of Fallot associated with a submicroscopic deletion of 22q11

    SciTech Connect

    Stratton, R.F.; Payne, R.M.

    1997-03-31

    We report on a 14-month-old girl with bifid nasal tip and tetralogy of Fallot. Several similar patients have been described with CNS or eye abnormalities. Chromosome analysis with FISH, using Oncor DiGeorge probes, confirmed a submicroscopic deletion of 22q11. Many patients with Shprintzen (velo-cardio-facial) syndrome have a similar deletion with conotruncal cardiac defects and an abnormal nasal shape, suggesting that a gene in this area, possibly affecting neural crest cells, influences facial and other midline development. 13 refs., 1 fig.

  19. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature.

    PubMed

    Yamamoto, Kayono; Yoshihashi, Hiroshi; Furuya, Noritaka; Adachi, Masanori; Ito, Susumu; Tanaka, Yukichi; Masuno, Mitsuo; Chiyo, Hideaki; Kurosawa, Kenji

    2009-03-01

    Basal cell nevus syndrome (BCNS; Gorlin syndrome) is an autosomal dominant disorder, characterized by a predisposition to neoplasms and developmental abnormalities. BCNS is caused by mutations in the human homolog of the Drosophila patched gene-1, PTCH1, which is mapped on chromosome 9q22.3. Nonsense, frameshift, in-frame deletions, splice-site, and missense mutations have been found in the syndrome. Haploinsufficiency of PTCH1, which is caused by interstitial deletion of 9q22.3, is also responsible for the syndrome. To date, 19 cases with interstitial deletion of long arm of chromosome 9 involving the region of q22 have been reported. We describe two unrelated patients with some typical features of BCNS associated with deletion of 9q21.33-q31.1 and determined the boundary of the deletion by fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones. The results showed that the size of deletions is between 15.33 and 16.04 Mb in patient 1 and between 18.08 and 18.54 Mb in patient 2. Although the size and breakpoints were different from those of previously reported cases, the clinical features are common to patients with 9q22 deletion associated with BCNS. Delineation of the 9q22 deletions and further consideration of the genes responsible for the characteristic manifestations may provide insight into this newly recognized deletion syndrome. PMID:19243411

  20. IAP gene deletion and conditional knockout models.

    PubMed

    Silke, John; Vaux, David L

    2015-03-01

    Gene deletion studies have helped reveal the unique and overlapping roles played by IAP proteins. Crossing IAP mutant mice has helped unravel the complex feed-back regulatory circuits in which cIAP1, cIAP2 and XIAP allow innate defensive responses to microbial pathogens, without the development of auto-inflammatory syndromes. Deletion of genes for Survivin and its homologs in yeasts, invertebrates and mammals has shown that it functions differently, as it is not a regulator of innate immunity or apoptosis, but acts together with INCENP, aurora kinase B and Borealin to allow chromosome segregation during mitosis. PMID:25545814

  1. Identification and molecular characterization of four new large deletions in the beta-globin gene cluster.

    PubMed

    Joly, Philippe; Lacan, Philippe; Garcia, Caroline; Couprie, Nicole; Francina, Alain

    2009-01-01

    Despite the fact that mutations in the human beta-globin gene cluster are essentially point mutations, a significant number of large deletions have also been described. We present here four new large deletions in the beta-globin gene cluster that have been identified on patients displaying an atypical hemoglobin phenotype (high HbF) at routine analysis. The first deletion, which spreads over 2.0 kb, removes the entire beta-globin gene, including its promoter, and is associated with a typical beta-thal minor phenotype. The three other deletions are larger (19.7 to 23.9 kb) and remove both the delta and beta-globin genes. Phenotypically, they look like an HPFH-deletion as they are associated with normal hematological parameters. The precise localization of their 5' and 3' breakpoints gives new insights about the differences between HPFH and (deltabeta)(0)-thalassemia at the molecular level. The importance of detection of these deletions in prenatal diagnosis and newborn screening of hemoglobinopathies is also discussed.

  2. Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants

    PubMed Central

    Park, Angela K.J.; Francis, Joshua M.; Park, Woong-Yang; Park, Joon-Oh; Cho, Jeonghee

    2015-01-01

    Genomic alterations targeting the Epidermal Growth Factor Receptor (EGFR) gene have been strongly associated with cancer pathogenesis. The clinical effectiveness of EGFR targeted therapies, including small molecules directed against the kinase domain such as gefitinib, erlotinib and afatinib, have been proven successful in treating non-small cell lung cancer patients with tumors harboring EGFR kinase domain mutations. Recent large-scale genomic studies in glioblastoma and lung cancer have identified an additional class of oncogenic mutations caused by the intragenic deletion of carboxy-terminal coding regions. Here, we report that combinations of exonic deletions of exon 25 to 28 lead to the oncogenic activation of EGF receptor in the absence of ligand and consequent cellular transformation, indicating a significant role of C-terminal domain in modulating EGFR activation. Furthermore, we show that the oncogenic activity of the resulting C-terminal deletion mutants are efficiently inhibited by EGFR-targeted drugs including erlotinib, afatinib, dacomitinib as well as cetuximab, expanding the therapeutic rationale of cancer genome-based EGFR targeted approaches. Finally, in vivo and in vitro preclinical studies demonstrate that constitutive asymmetric dimerization in mutant EGFR is a key mechanism for oncogenic activation and tumorigenesis by C-terminal deletion mutants. Therefore, our data provide compelling evidence for oncogenic activation of C-terminal deletion mutants at the molecular level and we propose that C-terminal deletion status of EGFR can be considered as a potential genomic marker for EGFR-targeted therapy. PMID:25826094

  3. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review

    PubMed Central

    2011-01-01

    Chronic Granulomatous Disease (CGD), a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans). Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB), located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome. PMID:22111908

  4. Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population.

    PubMed Central

    Jimenez Vaca, A. L.; Valdes-Flores, M. del R.; Rivera-Vega, M. R.; González-Huerta, L. M.; Kofman-Alfaro, S. H.; Cuevas-Covarrubias, S. A.

    2001-01-01

    BACKGROUND: X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. MATERIALS AND METHODS: STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. RESULTS: No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. CONCLUSION: These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients. PMID:11844872

  5. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

    SciTech Connect

    Melki, J.; Lefebvre, S.; Burglen, L.; Burlet, P.; Clermont, O.; Reboullet, S.; Benichou, B.; Zeviani, M. ); Millasseau, P. ); Le Paslier, D. )

    1994-06-03

    Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

  6. Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.

    PubMed

    Gutierrez, Mariana; Thiffault, Isabelle; Guerrero, Kether; Martos-Moreno, Gabriel Á; Tran, Luan T; Benko, William; van der Knaap, Marjo S; van Spaendonk, Rosalina M L; Wolf, Nicole I; Bernard, Geneviève

    2015-06-05

    POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.

  7. Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: Deletion detection and familial diagnosis

    SciTech Connect

    Patino, A.; Garcia-Delgado, M.; Narbona, J.

    1995-11-06

    Deletion studies were performed in 26 Duchenne muscular dystrophy (DMD) patients through amplification of nine different exons by multiplex polymerase chain reaction (PCR). DNA from paraffin-embedded muscle biopsies was analyzed in 12 of the 26 patients studied. Optimization of this technique is of great utility because it enables analysis of material stored in pathology archives. PCR deletion detection, useful in DMD-affected boys, is problematic in determining the carrier state in female relatives. For this reason, to perform familial linkage diagnosis, we made use of a dinucleotide repeat polymorphism (STRP, or short tandem repeat polymorphism) located in intron 49 of the gene. We designed a new pair of primers that enabled the detection of 22 different alleles in relatives in the 14 DMD families studied. The use of this marker allowed familial diagnosis in 11 of the 14 DMD families and detection of de novo deletions in 3 of the probands. 8 refs., 5 figs., 2 tabs.

  8. Clinical features of nine males with molecularly defined deletions of the Y chromosome long arm.

    PubMed

    Salo, P; Ignatius, J; Simola, K O; Tahvanainen, E; Kääriäinen, H

    1995-09-01

    Deletions of the long arm of the Y chromosome have previously been associated with azoospermia and short stature. We report the results of a detailed clinical and molecular study of nine males with partial deletions of Yq. Special emphasis was laid on congenital anomalies and dysmorphic features. Some of the patients have developmental problems or distinct facial features, namely a small chin and mouth, a high arched or cleft palate, downward slanting palpebral fissures, high nasal bridge, and dysmorphic ears. As far as we know, similar facial dysmorphism has not been previously described in association with del(Yq). These features are not, however, simply correlated to the size of the deletion. In none of these patients could evidence of aberrant Xq-Yq interchange be found.

  9. Angiotensin-converting enzyme gene insertion/deletion, not bradykinin B2 receptor -58T/C gene polymorphism, associated with angiotensin-converting enzyme inhibitor-related cough in Chinese female patients with non-insulin-dependent diabetes mellitus.

    PubMed

    Lee, Y J; Tsai, J C

    2001-11-01

    To investigate the genetic susceptibility associated with cough related to angiotensin-converting enzyme inhibitor (ACEI) therapy in patients with type 2 diabetes, 189 non-insulin-dependent diabetes mellitus (NIDDM) patients with proteinuria or hypertension treated with perindopril were studied. Cough was considered to be present if the patients had been bothered by a cough during treatment and if they had had related symptoms for at least 2 weeks without an identifiable cause. Polymerase chain reaction (PCR) coupled with single-strand conformation polymorphism (SSCP) was used to detect polymorphisms of ACE and bradykinin B2-receptor genes. After 8 weeks of treatment, 49.2% (93 of 189) of our NIDDM patients were found to be suffering from ACEI-related cough. ACEI-related cough was mainly associated with female patients, with 71.7% (76 of 106) of female and only 20.5% (17 of 83) of male patients experiencing cough after ACEI treatment. There was a significant association of ACE II genotype with ACEI-related cough. The genotype frequencies were 58.2% for II, 47.8% for ID, and 16.7% for DD in patients with ACEI-associated cough and 41.8% for II, 52.2% for ID, and 83.3% for DD in subjects without ACEI-associated cough (chi(2) = 10.268; df = 2, P =.006). As female patients made up the majority of the subjects suffering from ACEI-related cough, we further analyzed the association of ACE I/D genotype with ACEI-related cough separately by sex. Male patients with ACEI-related cough were not associated with ACE I/D genotype distribution, while female patients were strongly associated with ACE I/D genotype polymorphism (chi(2) = 16.12; df = 2; P <.001). There was no association between the bradykinin B2 receptor gene -58T/C polymorphism with ACEI-related cough. In conclusion, our results indicate that Chinese diabetic female subjects are susceptible to ACEI-related cough, and this susceptibility may be genetically predetermined. PMID:11699055

  10. 22q11 Deletion Syndrome: A Genetic Subtype of Schizophrenia

    PubMed Central

    Bassett, Anne S.; Chow, Eva W.C.

    2012-01-01

    Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (~2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms. PMID:10509171

  11. 77 FR 68737 - Procurement List, Proposed Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

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  12. 78 FR 65618 - Procurement List; Proposed Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-01

    ... From the Federal Register Online via the Government Publishing Office COMMITTEE FOR PURCHASE FROM... Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Deletions from the Procurement... Received on or Before: 12/2/2013. ADDRESSES: Committee for Purchase From People Who Are Blind or...

  13. Deletion 5q35.3

    SciTech Connect

    Stratton, R.F.; Tedrowe, N.A.; Tolworthy, J.A.; Patterson, R.M.; Ryan, S.G.; Young, R.S.

    1994-06-01

    The authors report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bellshaped chest, diastasis recti, short fingers, and mild developmental delay.

  14. Interstitial deletion (6)q13q15

    SciTech Connect

    Gershoni-Baruch, R.; Mandel, H.; Bar El, H.; Bar-Nizan, N.; Borochowitz, Z.; Dar, Hanna

    1996-04-24

    We report on a 2-year-old child with psychomotor retardation, facial and urogenital anomalies. His chromosome constitution was 46,XY,del(6)(q13q15). This case further contributes to the karyotype-phenotype correlation of proximal deletion 6q syndromes. 18 refs., 3 figs., 1 tab.

  15. 78 FR 23543 - Procurement List Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-19

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  16. 22q11 deletion syndrome: current perspective

    PubMed Central

    Hacıhamdioğlu, Bülent; Hacıhamdioğlu, Duygu; Delil, Kenan

    2015-01-01

    Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS. PMID:26056486

  17. 78 FR 77106 - Procurement List; Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

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  18. An atypical case of fragile X syndrome caused by a deletion that includes FMRI gene

    SciTech Connect

    Quan, F.; Zonana, J.; Gunter, K.; Peterson, K.L.; Magenis, R.E., Popovich, B.W.

    1995-05-01

    Fragile X syndrome is the most common form of inherited mental retardation and results from the transcriptional inactivation of the FMR1 gene. In the vast majority of cases, this is caused by the expansion of an unstable CGG repeat in the first exon of the FMR1 gene. We describe here a phenotypically atypical case of fragile X syndrome, caused by a deletion that includes the entire FMR1 gene and {ge}9.0 Mb of flanking DNA. The proband, RK, was a 6-year-old mentally retarded male with obesity and anal atresia. A diagnosis of fragile X syndrome was established by the failure of RK`s DNA to hybridize to a 558-bp PstI-XhoI fragment (pfxa3) specific for the 5{prime}-end of the FMR1 gene. The analysis of flanking markers in the interval from Xq26.3-q28 indicated a deletion extending from between 160-500 kb distal and 9.0 Mb proximal to the FMR1 gene. High-resolution chromosome banding confirmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpaternal X chromosome. The maternal transmission of the deletion was confirmed by FISH using a 34-kb cosmid (c31.4) containing most of the FMR1 gene. These results indicated that RK carried a deletion of the FMR1 region with the most proximal breakpoint described to date. This patient`s unusual clinical presentation may indicate the presence of genes located in the deleted interval proximal to the FMR1 locus that are able to modify the fragile X syndrome phenotype. 36 refs., 7 figs.

  19. Is 1p36 deletion associated with anterior body wall defects?

    PubMed

    Çöllü, Medis; Yüksel, Şirin; Şirin, Başak Kumbasar; Abbasoğlu, Latif; Alanay, Yasemin

    2016-07-01

    Epispadias and exstrophy of the cloaca, also known as OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects), respectively constitute the most benign and severe ends of the bladder exstrophy-epispadias complex (BEEC) spectrum. In 2009, El-Hattab et al. reported the first patient with OEIS complex associated with a chromosome 1p36 deletion. Here we report a second patient with 1p36 deletion who also has classic bladder exstrophy, supporting the possible role of genes in this region in the development of BEEC. The absence of omphalocele and imperforate anus in our patient places him toward classic bladder exstrophy while presence of spina bifida and the absence of coccyx suggest an overlap with OEIS complex. An additional differential diagnosis is the pentalogy of Cantrell in our patient as he also has a diaphragmatic hernia and an incomplete sternum. This is the second observation of a ventral midline birth defect in association with 1p36 deletion syndrome, following El-Hattab et al.'s report [2009]. The three genes (NOCL2, DVL1, and MMP23B) discussed as possible candidates are also among the deleted ones in our patient, supporting the possible role of these genes in BEEC spectrum. © 2016 Wiley Periodicals, Inc.

  20. Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for “double trouble” overlapping syndromes

    PubMed Central

    Ricci, Giulia; Scionti, Isabella; Alì, Greta; Volpi, Leda; Zampa, Virna; Fanin, Marina; Angelini, Corrado; Politano, Luisa; Tupler, Rossella; Siciliano, Gabriele

    2012-01-01

    We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient’s muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient. PMID:22245016

  1. Different pre-S deletion patterns and their association with hepatitis B virus genotypes

    PubMed Central

    Chen, Bing-Fang

    2016-01-01

    the start codon of the L protein was frequently observed in the HBV/C group (20.9% vs 9.3%, P = 0.228), particularly in the LC patients (42.9% vs 12.5%). Different patterns of pre-S deletions were also found between the HBV/B and HBV/C groups according to different clinical outcomes. In CH patients, deletion in the site for polymerized human serum albumin was more frequent in the HBV/B group (88.9% vs 36.4%, P = 0.028). In the LC-HCC patients, the rate of deletion in the pre-S2 region was significantly higher in the HBV/B group than in the HBV/C group (P < 0.05). CONCLUSION HBV/B- and HBV/C-infected carriers exhibit different patterns of pre-S deletion, which may be associated with the progression of liver diseases.

  2. Different pre-S deletion patterns and their association with hepatitis B virus genotypes

    PubMed Central

    Chen, Bing-Fang

    2016-01-01

    the start codon of the L protein was frequently observed in the HBV/C group (20.9% vs 9.3%, P = 0.228), particularly in the LC patients (42.9% vs 12.5%). Different patterns of pre-S deletions were also found between the HBV/B and HBV/C groups according to different clinical outcomes. In CH patients, deletion in the site for polymerized human serum albumin was more frequent in the HBV/B group (88.9% vs 36.4%, P = 0.028). In the LC-HCC patients, the rate of deletion in the pre-S2 region was significantly higher in the HBV/B group than in the HBV/C group (P < 0.05). CONCLUSION HBV/B- and HBV/C-infected carriers exhibit different patterns of pre-S deletion, which may be associated with the progression of liver diseases. PMID:27672298

  3. Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation.

    PubMed

    Lugtenberg, Dorien; Zangrande-Vieira, Luiz; Kirchhoff, Maria; Whibley, Annabel C; Oudakker, Astrid R; Kjaergaard, Susanne; Vianna-Morgante, Angela M; Kleefstra, Tjitske; Ruiter, Mariken; Jehee, Fernanda S; Ullmann, Reinhard; Schwartz, Charles E; Stratton, Michael; Raymond, F Lucy; Veltman, Joris A; Vrijenhoek, Terry; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke H M; Hehir-Kwa, Jayne Y; Froyen, Guy; Chelly, Jamel; Ropers, Hans Hilger; Moraine, Claude; Gècz, Jozef; Knijnenburg, Jeroen; Kant, Sarina G; Hamel, Ben C J; Rosenberg, Carla; van Bokhoven, Hans; de Brouwer, Arjan P M

    2010-03-01

    ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.

  4. Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children

    PubMed Central

    Zahir, Farah; Firth, Helen V; Baross, Agnes; Delaney, Allen D; Eydoux, Patrice; Gibson, William T; Langlois, Sylvie; Martin, Howard; Willatt, Lionel; Marra, Marco A; Friedman, Jan M

    2007-01-01

    Methods and results: We identified de novo submicroscopic chromosome 14q11.2 deletions in two children with idiopathic developmental delay and cognitive impairment. Vancouver patient 5566 has a ∼200 kb deletion and Vancouver patient 8326 has a ∼1.6 Mb deletion. The Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) revealed a third patient with idiopathic developmental delay and cognitive impairment, DECIPHER patient 126, who has a ∼1.1 Mb deletion of 14q11.2. The deletion of patient 5566 overlaps that of patient 126 and both of these deletions lie entirely within that of patient 8326. All three children have similar dysmorphic features, including widely‐spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip and similar auricular anomalies. Conclusion: The minimal common deletion region on chromosome 14q11.2 is only ∼35 kb (from 20.897 to 20.932, University of California at Santa Cruz (UCSC) Genome Browser; build hg18, March 2006) and includes only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotypes. The non‐recurrent breakpoints of these patients, the presence of normal copy number variants in the region and the local genomic structure support the notion that this region has reduced stability. PMID:17545556

  5. A Japanese boy with myalgia and cramps has a novel in-frame deletion of the dystrophin gene.

    PubMed

    Ishigaki, C; Patria, S Y; Nishio, H; Yabe, M; Matsuo, M

    1996-05-01

    We report a Japanese Becker muscular dystrophy (BMD) patient with occasional myalgia and cramps during normal activity that developed at the age of 28 months. His family history was negative for neuromuscular diseases. Muscle biopsy analyses, including dystrophin immunostaining, disclosed no clinically relevant findings. The diagnosis of BMD was initially made at the age of 10 years, when indications of persistent high serum levels of CK prompted us to screen deletions in the dystrophin gene by amplification of 19 deletion-prone exons from the genomic DNA by the polymerase chain reaction (PCR). Among the exons examined, exons 13 and 17 were deleted. To clarify the size of the deletion, the dystrophin transcript was analyzed by reverse transcription PCR. The determined nucleotide sequence of the amplified product encompassing exons 10 to 20 disclosed that the entire segment corresponding to exons 13 to 18 (810 bp) was absent, a deletion that would be expected to cause the production of a dystrophin protein lacking 270 amino acids from the rod domain. This result indicates that occasional myalgia and cramps could be early clinical manifestations of mild BMD, especially in patients who have a deletion in the rod domain, and that deletion screening of the dystrophin gene might be the only reliable method to diagnose such cases.

  6. Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions.

    PubMed

    Rosenfeld, Jill A; Crolla, John A; Tomkins, Susan; Bader, Patricia; Morrow, Bernice; Gorski, Jerome; Troxell, Robin; Forster-Gibson, Cynthia; Cilliers, Deirdre; Hislop, R Gordon; Lamb, Allen; Torchia, Beth; Ballif, Blake C; Shaffer, Lisa G

    2010-08-01

    Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.

  7. Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study

    PubMed Central

    Giagounidis, Aristoteles; Mufti, Ghulam J; Mittelman, Moshe; Sanz, Guillermo; Platzbecker, Uwe; Muus, Petra; Selleslag, Dominik; Beyne-Rauzy, Odile; te Boekhorst, Peter; del Cañizo, Consuelo; Guerci-Bresler, Agnès; Nilsson, Lars; Lübbert, Michael; Quesnel, Bruno; Ganser, Arnold; Bowen, David; Schlegelberger, Brigitte; Göhring, Gudrun; Fu, Tommy; Benettaib, Bouchra; Hellström-Lindberg, Eva; Fenaux, Pierre

    2014-01-01

    Objective A subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). Methods Patients received lenalidomide 10 mg/d (days 1–21; n = 47) or 5 mg/d (days 1–28; n = 43) on 28-d cycles or placebo (n = 45). From the placebo and lenalidomide 5 mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10 mg at 16 wk, respectively. Results Rates of red blood cell-transfusion independence (RBC-TI) ≥182 d were higher in the lenalidomide 10 mg (57.4%; P < 0.0001) and 5 mg (37.2%; P = 0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major + minor responses) were 56.8% (P < 0.0001), 23.1% (P = 0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10 mg, 5 mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC-TI ≥182 d vs. non-responders (P = 0.0072). The most common grade 3–4 adverse event was myelosuppression. Conclusions These data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q). PMID:24813620

  8. Interstitial deletion of distal 13q associated with Hirschsprung's disease.

    PubMed Central

    Lamont, M A; Fitchett, M; Dennis, N R

    1989-01-01

    Three cases of interstitial deletion of chromosome 13 involving the common segment 13q22.1----q32.1 are reported. In addition to the recognised clinical features of this deletion, two had Hirschsprung's disease. Images PMID:2918536

  9. Velopharyngeal Anatomy in 22q11.2 Deletion Syndrome: A Three-Dimensional Cephalometric Analysis

    PubMed Central

    Ruotolo, Rachel A.; Veitia, Nestor A.; Corbin, Aaron; McDonough, Joseph; Solot, Cynthia B.; McDonald-McGinn, Donna; Zackai, Elaine H.; Emanuel, Beverly S.; Cnaan, Avital; LaRossa, Don; Arens, Raanan; Kirschner, Richard E.

    2010-01-01

    Objective 22q11.2 deletion syndrome is the most common genetic cause of velopharyngeal dysfunction (VPD). Magnetic resonance imaging (MRI) is a promising method for noninvasive, three-dimensional (3D) assessment of velopharyngeal (VP) anatomy. The purpose of this study was to assess VP structure in patients with 22q11.2 deletion syndrome by using 3D MRI analysis. Design This was a retrospective analysis of magnetic resonance images obtained in patients with VPD associated with a 22q11.2 deletion compared with a normal control group. Setting This study was conducted at The Children’s Hospital of Philadelphia, a pediatric tertiary care center. Patients, Participants The study group consisted of 5 children between the ages of 2.9 and 7.9 years, with 22q11.2 deletion syndrome confirmed by fluorescence in situ hybridization analysis. All had VPD confirmed by nasendoscopy or videofluoroscopy. The control population consisted of 123 unaffected patients who underwent MRI for reasons other than VP assessment. Interventions Axial and sagittal T1- and T2-weighted magnetic resonance images with 3-mm slice thickness were obtained from the orbit to the larynx in all patients by using a 1.5T Siemens Visions system. Outcome Measures Linear, angular, and volumetric measurements of VP structures were obtained from the magnetic resonance images with VIDA image- processing software. Results The study group demonstrated greater anterior and posterior cranial base and atlanto-dental angles. They also demonstrated greater pharyngeal cavity volume and width and lesser tonsillar and adenoid volumes. Conclusion Patients with a 22q11.2 deletion demonstrate significant alterations in VP anatomy that may contribute to VPD. PMID:16854203

  10. 76 FR 20994 - Privacy Act of 1974; Deletion of an Existing System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-14

    ...In accordance with the requirements of the Privacy Act of 1974, HRSA is deleting an existing system of records titled Record of Patient's Personal Valuables and Monies, HRSA SOR 09-15-0002, established at Vol. 59, No. 61 Federal Register pp 6854-6, December 28,...

  11. Patterns of Comprehension Performance in Agrammatic Broca's Aphasia: A Test of the Trace Deletion Hypothesis

    ERIC Educational Resources Information Center

    Caramazza, A.; Capasso, R.; Capitani, E.; Miceli, G.

    2005-01-01

    We tested the core prediction of the Trace Deletion Hypothesis (TDH) of agrammatic Broca's aphasia, which contends that such patients' comprehension performance is normal for active reversible sentences but at chance level for passive reversible sentences. We analyzed the comprehension performance of 38 Italian Broca's aphasics with verified…

  12. Deletions of VCX-A and NLGN4: A Variable Phenotype Including Normal Intellect

    ERIC Educational Resources Information Center

    Macarov, M.; Zeigler, M.; Newman, J. P.; Strich, D.; Sury, V.; Tennenbaum, A.; Meiner, V.

    2007-01-01

    Background: Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, "VCX-A" (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports…

  13. Core Neuropsychological Characteristics of Children and Adolescents with 22q11.2 Deletion

    ERIC Educational Resources Information Center

    Jacobson, C.; Shearer, J.; Habel, A.; Kane, F.; Tsakanikos, E.; Kravariti, E.

    2010-01-01

    Background: The 22q11.2 deletion syndrome (22qDS) confers high risk for intellectual disability and neuropsychological/academic impairment, although a minority of patients show average intelligence. Intellectual heterogeneity and the high prevalence of psychiatric diagnoses in earlier studies may have obscured the prototypical neuropsychological…

  14. MECP2 deletions and genotype-phenotype correlation in Rett syndrome.

    PubMed

    Scala, Elisa; Longo, Ilaria; Ottimo, Federica; Speciale, Caterina; Sampieri, Katia; Katzaki, Eleni; Artuso, Rosangela; Mencarelli, Maria Antonietta; D'Ambrogio, Tatiana; Vonella, Giuseppina; Zappella, Michele; Hayek, Giuseppe; Battaglia, Agatino; Mari, Francesca; Renieri, Alessandra; Ariani, Francesca

    2007-12-01

    Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).

  15. Velo-cardio-facial and partial DiGeorge phenotype in a child with interstitial deletion at 10p13 - implications for cytogenetics and molecular biology

    SciTech Connect

    Lipson, A.; Sholler, G.; Issacs, D.

    1996-11-11

    We report on a female with a interstitial deletion of 10p13 and a phenotype similar to that seen with the 22q deletion syndromes (DiGeorge/velo-cardio-facial). She had a posterior cleft palate, perimembranous ventricular septal defect, dyscoordinate swallowing, T-cell subset abnormalities, small ears, maxillary and mandibular hypoplasia, broad nasal bridge, deficient alae nasi, contractures of fingers and developmental delay. This could indicate homology of some developmental genes at 22q and 10p so that patients with the velocardiofacial phenotype who do not prove to be deleted on 22q are candidates for a 10p deletion. 58 refs., 3 figs.

  16. Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies.

    PubMed

    Puda, Ana; Milosevic, Jelena D; Berg, Tiina; Klampfl, Thorsten; Harutyunyan, Ashot S; Gisslinger, Bettina; Rumi, Elisa; Pietra, Daniela; Malcovati, Luca; Elena, Chiara; Doubek, Michael; Steurer, Michael; Tosic, Natasa; Pavlovic, Sonja; Guglielmelli, Paola; Pieri, Lisa; Vannucchi, Alessandro M; Gisslinger, Heinz; Cazzola, Mario; Kralovics, Robert

    2012-03-01

    Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 gene--member of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders.

  17. Expanding the ocular phenotype of 14q terminal deletions: A novel presentation of microphthalmia and coloboma in ring 14 syndrome with associated 14q32.31 deletion and review of the literature.

    PubMed

    Salter, Claire G; Baralle, Diana; Collinson, Morag N; Self, James E

    2016-04-01

    A variety of ocular anomalies have been described in the rare ring 14 and 14q terminal deletion syndromes, yet the character, prevalence, and extent of these anomalies are not well defined. Identification of these ocular anomalies can be central to providing diagnoses and facilitating optimal individual patient management. We report a child with a 14q32.31 terminal deletion and ring chromosome formation, presenting with severe visual impairment secondary to significant bilateral coloboma and microphthalmia. This patient is compared to previously reported patients with similar ocular findings and deletion sizes to further refine a locus for coloboma in the 14q terminal region. Those with ring formation and linear deletions are compared and the possibility of ring formation affecting the proximal 14q region is discussed. This report highlights the severity of ocular anomalies that can be associated with ring 14 and 14q terminal deletion syndromes and reveals the limited documentation of ocular examination in these two related syndromes. This suggests that many children with these genetic changes do not undergo an ophthalmology examination as part of their clinical assessment, yet it is only when this evaluation becomes routine that the true prevalence and extent of ocular involvement can be defined. This report therefore advocates for a thorough ophthalmological exam in children with ring 14 or 14q terminal deletion syndrome.

  18. Genotype/phenotype correlation in women with nonmosaic X chromosome deletions and Turner syndrome

    SciTech Connect

    Zinn, A.R.

    1994-09-01

    Turner syndrome is a complex human developmental disorder associated with the absence of the second sex chromosome (monosomy X). Cardinal features of the Turner phenotype include high intrauterine lethality, growth retardation, gonadal failure, and the variable presence of specific somatic abnormalities such as webbed neck, lymphedema, and skeletal abnormalities. Recent observations support the hypothesis that the phenotype associated with monosomy X results from haploid dosage of genes common the X and Y chromosomes that escape X-inactivation ({open_quotes}Turner genes{close_quotes}). Apart from a locus causing short stature that maps to the pseudoautosomal region on the distal short arm, the location of X-linked Turner genes is not known. Karyotype/phenotype correlations in women with partial X deletions have been inconsistent. However, previous studies have focused on sporadic sex chromosome aberrations and may have been confounded by occult mosaicism. In addition, mapping of deletions was limited by the resolution of cytogenetic techniques. I am reexamining genotype/phenotype correlations in partial X monosomy, focusing on a subset of cases in which mosaicism is highly unlikely (e.g., unbalanced X-autosome translocations, familial X deletions), and using molecular techniques to map deletions. I have collected eight cases of nonmosaic X deletions in women with varied manifestations of Turner syndrome. Cytogenetic data suggests that genes responsible for Turner anatomic abnormalities may lie within a critical region of the very proximal portion of the short arm (Xp11). Molecular characterization of the deletions is in progress. Methods include (1) fluorescence in situ hybridization of metaphase spreads from patient-derived cell lines, using cosmid probes that map to known locations on Xp, and (2) sequence tagged site (STS) content mapping of somatic cell hybrids retaining the deleted X chromosomes derived from these cell lines.

  19. Chromosome 22q11.2 deletion in a boy with Opitz (G/BBB) syndrome

    SciTech Connect

    Fryburg, J.S.; Lin, K.Y.; Golden, W.L.

    1996-03-29

    This report is on a 14-month-old boy with manifestations of Opitz (G/BBB) syndrome in whom a 22q11.2 deletion was found. Deletion analysis was requested because of some findings in this patient reminiscent of velocardiofacial (VCF) syndrome. The extent of aspiration and of respiratory symptoms in this child is not usually seen in VCF syndrome. Opitz syndrome maps to at least two loci, one on Xp, the other on 22q11.2. 12 refs., 2 figs.

  20. 21q21 deletion involving NCAM2: report of 3 cases with neurodevelopmental disorders.

    PubMed

    Petit, Florence; Plessis, Ghislaine; Decamp, Matthieu; Cuisset, Jean-Marie; Blyth, Moira; Pendlebury, Maria; Andrieux, Joris

    2015-01-01

    Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment. PMID:25464110

  1. 21q21 deletion involving NCAM2: report of 3 cases with neurodevelopmental disorders.

    PubMed

    Petit, Florence; Plessis, Ghislaine; Decamp, Matthieu; Cuisset, Jean-Marie; Blyth, Moira; Pendlebury, Maria; Andrieux, Joris

    2015-01-01

    Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.

  2. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

    PubMed Central

    La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J.; Mecucci, Cristina

    2016-01-01

    Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. PMID:27151989

  3. Genetics Home Reference: 22q11.2 deletion syndrome

    MedlinePlus

    ... Home Health Conditions 22q11.2 deletion syndrome 22q11.2 deletion syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description 22q11.2 deletion syndrome (which is also known by several ...

  4. Genetics Home Reference: 22q13.3 deletion syndrome

    MedlinePlus

    ... Home Health Conditions 22q13.3 deletion syndrome 22q13.3 deletion syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description 22q13.3 deletion syndrome , which is also commonly known as ...

  5. Rac1 deletion causes thymic atrophy.

    PubMed

    Hunziker, Lukas; Benitah, Salvador Aznar; Aznar Benitah, Salvador; Braun, Kristin M; Jensen, Kim; McNulty, Katrina; Butler, Colin; Potton, Elspeth; Nye, Emma; Boyd, Richard; Laurent, Geoff; Glogauer, Michael; Wright, Nick A; Watt, Fiona M; Janes, Sam M

    2011-04-29

    The thymic stroma supports T lymphocyte development and consists of an epithelium maintained by thymic epithelial progenitors. The molecular pathways that govern epithelial homeostasis are poorly understood. Here we demonstrate that deletion of Rac1 in Keratin 5/Keratin 14 expressing embryonic and adult thymic epithelial cells leads to loss of the thymic epithelial compartment. Rac1 deletion led to an increase in c-Myc expression and a generalized increase in apoptosis associated with a decrease in thymic epithelial proliferation. Our results suggest Rac1 maintains the epithelial population, and equilibrium between Rac1 and c-Myc may control proliferation, apoptosis and maturation of the thymic epithelial compartment. Understanding thymic epithelial maintenance is a step toward the dual goals of in vitro thymic epithelial cell culture and T cell differentiation, and the clinical repair of thymic damage from graft-versus-host-disease, chemotherapy or irradiation.

  6. A child with an inherited 0.31 Mb microdeletion of chromosome 14q32.33: further delineation of a critical region for the 14q32 deletion syndrome.

    PubMed

    Holder, J Lloyd; Lotze, Timothy E; Bacino, Carlos; Cheung, Sau-Wai

    2012-08-01

    Chromosome 14q32.3 deletions are uncommon, with most described patients harboring a ring chromosome 14. Only 15 deletions have been described not associated with ring formation or other complex chromosomal rearrangements. Here, we describe a child with the smallest deletion of chromosome 14q32.3 reported in the literature. This child's deletion encompasses at most 0.305 Mb and six genes including NUDT14, BRF1, BTBD6, PACS2, MTA1, and TEX22. He has similar clinical findings, including mild facial dysmorphisms and intellectual disability, as other individuals with much larger deletions of the terminus of the long arm of chromosome 14. This suggests that the genes deleted in our patient contribute to the 14q32 deletion syndrome.

  7. Fine characterisation of a recombination hotspot at the DPY19L2 locus and resolution of the paradoxical excess of duplications over deletions in the general population.

    PubMed

    Coutton, Charles; Abada, Farid; Karaouzene, Thomas; Sanlaville, Damien; Satre, Véronique; Lunardi, Joël; Jouk, Pierre-Simon; Arnoult, Christophe; Thierry-Mieg, Nicolas; Ray, Pierre F

    2013-03-01

    We demonstrated previously that 75% of infertile men with round, acrosomeless spermatozoa (globozoospermia) had a homozygous 200-Kb deletion removing the totality of DPY19L2. We showed that this deletion occurred by Non-Allelic Homologous Recombination (NAHR) between two homologous 28-Kb Low Copy Repeats (LCRs) located on each side of the gene. The accepted NAHR model predicts that inter-chromatid and inter-chromosome NAHR create a deleted and a duplicated recombined allele, while intra-chromatid events only generate deletions. Therefore more deletions are expected to be produced de novo. Surprisingly, array CGH data show that, in the general population, DPY19L2 duplicated alleles are approximately three times as frequent as deleted alleles. In order to shed light on this paradox, we developed a sperm-based assay to measure the de novo rates of deletions and duplications at this locus. As predicted by the NAHR model, we identified an excess of de novo deletions over duplications. We calculated that the excess of de novo deletion was compensated by evolutionary loss, whereas duplications, not subjected to selection, increased gradually. Purifying selection against sterile, homozygous deleted men may be sufficient for this compensation, but heterozygously deleted men might also suffer a small fitness penalty. The recombined alleles were sequenced to pinpoint the localisation of the breakpoints. We analysed a total of 15 homozygous deleted patients and 17 heterozygous individuals carrying either a deletion (n = 4) or a duplication (n = 13). All but two alleles fell within a 1.2-Kb region central to the 28-Kb LCR, indicating that >90% of the NAHR took place in that region. We showed that a PRDM9 13-mer recognition sequence is located right in the centre of that region. Our results therefore strengthen the link between this consensus sequence and the occurrence of NAHR. PMID:23555282

  8. Fine Characterisation of a Recombination Hotspot at the DPY19L2 Locus and Resolution of the Paradoxical Excess of Duplications over Deletions in the General Population

    PubMed Central

    Coutton, Charles; Abada, Farid; Karaouzene, Thomas; Sanlaville, Damien; Satre, Véronique; Lunardi, Joël; Jouk, Pierre-Simon; Arnoult, Christophe; Thierry-Mieg, Nicolas; Ray, Pierre F.

    2013-01-01

    We demonstrated previously that 75% of infertile men with round, acrosomeless spermatozoa (globozoospermia) had a homozygous 200-Kb deletion removing the totality of DPY19L2. We showed that this deletion occurred by Non-Allelic Homologous Recombination (NAHR) between two homologous 28-Kb Low Copy Repeats (LCRs) located on each side of the gene. The accepted NAHR model predicts that inter-chromatid and inter-chromosome NAHR create a deleted and a duplicated recombined allele, while intra-chromatid events only generate deletions. Therefore more deletions are expected to be produced de novo. Surprisingly, array CGH data show that, in the general population, DPY19L2 duplicated alleles are approximately three times as frequent as deleted alleles. In order to shed light on this paradox, we developed a sperm-based assay to measure the de novo rates of deletions and duplications at this locus. As predicted by the NAHR model, we identified an excess of de novo deletions over duplications. We calculated that the excess of de novo deletion was compensated by evolutionary loss, whereas duplications, not subjected to selection, increased gradually. Purifying selection against sterile, homozygous deleted men may be sufficient for this compensation, but heterozygously deleted men might also suffer a small fitness penalty. The recombined alleles were sequenced to pinpoint the localisation of the breakpoints. We analysed a total of 15 homozygous deleted patients and 17 heterozygous individuals carrying either a deletion (n = 4) or a duplication (n = 13). All but two alleles fell within a 1.2-Kb region central to the 28-Kb LCR, indicating that >90% of the NAHR took place in that region. We showed that a PRDM9 13-mer recognition sequence is located right in the centre of that region. Our results therefore strengthen the link between this consensus sequence and the occurrence of NAHR. PMID:23555282

  9. A review of 18p deletions.

    PubMed

    Hasi-Zogaj, Minire; Sebold, Courtney; Heard, Patricia; Carter, Erika; Soileau, Bridgette; Hill, Annice; Rupert, David; Perry, Brian; Atkinson, Sidney; O'Donnell, Louise; Gelfond, Jon; Lancaster, Jack; Fox, Peter T; Hale, Daniel E; Cody, Jannine D

    2015-09-01

    Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development. PMID:26250845

  10. Probabilistic phylogenetic inference with insertions and deletions.

    PubMed

    Rivas, Elena; Eddy, Sean R

    2008-01-01

    A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth-death) evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new "concordance test" benchmark on real ribosomal RNA alignments, we show that the extended program dnamlepsilon improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm. PMID:18787703

  11. An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

    PubMed

    Pebrel-Richard, Céline; Debost-Legrand, Anne; Eymard-Pierre, Eléonore; Greze, Victoria; Kemeny, Stéphan; Gay-Bellile, Mathilde; Gouas, Laetitia; Tchirkov, Andreï; Vago, Philippe; Goumy, Carole; Francannet, Christine

    2014-03-01

    With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

  12. Deletion at 14q22-23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies.

    PubMed

    Nolen, Leisha D; Amor, David; Haywood, Ashley; St Heaps, Luke; Willcock, Chris; Mihelec, Marija; Tam, Patrick; Billson, Frank; Grigg, John; Peters, Greg; Jamieson, Robyn V

    2006-08-15

    Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high-resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22-23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22-23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22-23 deletion patients.

  13. Unique de novo interstitial deletion of chromosome 17, del(17) (q23.2q24.3) in a female newborn with multiple congenital anomalies

    SciTech Connect

    Levin, M.L.; Shaffer, L.G.; Lewis, R.L.

    1995-01-02

    We describe a newborn with a novel interstitial deletion of the long arm of chromosome 17 (del(17) (q23.2q24.3)) who died on day of life 17 during a recurrent apneic episode. Her phenotype included severe growth retardation, multiple facial anomalies, maldeveloped oralpharyngeal structures, and digital and widespread skeletal anomalies. This patient`s phenotype was compared to two other reported patients with deletion 17q with minor clinical overlap consistent with a unique deletion. 9 refs., 2 figs.

  14. A 50 kb L1-type deletion mutation of the HEXB gene in Sandhoff disease

    SciTech Connect

    Zhang, Z.X.; Wakamatsu, N.; Akerman, B.R.

    1994-09-01

    Sandhoff disease is an autosomal recessive lysosomal storage disease resulting from mutations of the HEXB gene encoding the {beta}-subunit of {beta}-hexosaminidase A. A 16 kb deletion spanning the promoter region to intron 5 of the HEXB gene, occurring in {approximately}25% of mutant alleles, is the most common mutation known. We have identified a second large deletion in a patient with the severe, infantile form of Sandhoff disease. Single strand conformational polymorphism (SSCP) analysis revealed that the proband, a carrier sister and their mother had one dose of the HEXB gene. This was distinguished through the identification of several polymorphic sites between the promoter and exon 5 (father heterozygous at all sites, others {open_quotes}hemizygous{close_quotes}). Using a combination of pulse field electrophoresis and fine mapping by Southern blot analysis, we found that the deletion begins {approximately}25 kb 5{prime} of the HEXB promoter and ends within a BamHI/MscI fragment in intron 6. Sequence analysis of the region abutting the site of the deletion in intron 6 suggests that the deletion arose from recombination between L1-type sequence repeats. The second mutation, inherited from the father, was found by SSCP analysis and direct sequencing of exon 1 PCR products to be C{sub 185}{yields}T (S62T) and was not present in 60 control chromosomes.

  15. Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

    PubMed Central

    Sogaard, Marie; Tümer, Zeynep; Hjalgrim, Helle; Hahnemann, Johanne; Friis, Birgitte; Ledaal, Paal; Pedersen, Vibeke Faurholt; Baekgaard, Peter; Tommerup, Niels; Cingöz, Sultan; Duno, Morten; Brondum-Nielsen, Karen

    2005-01-01

    Background Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. Methods We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. Results We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Conclusion Subtelomeric screening is a useful adjunct to conventional cytogenetic analyses, and should be considered in mentally retarded subjects with dysmorphic features and unknown cause. PMID:15904506

  16. Duplication and deletion of CFC1 associated with heterotaxy syndrome.

    PubMed

    Cao, Ruixue; Long, Fei; Wang, Liping; Xu, Yuejuan; Guo, Ying; Li, Fen; Chen, Sun; Sun, Kun; Xu, Rang

    2015-02-01

    Heterotaxy syndrome, which causes significant morbidity and mortality, is a class of congenital disorders, in which normal left-right asymmetry cannot be properly established. To explore the role of copy number variants (CNVs) in the occurrence of heterotaxy syndrome, we recruited 93 heterotaxy patients and studied 12 of them by the Affymetrix Genome-Wide Human SNP 6.0 Array. The results were confirmed in the remaining 81 patients and 500 healthy children by quantitative real-time polymerase chain reaction (qPCR). The analysis of the SNP6.0 array showed a duplication of chromosome 2q21.1, which was verified by qPCR. The result of qPCR in the other 81 patients showed that 8/81 patients had the CNVs of 2q21.1 and the only overlapping gene in these patients is CFC1. However, in the 500 healthy children, only one carried the duplication of CFC1 (p=3.5×10(-7)). The duplication and deletion of CFC1 may play key roles in the occurrence of heterotaxy syndrome. Moreover, the transposed great arteries, double outlet right ventricle, single atrium, and single ventricle may share a common genetic etiology with the heterotaxy syndrome. PMID:25423076

  17. Renal Failure Associated with APECED and Terminal 4q Deletion: Evidence of Autoimmune Nephropathy

    PubMed Central

    Al-Owain, Mohammed; Kaya, Namik; Al-Zaidan, Hamad; Bin Hussain, Ibrahim; Al-Manea, Hadeel; Al-Hindi, Hindi; Kennedy, Shelley; Iqbal, M. Anwar; Al-Mojalli, Hamad; Al-Bakheet, Albandary; Puel, Anne; Casanova, Jean-Laurent; Al-Muhsen, Saleh

    2010-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion. PMID:21197407

  18. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3

    SciTech Connect

    White, P.S.; Maris, J.M.; Beltinger, C.

    1995-06-06

    Deletion of the short arm of human chromosome 1 is the most common cytogenetic abnormality observed in neuroblastoma. To characterize the region of consistent deletion, we performed loss of heterozygosity (LOH) studies on 122 neuroblastoma tumor samples with 30 distal chromosome 1p polymorphisms. LOH was detected in 32 of the 122 tumors (26%). A single region of LOH, marked distally by D1Z2 and proximally by D1S228, was detected in all tumors demonstrating loss. Also, cells from a patient with a constitutional deletion of 1p36, and from a neuroblastoma cell line with a small 1p36 deletion, were analyzed by fluorescence in situ hybridization. Cells from both sources had interstitial deletions of 1p36.2-36.3 which overlapped the consensus region of LOH defined by the tumors. Interstitial deletion in the constitutional case was confirmed by allelic loss studies using the panel of polymorphic markers. Four proposed candidate genes-DAN, ID3 (heir-1), CDC2L1 (p58), and TNFR2-were shown to lie outside of the consensus region of allelic loss, as defined by the above deletions. These results more precisely define the location of a neuroblastoma suppressor gene within 1p36.2-36.3, eliminating 33 centimorgans of proximal 1p36 from consideration. Furthermore, a consensus region of loss, which excludes the four leading candidate genes, was found in all tumors with 1p36 LOH. 31 refs., 4 figs.

  19. 2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3.

    PubMed

    Mehraein, Yasmin; Pfob, Martina; Steinlein, Ortrud; Aichinger, Eric; Eggert, Marlene; Bubendorff, Valerie; Mannhart, Adelina; Müller, Stefan

    2015-01-01

    2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ∼ 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37. PMID:26112830

  20. Experimental quantum deletion in an NMR quantum information processor

    NASA Astrophysics Data System (ADS)

    Long, Yu; Feng, GuanRu; Pearson, Jasong; Long, GuiLu

    2014-07-01

    We report an NMR experimental realization of a rapid quantum deletion algorithm that deletes marked states in an unsorted database. Unlike classical deletion, where search and deletion are equivalent, quantum deletion can be implemented with only a single query, which achieves exponential speed-up compared to the optimal classical analog. In the experimental realization, the GRAPE algorithm was used to obtain an optimized NMR pulse sequence, and the efficient method of maximum-likelihood has been used to reconstruct the experimental output state.

  1. Deletion of pyruvate decarboxylase by a new method for efficient markerless gene deletions in Gluconobacter oxydans.

    PubMed

    Peters, Björn; Junker, Anja; Brauer, Katharina; Mühlthaler, Bernadette; Kostner, David; Mientus, Markus; Liebl, Wolfgang; Ehrenreich, Armin

    2013-03-01

    Gluconobacter oxydans, a biotechnologically relevant species which incompletely oxidizes a large variety of carbohydrates, alcohols, and related compounds, contains a gene for pyruvate decarboxylase (PDC). This enzyme is found only in very few species of bacteria where it is normally involved in anaerobic ethanol formation via acetaldehyde. In order to clarify the role of PDC in the strictly oxidative metabolism of acetic acid bacteria, we developed a markerless in-frame deletion system for strain G. oxydans 621H which uses 5-fluorouracil together with a plasmid-encoded uracil phosphoribosyltransferase as counter selection method and used this technique to delete the PDC gene (GOX1081) of G. oxydans 621H. The PDC deletion mutant accumulated large amounts of pyruvate but almost no acetate during growth on D-mannitol, D-fructose or in the presence of L-lactate. This suggested that in G. oxydans acetate formation occurs by decarboxylation of pyruvate and subsequent oxidation of acetaldehyde to acetate. This observation and the efficiency of the markerless deletion system were confirmed by constructing deletion mutants of two acetaldehyde dehydrogenases (GOX1122 and GOX2018) and of the acetyl-CoA-synthetase (GOX0412). Acetate formation during growth of these mutants on mannitol did not differ significantly from the wild-type strain.

  2. Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: Evidence for a role of an adjacent locus

    SciTech Connect

    Leu, Y.; Grander, D.; Linder, S.; Einhorn, S.; Soederhall, S. ); Szekely, L. ); Juliusson, G.; Gahrton, G. )

    1993-09-15

    The authors have previously shown that 30% of patients with B-cell chronic lymphocytic leukemia (B-CLL) have hemizygous deletions of the retinoblastoma (RB1) gene at 13q14. RB1 gene deletions may thus participate in malignant transformation of B-CLL, but is it also possible that a neighboring gene on 13q is the relevant one. To answer this question the remaining RB1 allele of eight clones with hemizygous deletions was studied by reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and immunofluorescense techniques. Cells from 10 patients without RB1 gene deletions were also studied by these methods. Lack of RB1 mRNA and RB protein expression was seen in leukemia cells from one of the patients. All other cases were found to be normal with regard to immunofluorescense, RT-PCR, and SSCP analysis, indicating at least one functional RB1 allele and supporting the importance of another gene in the 13q14 deletions. The authors then performed extended Southern blot analysis of the 13q region, using probes for 10 different loci. In 14 of 31 CLL clones (45%), deletions of a region telomeric to the RB1 gene (D13S25) were observed. In 4 of the cases the deletions were homozygous. Hemizygous deletions of the RB1 gene were observed in 11 of these patients and in one of the patients without D13S25 deletions. These data thus indicate that a gene(s) telomeric to RB1 is involved in the malignant transformation of CLL clones and that deletions of this region are a common event in this disease. 20 refs., 3 figs., 3 tabs.

  3. Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-q34.3.

    PubMed

    Xu, Wenbo; Ahmad, Ayesha; Dagenais, Susan; Iyer, Ramaswamy K; Innis, Jeffrey W

    2012-03-01

    The 4q deletion syndrome is a rare chromosome deletion syndrome with a wide range of clinical phenotypes. There is limited clinical phenotype and molecular correlation for congenital heart defects (CHDs) reported so far for this region primarily because many cases are large deletions, often terminal, and because high-resolution array has not been reported in the evaluation of this group of patients. CHDs are reported in about 60% of patients with 4q deletion syndrome, occurring in the presence or absence of dHAND deletion, implying the existence of additional genes in 4q whose dosage influences cardiac development. We report an 8-month-old patient with a large mid-muscular to outlet ventricular septal defect (VSD), moderate-sized secundum-type atrial septal defect (ASD), thickened, dysplastic pulmonary valve with mild stenosis and moderate pulmonic regurgitation, and patent ductus arteriosus (PDA). Illumina CytoSNP array analysis disclosed a de novo, heterozygous, interstitial deletion of 11.6 Mb of genomic material from the long arm of chromosome 4, at 4q32.3-q34.3 (Chr4:167236114-178816031; hg18). The deleted region affects 37 RefSeq genes (hg18), including two provisional microRNA stemloops. Three genes in this region, namely TLL1 (Tolloid-like-1), HPGD (15-hydroxyprostaglandin dehydrogenase), and HAND2 (Heart and neural crest derivatives-expressed protein 2), are known to be involved in cardiac morphogenesis. This report narrows the critical region responsible for CHDs seen in 4q deletion syndrome. PMID:22302627

  4. Detection of an atypical teratoid rhabdoid brain tumor gene deletion in circulating blood using next-generation sequencing.

    PubMed

    Chakravadhanula, Madhavi; Tembe, Waibhav; Legendre, Christophe; Carpentieri, David; Liang, Winnie S; Bussey, Kimberly J; Carpten, John; Berens, Michael E; Bhardwaj, Ratan D

    2014-09-01

    Circulating biomarkers such as somatic chromosome mutations are novel diagnostic tools to detect cancer noninvasively. We describe focal deletions found in a patient with atypical teratoid rhabdoid tumor, a highly aggressive early childhood pediatric tumor. First, we used magnetic resonance imaging (MRI) and histopathology to study the tumor anatomy. Next, we used whole genome sequencing (Next Gen Sequencing) and Bioinformatics interrogation to discover the presence of 3 focal deletions in tumor tissue and 2 of these 3 focal deletions in patient's blood also. About 20% of the blood DNA sequencing reads matched the tumor DNA reads at the SMARCB1 gene locus. Circulating, tumor-specific DNA aberrations are a promising biomarker for atypical teratoid rhabdoid tumor patients. The high percentage of tumor DNA detected in blood indicates that either circulating brain tumor cells lyse in the blood or that contents of brain tumor cells traverse a possibly compromised blood-brain barrier in this patient.

  5. Lethal osteogenesis imperfecta congenita and a 300 base pair gene deletion for an alpha 1(I)-like collagen.

    PubMed Central

    Pope, F M; Cheah, K S; Nicholls, A C; Price, A B; Grosveld, F G

    1984-01-01

    Broad boned lethal osteogenesis imperfecta is a severely crippling disease of unknown cause. By means of recombinant DNA technology a 300 base pair deletion in an alpha 1(I)-like collagen gene was detected in six patients and four complete parent-child groups including patients with this disease. One from each set of the patients' clinically unaffected parents also carried the deletion, implying that affected patients were genetic compounds. The study suggests that prenatal diagnosis should be possible with 100% accuracy in subjects without the deletion and with 50% accuracy in those who possess it (who would be either heterozygous--normal, or affected with the disease). Images FIG 1 FIG 2 FIG 3 FIG 4 PMID:6419953

  6. Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.

    PubMed

    Vincent, Marie; Collet, Corinne; Verloes, Alain; Lambert, Laetitia; Herlin, Christian; Blanchet, Catherine; Sanchez, Elodie; Drunat, Séverine; Vigneron, Jacqueline; Laplanche, Jean-Louis; Puechberty, Jacques; Sarda, Pierre; Geneviève, David

    2014-01-01

    Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.

  7. A phenylalanine codon deletion at the UGT1 gene complex locus of a Crigler-Najjar type I patient generates a pH-sensitive bilirubin UDP-glucuronosyltransferase.

    PubMed

    Ritter, J K; Yeatman, M T; Kaiser, C; Gridelli, B; Owens, I S

    1993-11-01

    The characterization (Ritter, J. K., Chen, F., Sheen, Y. Y., Tran, H. M., Kimura, S., Yeatman, M. T., and Owens, I. S. (1992) J. Biol. Chem. 267, 3257-3261) of the single-copy UGT1 gene complex encoding both bilirubin and phenol UDP-glucuronosyltransferases (transferase) has been critical to the determination of genetic defects in Crigler-Najjar Type I patients. The complex (UGT1A-UGT1G) codes for at least two bilirubin, three bilirubin-like, and two phenol transferases. Seven different exons 1, each with an upstream promoter and each encoding the amino terminus of an isoform, are arrayed in series with four common exons (encoding seven identical carboxyl termini) in the 3'-region of the locus. Predictably, a critical mutation in a common exon inactivates the entire locus. A deleterious mutation in an exon 1, as we report here for the UGT1A gene in a Crigler-Najjar Type I patient, predictably affects the amino terminus of that single isoform. The code for the predominant bilirubin isozyme, the HUG-Br1 protein, is missing the phenylalanine codon at position 170 in exon 1 of UGT1A, abolishing a conserved diphenylalanine. We demonstrate that, at the pH (7.6) routinely used for bilirubin glucuronidation studies, both the HUG-Br1 protein and human liver microsomes have approximately one-third the activity seen at the major pH optimum of 6.4 and at low ionic strength. The altered isozyme with nearly normal activity at pH 7.6 is inactive at pH 6.4, a result consistent with the definition of a pH-sensitive mutant. The Km value for bilirubin using the wild-type protein is approximately 2.5 microM at both pH 6.4 and 7.6 and that for the mutant is 5.0 microns at pH 7.6. The structure of the wild-type enzyme compared to that of the mutant indicates that hydrophobic properties at the active center are critical for metabolizing the lipophile-like substrate. The low ion/pH requirements for bilirubin glucuronidation may signal the basis for the distribution of these isozymes to an

  8. Syndrome of proximal interstitial deletion 4p15: Report of three cases and review of the literature

    SciTech Connect

    Chitayat, D.; Babul, R.; Teshima, I.E.

    1995-01-16

    We report on two boys and a girl with interstitial deletion in the short arm of chromosome 4 including the segment p15.2p15.33. All had normal growth with psychomotor retardation, multiple minor congenital anomalies, and a characteristic face distinct from that of the Wolf-Hirschhorn syndrome. One of the patients had congenitally enlarged penis. These patients resemble some of the previously reported patients with similar cytogenetic abnormalities and suggests the recognition of a specific clinical chromosome deletion syndrome. 12 refs., 6 figs., 1 tab.

  9. Deletion 2q37.3 and autism: molecular cytogenetic mapping of the candidate region for autistic disorder.

    PubMed

    Lukusa, T; Vermeesch, J R; Holvoet, M; Fryns, J P; Devriendt, K

    2004-01-01

    Fine mapping of deletion regions in autistic patients represents a valuable screening tool for identifying candidate genes for autism. A number of studies have ascertained associations between autism and terminal 2q deletion with the breakpoint within 2q37. Here we describe a 12-year-old female patient with terminal 2q37.3 cryptic deletion and autistic behaviour. Her clinical features included hypotonia and feeding difficulties during infancy, coarse face with notably prominent forehead, prominent eyebrows, broad flat nasal bridge and round cheeks, small hands and feet with bilateral brachymetaphalangism, proximal implantation of the thumbs and short toenails, mild mental retardation and autistic behaviour. Recorded autistic features included early lack of eye contact and, during infancy, little social interactions, propensity to be stereotypically busy and to get anxious. In order to more closely delineate the linkage region for autism within 2q37, the findings in this patient were combined to those in 2 previously reported siblings with a well documented 2q37.3 deletion, but without autistic disorder. The exact size of the deleted segment was determined by mapping the deleted region in each group with a series of specific BAC clones linearly ordered on the 2q37 region. The deletion in the autistic patient appeared to be larger [breakpoint flanked by more centromeric clones RP11-680016 (236.9 Mb) and 201F21 (237.4 Mb)] than in the non autistic siblings [more telomeric clones RP11-205L13 (237.8 Mb) and 346114 (238.2 Mb)], revealing a distance of maximum 1.3 Mb between the breakpoints. Accordingly, the extent of the candidate region for susceptibility genes for autism on distal 2q is reduced to maximum 1.3 Mb. Comparison with another well documented autistic patient from the literature results in the same conclusion. These findings represent thus a further step towards identifying genes predisposing to autism.

  10. Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene deletion, the mutation for spinocerebellar ataxia type 15, in Japan screened by gene dosage.

    PubMed

    Obayashi, Masato; Ishikawa, Kinya; Izumi, Yuishin; Takahashi, Makoto; Niimi, Yusuke; Sato, Nozomu; Onodera, Osamu; Kaji, Ryuji; Nishizawa, Masatoyo; Mizusawa, Hidehiro

    2012-03-01

    Spinocerebellar ataxia type 15 (SCA15) is an autosomal dominant neurodegenerative disorder clinically characterized by late-onset, slowly progressive pure cerebellar ataxia. This disease is caused by a heterozygous deletion of the inositol 1, 4, 5-triphosphate receptor type 1 (ITPR1) gene, suggesting that haploinsufficiency of the receptor function is the plausible disease mechanism. To clarify the prevalence of SCA15 in Japan, we designed four sets of probes and primers in different regions of ITPR1 and performed TaqMan PCR assay to search for gene deletions in 226 index SCA patients excluded for repeat expansion disorders. Deletion was found in only one patient, in whom gait ataxia started at 51 years of age and progressed to show cerebellar ataxia. This study demonstrates a simple but efficient method for screening ITPR1 deletion. We also conclude that ITPR1 gene deletions are much rare in Japan than in Europe, comprising only 0.3% in all SCAs in Japan.

  11. Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.

    PubMed

    Bartsch, Oliver; Rasi, Sasan; Delicado, Alicia; Dyack, Sarah; Neumann, Luitgard M; Seemanová, Eva; Volleth, Marianne; Haaf, Thomas; Kalscheuer, Vera M

    2006-09-01

    Rubinstein-Taybi syndrome (RSTS) is a well-known autosomal dominant mental retardation syndrome with typical facial and skeletal abnormalities. Previously, we have reported two patients presenting with RSTS and additional clinical features including failure to thrive, seizures, and intractable infections (Bartsch et al. in Eur J Hum Genet 7:748-756, 1999). Recently we identified a third patient with this condition, termed here severe RSTS, or chromosome 16p13.3 deletion syndrome. The three patients died in infancy, and all displayed a specific mutation, a chromosomal microdeletion including the 3'-end of the CREBBP gene. Using fluorescence in situ hybridization and closely spaced DNA probes, we characterized the deletion intervals in these patients and in three individuals with a deletion of CREBBP and typical RSTS. The deleted DNA segments were found to greatly vary in size, spanning from approximately 40 kb to >3 Mb. Four individuals, including the patients with severe RSTS, exhibited deletions containing gene/s in addition to CREBBP. The patients with severe RSTS all had deletions comprising telomeric neighbor genes of CREBBP, including DNASE1, a dominant gene encoding a nuclease that has been associated with systemic lupus erythematodes. Our findings suggest that severe RSTS is distinct from RSTS and represents a novel true contiguous gene syndrome (chromosome 16p13.3 deletion syndrome). Because of the risk of critical infections and high mortality rate, we recommend that the size of the deletion interval should be determined in CREBBP deletion-positive patients with RSTS, especially in young children. Further studies are needed to delineate the clinical spectrum of the new disorder and to clarify the role of DNASE1.

  12. Growth hormone deficiency in 18q deletion syndrome

    SciTech Connect

    Ghidoni, P.D.; Cody, J.; Danney, J.

    1994-09-01

    The 18q- syndrome is one of the most common chromosomal deletion syndromes. Clinical characteristics are variable but may include: hypotonia, cleft palate, mental retardation and hearing impairment. Growth failure (GF) (<3% weight/height) is present in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 15 patients with 18q- syndrome. Of these 15 patients, 10 have growth failure (<3% weight/height); of the remaining 5, 3 had normal growth parameters and 2 had growth along the 5%. Twelve patients failed to produce adequate GH following standard stimulation testing. Of these 12 patients with inadequate GH production, 2 had normal growth (above 3%). Of the 15, only 1 has normal GH production and normal growth parameters. Bone age was obtained on 1 patient with both GH deficiency and GF, and revealed significant delays. GH levels in response to GH releasing factor were normal in 3 out of 4 patients. MRI studies of GH-deficient patients indicated normal midline structures. Myelination in the few studied GH-deficient patients appeared delayed. The gene for myelin basic protein (MBP) is known to be located on the terminal portion of the long arm of chromosome 18. Neither the gene for GH, GH releasing factor nor GH releasing factor receptor is on chromosome 18. These genes are located on chromosomes 17, chromosome 20 and chromosome 7, respectively. Findings to date suggest that GH deficiency is common in individuals with 18q- syndrome. The etiology of this finding is unknown. We postulate that a gene(s) on chromosome 18q is involved in GH expression.

  13. Low prevalence of hepatitis B virus pre-S deletion mutation in Indonesia.

    PubMed

    Utama, Andi; Siburian, Marlinang Diarta; Fanany, Ismail; Intan, Mariana Destila Bayu; Dhenni, Rama; Kurniasih, Tri Shinta; Lelosutan, Syafruddin A R; Achwan, Wenny Astuti; Arnelis; Lukito, Benyamin; Yusuf, Irawan; Lesmana, Laurentius Adrianus; Sulaiman, Ali; Tai, Susan

    2011-10-01

    The molecular epidemiological study of hepatitis B virus (HBV) in Indonesia is still limited. This study was aimed to identify the prevalence of HBV pre-S deletion/insertion mutations, and to assess the association of pre-S deletion mutation with liver disease progression in Indonesia. Pre-S mutations were identified by direct sequencing. Of the 265 subjects, 32 samples (12.1%) harbored pre-S deletion/insertion mutations. The prevalence of those pre-S mutations was 2.7% (2/75), 12.9% (8/62), 16.7% (11/66), and 17.7% (11/62) in asymptomatic carrier, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma groups, respectively. Statistical analysis showed significant difference among them (P = 0.024). In HBV genotype B (HBV/B), pre-S1, pre-S1/S2, and pre-S2 deletion mutations were detected respectively in 3 (17.6%), 4 (23.5%), and 9 (52.9%) of 17 samples. On the other hand, in HBV/C, 12 of 15 samples (80.0%) showed a pre-S2 deletion mutation, and only 2 samples (13.3%) demonstrated a pre-S1/S2 deletion mutation. These results suggest that in HBV/B deletion mutation tends to occur in pre-S1 or pre-S1/S2 region, while in HBV/C the deletion mutation usually occurs in the pre-S2 region. Analysis of complete genome of four viruses confirmed that 3 isolates were classified into HBV/B3, and 1 isolate was HBV/C1. However, SimPlot and BootScan analyses showed that isolate 08.10.002 was an intragenotypic recombinant between HBV/B3 and HBV/B4. As conclusion, the prevalence of HBV pre-S mutations was relatively low in Indonesian patients compared to those from Taiwan, Japan, and other Asian countries. There was a weak association between pre-S deletion mutation and progressive liver disease.

  14. Independent De Novo 22q11.2 Deletions in First Cousins With DiGeorge/Velocardiofacial Syndrome

    PubMed Central

    Saitta, Sulagna C.; Harris, Stacy E.; McDonald-McGinn, Donna M.; Emanuel, Beverly S.; Tonnesen, Melissa K.; Zackai, Elaine H.; Seitz, Suzanne C.; Driscoll, Deborah A.

    2010-01-01

    Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin’s deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk. PMID:14708107

  15. Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior

    PubMed Central

    Normand, Elizabeth A.; Crandall, Shane R.; Thorne, Catherine A.; Murphy, Emily M.; Voelcker, Bettina; Browning, Catherine; Machan, Jason T.; Moore, Christopher I.; Connors, Barry W.; Zervas, Mark

    2013-01-01

    SUMMARY Tuberous Sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest the thalamus may be affected in Tuberous Sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E)12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. Only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism. PMID:23664552

  16. Overlapping submicroscopic deletions in Xq28 in two unrelated boys with developmental disorders: Identification of a gene near FRAXE

    SciTech Connect

    Gedeon, A.K.; Sutherland, G.R. |; Ades, L.C.; Gecz, J.; Baker, E.; Mulley, J.C.; Keinaenen, M.; Kaeaeriaeinen, H.

    1995-04-01

    Two unrelated boys are described with delay in development and submicroscopic deletions in Xq28, near FRAXE. Molecular diagnosis to exclude the fragile X (FRAXA) syndrome used the direct probe pfxa3, together with a control probe pS8 (DXS296), against PstI restriction digests of DNA. Deletions were detected initially by the control probe pS8, which is an anonymous fragment subcloned from YAC 539, within 1 Mb distal to FRAXA. Further molecular analyses determined that the maximum size of the deletion is <100 kb in one boy (MK) and is wholly overlapped by the deletion of up to {approximately}200 kb in the other (CB). These deletions lie between the sequences detected by the probe VK21C (DXS296) and a dinucleotide repeat VK18AC (DXS295). The patient MK had only speech delay with otherwise normal development, while patient CB had global developmental delay that included speech delay. Detection of overlapping deletions in these two cases led to speculation that coding sequences of a gene(s) important in language development may be affected. Hybridization of the pS8 and VK21A probes to zooblots revealed cross-species homology. This conservation during evolution suggested that this region contains sequences with functional significance in normal development. The VK21A probe detected a 9.5-kb transcript in placenta and brain and a smaller, 2.5-kb, transcript in other tissues analyzed. 26 refs., 6 figs.

  17. A 4-Mb deletion in the region Xq27.3-q28 is associated with non-random inactivation of the non-mutant X chromosome

    SciTech Connect

    Clarke, J.T.R.; Han, L.P.; Michalickova, K.

    1994-09-01

    A girl with severe Hunter disease was found to have a submicroscopic deletion distrupting the IDS locus in the region Xq27.3-q28 together with non-random inactivation of the non-mutant X chromosome. Southern analysis of DNA from the parents and from hamster-patient somatic cell hybrids containing only the mutant X chromosome revealed that the deletion represented a de novo mutation involving the paternal X chromosome. Methylation-sensitive RFLP analysis of DNA from maternal fibroblasts and lymphocytes showed methylation patterns consistent with random X-inactivation, indicating that the non-random X-inactivation in the patient was not inherited and was likely a direct result of the Xq27.3-q28 deletion. A 15 kb EcoRI junction fragment, identified in patient DNA using IDS cDNA probes, was cloned from a size-selected patient DNA library. Clones containing the deletion junction were restriction mapped and fragments were subcloned and used to isolate normal sequence on either side of the deletion from normal X chromosome libraries. Comparison of the sequences from normal and mutant X chromosome clones straddling the deletion breakpoint showed that the mutation had occurred by recombination between Alu repeats. Screening of YAC contigs containing normal X chromosome sequence from the region of the mutation, using probes from either side of the deletion breakpoint, showed that the deletion was approximately 4 Mb in size. Probing of mutant DNA with 16 STSs distributed throughout the region of the deletion confirmed that the mutation is a simple deletion with no complex rearrangements of islands of retained DNA. A search for sequences at Xq27.3-q28 involved in X chromosome inactivation is in progress.

  18. Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data

    PubMed Central

    Mok, Kin Y; Sheerin, Una; Simón-Sánchez, Javier; Salaka, Afnan; Chester, Lucy; Escott-Price, Valentina; Mantripragada, Kiran; Doherty, Karen M; Noyce, Alastair J; Mencacci, Niccolo E; Lubbe, Steven J; Williams-Gray, Caroline H; Barker, Roger A; van Dijk, Karin D; Berendse, Henk W; Heutink, Peter; Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis; Brockmann, Kathrin; Schulte, Claudia; Gasser, Thomas; Foltynie, Thomas; Limousin, Patricia; Morrison, Karen E; Clarke, Carl E; Sawcer, Stephen; Warner, Tom T; Lees, Andrew J; Morris, Huw R; Nalls, Mike A; Singleton, Andrew B; Hardy, John; Abramov, Andrey Y; Plagnol, Vincent; Williams, Nigel M; Wood, Nicholas W

    2016-01-01

    Summary Background Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. Methods We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. Findings We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0–55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5–61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). Interpretation Clinicians should be alert to the possibility of 22q11.2 deletions in

  19. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia.

    PubMed

    Raynaud, S; Cave, H; Baens, M; Bastard, C; Cacheux, V; Grosgeorge, J; Guidal-Giroux, C; Guo, C; Vilmer, E; Marynen, P; Grandchamp, B

    1996-04-01

    A recurrent t(12;21)(p13;q22) has recently been described in human acute lymphoblastic leukemias (ALLs). This translocation fuses TEL and AML1, two genes previously cloned from translocation breakpoints in myeloid leukemias. In addition, allelic loss of the TEL gene can be detected in 15% to 22% of childhood ALLs. In the present study, we have sought allelic deletions of TEL and the presence of the t(12;21) in 50 children with B-lineage ALL, using a combination of microsatellite typing, fluorescent in situ hybridization (FISH), and analysis of the fusion transcripts resulting from the TEL-AML1 gene fusion. Our results indicate that the association between the t(12;21) and the deletion of the nontranslocated allele of TEL is among the most frequent abnormalities observed in B-lineage ALLs. FISH analysis using several cosmid probes showed that, in one patient with a t(12;21) translocation involving TEL, the second allele had an intragenic deletion. This observation points to TEL as the actual target of 12p12-13 deletions in patients that associate a t(12;21) with a deletion. The TEL-AML1 fusion RNA was found in all patients with the t(12;21) whereas the reciprocal AML1-TEL transcript was only found in a subset of patients, suggesting that only the protein product encoded by TEL-AML1 is likely to play a role in leukemogenesis. The observation that, in two patients with the t(12;21), a deletion of TEL was only present in a subclone indicates that this deletion was a secondary event that occurred after the translocation. The frequent occurrence of TEL deletions in patients with t(12;21) suggests that the deletion of the normal TEL allele subsequent to the t(12;21) provides a further proliferative advantage to leukemic cells.

  20. Deletion of the Olfactomedin 4 Gene Is Associated with Progression of Human Prostate Cancer

    PubMed Central

    Li, Hongzhen; Rodriguez-Canales, Jaime; Liu, Wenli; Zhu, Jianqiong; Hanson, Jeffrey C.; Pack, Svetlana; Zhuang, Zhengping; Emmert-Buck, Michael R.; Rodgers, Griffin P.

    2014-01-01

    The olfactomedin 4 (OLFM4) gene is located on chromosome 13q14.3, which frequently is deleted in human prostate cancer. However, direct genetic evidence of OLFM4 gene alteration in human prostate cancer has not yet been obtained. In this study, we investigated the genetics, protein expression, and functions of the OLFM4 gene in human prostate cancer. We found overall 25% deletions within the OLFM4 gene in cancerous epithelial cells compared with adjacent normal epithelial cells that were microdissected from 31 prostate cancer specimens using laser-capture microdissection and genomic DNA sequencing. We found 28% to 45% hemizygous and 15% to 57% homozygous deletions of the OLFM4 gene via fluorescence in situ hybridization analysis from 44 different prostate cancer patient samples. Moreover, homozygous deletion of the OLFM4 gene significantly correlated with advanced prostate cancer. By using immunohistochemical analysis of 162 prostate cancer tissue array samples representing a range of Gleason scores, we found that OLFM4 protein expression correlated inversely with advanced prostate cancer, consistent with the genetic results. We also showed that a truncated mutant of OLFM4 that lacks the olfactomedin domain eliminated suppression of PC-3 prostate cancer cell growth. Together, our findings indicate that OLFM4 is a novel candidate tumor-suppressor gene for chromosome 13q and may shed new light on strategies that could be used for the diagnosis, prognosis, and treatment of prostate cancer patients. PMID:24070418

  1. A New Case of an Extremely Rare 3p21.31 Interstitial Deletion

    PubMed Central

    Lovrecic, Luca; Bertok, Sara; Žerjav Tanšek, Mojca

    2016-01-01

    Interstitial 3p21.31 deletions have been very rarely reported. We describe a 7-year-old boy with global developmental delay, specific facial characteristics, hydronephrosis, and hypothyreosis with a de novo deletion of 3p21.31, encompassing 29 OMIM genes. Despite the wide use of microarrays, no similar case has been reported in the literature so far. Five overlapping cases are deposited in the DECIPHER database, 2 of which have significant overlapping chromosomal aberrations. They both share some phenotypic characteristics with our case, e.g. developmental delay, intellectual disability and facial dysmorphism (arched eyebrows, hypertelorism, low-set ears, and a large nose tip). In addition, loss-of-function mutations in the SETD2 gene (OMIM 612778) of the deleted region have been described in 3 patients, presenting with some similar clinical features, namely overgrowth, intellectual disability, speech delay, hypotonia, autism, and epilepsy. Therefore, SETD2 may explain part of the phenotype in our case. We focused on 3 other genes in the deleted region, based on their known functions, namely CSPG5 (OMIM 606775), PTH1R (OMIM 168468) and SMARCC1 (OMIM 601732), and assessed their potentially important role in describing the patient's phenotype. Additional cases with haploinsufficiency of this region are needed to elucidate further genotype-phenotype correlations. PMID:27385966

  2. Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood

    PubMed Central

    Lewis-Smith, David; Kamer, Kimberli J.; Griffin, Helen; Childs, Anne-Marie; Pysden, Karen; Titov, Denis; Duff, Jennifer; Pyle, Angela; Taylor, Robert W.; Yu-Wai-Man, Patrick; Ramesh, Venkateswaran; Horvath, Rita; Mootha, Vamsi K.

    2016-01-01

    Objective: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy. Methods: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. Results: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. Conclusions: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1. PMID:27123478

  3. A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5

    PubMed Central

    2014-01-01

    Background Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Case presentation Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. Conclusion The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed. PMID:24517234

  4. Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion.

    PubMed

    Esposito, Gabriella; Imperato, Maria Rosaria; Ieno, Luigi; Sorvillo, Rosa; Benigno, Vincenzo; Parenti, Giancarlo; Parini, Rossella; Vitagliano, Luigi; Zagari, Adriana; Salvatore, Francesco

    2010-12-01

    Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease caused by impaired functioning of human liver aldolase (ALDOB). At least 54 subtle/point mutations and only two large intragenic deletions have been found in the ALDOB gene. Here we report two novel ALDOB variants (p.R46W and p.Y343H) and an intragenic deletion that we found in patients with suspected HFI. The residual catalytic activity of the recombinant p.R46W and p.Y343H variants toward F1P was particularly altered. We also characterized a large intragenic deletion that we found in six unrelated patients. This is the first report of six unrelated patients sharing the same ALDOB deletion, thus indicating a founder effect for this allele in our geographic area. Because this deletion involves ALDOB exon 5, it can mimic worldwide common pathogenic genotypes, that is, homozygous p.A150P and p.A175D. Finally, the identification of only one ALDOB mutation in symptomatic patients suggests that HFI symptoms can, albeit rarely, appear also in heterozygotes. Therefore, an excessive and continuous fructose dietary intake may have deleterious effects even in apparently asymptomatic HFI carriers.

  5. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome.

    PubMed

    de la Morena, M Teresa; Eitson, Jennifer L; Dozmorov, Igor M; Belkaya, Serkan; Hoover, Ashley R; Anguiano, Esperanza; Pascual, M Virginia; van Oers, Nicolai S C

    2013-04-01

    Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4× normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance.

  6. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

    PubMed Central

    de la Morena, M. Teresa; Eitson, Jennifer L.; Dozmorov, Igor M.; Belkaya, Serkan; Hoover, Ashley R.; Anguiano, Esperanza; Pascual, M. Virginia; van Oers, Nicolai S.C.

    2013-01-01

    Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3 Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4× normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance. PMID:23454892

  7. A prenatally ascertained de novo terminal deletion of chromosomal bands 1q43q44 associated with multiple congenital abnormalities in a female fetus.

    PubMed

    Sismani, Carolina; Christopoulou, Georgia; Alexandrou, Angelos; Evangelidou, Paola; Donoghue, Jacqueline; Konstantinidou, Anastasia E; Velissariou, Voula

    2015-01-01

    Terminal deletions in the long arm of chromosome 1 result in a postnatally recognizable disorder described as 1q43q44 deletion syndrome. The size of the deletions and the resulting phenotype varies among patients. However, some features are common among patients as the chromosomal regions included in the deletions. In the present case, ultrasonography at 22 weeks of gestation revealed choroid plexus cysts (CPCs) and a single umbilical artery (SUA) and therefore amniocentesis was performed. Chromosomal analysis revealed a possible terminal deletion in 1q and high resolution array CGH confirmed the terminal 1q43q44 deletion and estimated the size to be approximately 8 Mb. Following termination of pregnancy, performance of fetopsy allowed further clinical characterization. We report here a prenatal case with the smallest pure terminal 1q43q44 deletion, that has been molecularly and phenotypically characterized. In addition, to our knowledge this is the first prenatal case reported with 1q13q44 terminal deletion and Pierre-Robin sequence (PRS). Our findings combined with review data from the literature show the complexity of the genetic basis of the associated syndrome.

  8. A MOLECULARLY CHARACTERIZED INTERSTITIAL DELETION ENCOMPASSING THE 11q14.1-q23.3 REGION IN A CASE WITH MULTIPLE CONGENITAL ABNORMALITIES.

    PubMed

    Cetin, Z; Altiok-Clark, O; Yakut, S; Guzel-Nur, B; Mihci, E; Berker-Karauzum, S

    2016-01-01

    Interstitial deletion of chromosome 11 long arm is a rare event. In most of the interstitial deletions on the long arm of chromosome 11 both the position and the size of these deletions are heterogeneous making a precise karyotype-phenotype correlation. In only a few of the reported cases has the deletion been molecularly characterized. Our patient was a 13-year-old male presented; mental motor retardation, strabismus, myopia, retinopathy, sensorineural hearing loss, a long and triangular face, a broad forehead, hypotelorism, nasal septal deviation, a beaked nose, hypoplastic ala nasie, bilateral low-set ears, a high arched palate, crowded teeth, retrognathia, thin lips, a long neck, and sloping shoulders, hyperactive behavior, pulmonary stenosis and lumbar scoliosis. Conventional cytogenetic analysis revealed 46,XY,del(11)(q14.1-q23.3) karyotype in the patient. Array-CGH analysis of the patient's DNA revealed an interstitial deletion encompassing 33.2 Mb in the 11q14.1-q23.3 genomic region (chr11: 83,161,443-116,401,751 ; Hg19). In this report, we present a patient with an interstitial deletion on the long arm of chromosome 11 that encompassed the 11q14.1-q23.3 region; and, using array-CGH analysis, we molecularly characterized the deleted region.

  9. A MOLECULARLY CHARACTERIZED INTERSTITIAL DELETION ENCOMPASSING THE 11q14.1-q23.3 REGION IN A CASE WITH MULTIPLE CONGENITAL ABNORMALITIES.

    PubMed

    Cetin, Z; Altiok-Clark, O; Yakut, S; Guzel-Nur, B; Mihci, E; Berker-Karauzum, S

    2016-01-01

    Interstitial deletion of chromosome 11 long arm is a rare event. In most of the interstitial deletions on the long arm of chromosome 11 both the position and the size of these deletions are heterogeneous making a precise karyotype-phenotype correlation. In only a few of the reported cases has the deletion been molecularly characterized. Our patient was a 13-year-old male presented; mental motor retardation, strabismus, myopia, retinopathy, sensorineural hearing loss, a long and triangular face, a broad forehead, hypotelorism, nasal septal deviation, a beaked nose, hypoplastic ala nasie, bilateral low-set ears, a high arched palate, crowded teeth, retrognathia, thin lips, a long neck, and sloping shoulders, hyperactive behavior, pulmonary stenosis and lumbar scoliosis. Conventional cytogenetic analysis revealed 46,XY,del(11)(q14.1-q23.3) karyotype in the patient. Array-CGH analysis of the patient's DNA revealed an interstitial deletion encompassing 33.2 Mb in the 11q14.1-q23.3 genomic region (chr11: 83,161,443-116,401,751 ; Hg19). In this report, we present a patient with an interstitial deletion on the long arm of chromosome 11 that encompassed the 11q14.1-q23.3 region; and, using array-CGH analysis, we molecularly characterized the deleted region. PMID:27192892

  10. Novel microdeletion syndromes detected by chromosome microarrays.

    PubMed

    Slavotinek, Anne M

    2008-08-01

    Array comparative genomic hybridization (array CGH) has revolutionized the cytogenetic testing available for patients with learning disabilities who have "chromosomal" phenotypes with dysmorphic features and multiple anomalies. Screening large patient cohorts with mental retardation by array CGH has recently lead to the characterization of many novel microdeletion and microduplication syndromes, initially according to the shared cytogenetic aberrations, with secondary characterization of the corresponding phenotypes. This review provides a detailed clinical and molecular cytogenetic description of several of the most common of these aberrations. We have chosen to focus on patients in whom the cytogenetic abnormalities were principally described by array CGH, rather than by G-banded karyotyping or fluorescence in-situ hybridization. The syndromes that we have chosen include the 17q21.31 deletion and 17q21.31 duplication syndromes, 15q13.3 deletion syndrome, 16p11.2 deletion syndrome, 15q24 deletion syndrome, 1q41q42 deletion syndrome, 2p15p16.1 deletion syndrome and 9q22.3 deletion syndrome. In time, we hypothesize that at least some of these will become as clinically well characterized and recognizable to the clinician as the commoner microdeletion syndromes today. Although the full extent of the phenotypes is still evolving for many of these novel microdeletions, it is clear that array CGH has heralded an unparalleled era of discovery for clinical cytogenetics. PMID:18512078

  11. Deletion of ultraconserved elements yields viable mice

    SciTech Connect

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  12. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector, the cloning vector having an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe.

  13. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, J.J.; Quesada, M.A.; Randesi, M.

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector. The cloning vector has an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe. 1 fig.

  14. Are there ethnic differences in deletions in the dystrophin gene?

    SciTech Connect

    Banerjee, M.; Verma, I.C.

    1997-01-20

    We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene. 38 refs., 2 figs., 3 tabs.

  15. Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

    PubMed

    Jiang, Yong-Hui; Pan, Yanzhen; Zhu, Li; Landa, Luis; Yoo, Jong; Spencer, Corinne; Lorenzo, Isabel; Brilliant, Murray; Noebels, Jeffrey; Beaudet, Arthur L

    2010-08-20

    Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-A