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Sample records for 15q24 deleted patients

  1. Further clinical and molecular delineation of the 15q24 microdeletion syndrome

    PubMed Central

    Rosenfeld, Jill A; Shur, Natasha; Slavotinek, Anne M; Cox, Victoria A; Hennekam, Raoul C; Firth, Helen V; Willatt, Lionel; Wheeler, Patricia; Morrow, Eric M; Cook, Joseph; Sullivan, Rachel; Oh, Albert; McDonald, Marie T; Zonana, Jonathan; Keller, Kory; Hannibal, Mark C; Ball, Susie; Kussmann, Jennifer; Gorski, Jerome; Zelewski, Susan; Banks, Valerie; Smith, Wendy; Smith, Rosemarie; Paull, Lindsay; Rosenbaum, Kenneth N; Amor, David J; Silva, Joao; Lamb, Allen; Eichler, Evan E

    2011-01-01

    Background Chromosome 15q24 microdeletion syndrome is a rare genomic disorder characterised by intellectual disability, growth retardation, unusual facial morphology and other anomalies. To date, 20 patients have been reported; 18 have had detailed breakpoint analysis. Aim To further delineate the features of the 15q24 microdeletion syndrome, the clinical and molecular characterisation of fifteen patients with deletions in the 15q24 region was performed, nearly doubling the number of reported patients. Methods Breakpoints were characterised using a custom, high-density array comparative hybridisation platform, and detailed phenotype information was collected for each patient. Results Nine distinct deletions with different breakpoints ranging in size from 266 kb to 3.75 Mb were identified. The majority of breakpoints lie within segmental duplication (SD) blocks. Low sequence identity and large intervals of unique sequence between SD blocks likely contribute to the rarity of 15q24 deletions, which occur 8–10 times less frequently than 1q21 or 15q13 microdeletions in our series. Two small, atypical deletions were identified within the region that help delineate the critical region for the core phenotype in the 15q24 microdeletion syndrome. Conclusion The molecular characterisation of these patients suggests that the core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a 1.1–Mb critical region. However, genes just distal to the critical region also play an important role in cognition and in the development of characteristic facial features associated with 15q24 deletions. Clearly, deletions in the 15q24 region are variable in size and extent. Knowledge of the breakpoints and size of deletion combined with the natural history and medical problems of our patients provide insights that will inform management guidelines. Based on common phenotypic features, all

  2. A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH.

    PubMed

    Klopocki, Eva; Graul-Neumann, Luitgard M; Grieben, Ulrike; Tönnies, Holger; Ropers, Hans-Hilger; Horn, Denise; Mundlos, Stefan; Ullmann, Reinhard

    2008-08-01

    We report on a 10-year-old patient with developmental delay, craniofacial dysmorphism, digital and genital abnormalities. In addition, muscular hypotonia, strabism, and splenomegaly were observed; inguinal and umbilical hernias were surgically corrected. Mucopolysaccharidoses and CDG syndromes could not be found. Chromosome analysis revealed a normal male karyotype (46,XY). A more detailed investigation of the patient's genomic DNA by microarray-based comparative genomic hybridization (array CGH) detected an interstitial 3.7 Mb deletion ranging from 15q24.1 to 15q24.3 which was shown to be de novo. Interstitial deletions involving 15q24 are rare. Sharp et al. (Hum Mol Genet 16:567-572, 2007) recently characterized a recurrent 15q24 microdeletion syndrome with breakpoints in regions of segmental duplications. The de novo microdeletion described here colocalizes with the minimal deletion region of the 15q24 microdeletion syndrome. The distinct clinical phenotype associated with this novel microdeletion syndrome is similar to the phenotype of our patient with respect to specific facial features, developmental delay, microcephaly, digital abnormalities, and genital abnormalities in males. We present a genotype-phenotype correlation and comparison with patients from the literature. PMID:17932688

  3. Characterization of a recurrent 15q24 microdeletion syndrome.

    PubMed

    Sharp, Andrew J; Selzer, Rebecca R; Veltman, Joris A; Gimelli, Stefania; Gimelli, Giorgio; Striano, Pasquale; Coppola, Antonietta; Regan, Regina; Price, Sue M; Knoers, Nine V; Eis, Peggy S; Brunner, Han G; Hennekam, Raoul C; Knight, Samantha J L; de Vries, Bert B A; Zuffardi, Orsetta; Eichler, Evan E

    2007-03-01

    We describe multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24 (1.7-3.9 Mb in size). High-resolution analysis showed that in three patients both proximal and distal breakpoints co-localized to highly identical segmental duplications (>51 kb in length, > 94% identity), suggesting non-allelic homologous recombination as the likely mechanism of origin. Sequencing studies in a fourth individual provided base pair resolution and showed that both breakpoints in this case were located in unique sequence. Despite the differences in the size and location of the deletions, all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue) and resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip), indicating that this represents a novel syndrome caused by haploinsufficiency of one or more dosage-sensitive genes in the minimal deletion region. Our results define microdeletion of 15q24 as a novel recurrent genomic disorder. PMID:17360722

  4. 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

  5. Paratesticular leiomyoma with a der(14)t(12;14)(q15;q24).

    PubMed

    Gorunova, Ludmila; Bjerkehagen, Bodil; Heim, Sverre

    2011-08-01

    While uterine leiomyomas are among the most common and best cytogenetically characterized solid tumors, leiomyomas at other sites are rare. Only two karyotypically abnormal leiomyomas in males have been reported to date, both of them with unspecific chromosome aberrations. We recently analyzed by G-banding a paratesticular leiomyoma, a tumor type not cytogenetically examined before, and found the pseudodiploid karyotype 46,XY,der(5)t(5;14)(q31;q24),der(14)t(12;14)(q15;q24). The leiomyoma cells demonstrated strong immunohistochemical nuclear expression of the HMGA2 protein, supporting a role of HMGA2 as the target gene in 12q14∼15 rearrangements. In uterine leiomyomas, the t(12;14)(q15;q24) is the most frequent translocation leading to overexpression of HMGA2, therefore it seems that a common pathogenetic pathway exists for benign smooth muscle tumors of both the female and male reproductive organs. The finding of this abnormality may help identify a scrotal tumor of uncertain biologic potential but with smooth muscle differentiation as benign. PMID:21962898

  6. 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

  7. 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

  8. Genetics Home Reference: 15q24 microdeletion

    MedlinePlus

    ... a full lower lip, and a long, smooth space between the upper lip and nose (philtrum). Related Information What does it mean if a disorder seems to run in my family? What is the prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency ...

  9. 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. PMID:26620342

  10. Deletion of the entire NF1 gene detected by FISH: Four deletion patients associated with severe manifestations

    SciTech Connect

    Wi, Bai-Lin; Austin, M.A.; Schneider, G.H.; Boles, R.G.; Korf, B.R.

    1995-12-04

    Genetic analysis of NF1 has indicated a wide diversity of mutations, including chromosome rearrangements, deletions, insertions, duplications, and point mutations. Recently, five severely affected individuals have been found by Kayes et al. to have deletions encompassing the entire gene. These deletions were detected by quantitative Southern analysis. To simplify deletion detection, we have employed fluorescence in situ hybridization (FISH) using intragenic probes. Thirteen unrelated individuals with NF1 have been studied. Among six with severe manifestations, four have been found to have deletions detected by probes cFF13, cFB5D, cP5, yA43A9, yA113D7 and yD8F4. All four deletion patients have severe developmental delay, minor and major anomalies (including one with bilateral iris colobomas), and multiple cutaneous neurofibromas or plexiform neurofibromas which were present before age 5 years. FISH provides a simple and rapid means of identification of NF1 gene deletions and will allow more rigorous testing of the hypothesis that such deletions are associated with severe manifestations. 15 refs., 3 figs., 2 tabs.

  11. 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.

  12. 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.

  13. Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B.

    PubMed

    Wu, X; Lu, Y; Ding, Q; You, G; Dai, J; Xi, X; Wang, H; Wang, X

    2014-09-01

    Large deletions in the F9 gene are detected in approximately 5% of patients with severe haemophilia B, but only a few deletion breakpoints have been characterised precisely until now. In this study we identified a total of seven large F9 deletions in the index patients and nine female carriers by the AccuCopy technique. We also successfully characterised the exact breakpoints for each large deletion including four deletions encompassing the entire F9 gene by the genome walking method combined with primer walking strategy. The extents of deletion regions ranged from 11.1 to 884 kb. Microhomologies ranged from 2 to 6 bp were identified in the breakpoint junctions of six deletions. The other deletion occurred between two highly homologous sequences of the same long interspersed nuclear element 1 (LINE/L1). Non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) may be the main causative mechanisms for the six large deletions with microhomologies. Non-allelic homologous recombination (NAHR) may mediate the deletion occurred between the two tandem LINEs in the other large deletion. Repetitive elements and non-B DNA forming motifs identified in the junction regions may contribute to DNA breakage leading to large deletions. PMID:24816826

  14. Phenotypic characterization of patients with deletions in the 3'-flanking SHOX region.

    PubMed

    Kant, Sarina G; Broekman, Sander J; de Wit, Caroline C; Bos, Marloes; Scheltinga, Sitha A; Bakker, Egbert; Oostdijk, Wilma; van der Kamp, Hetty J; van Zwet, Erik W; van der Hout, Annemieke H; Wit, Jan M; Losekoot, Monique

    2013-01-01

    Context. Leri-Weill dyschondrosteosis is a clinically variable skeletal dysplasia, caused by SHOX deletion or mutations, or a deletion of enhancer sequences in the 3'-flanking region. Recently, a 47.5 kb recurrent PAR1 deletion downstream of SHOX was reported, but its frequency and clinical importance are still unknown. Objective. This study aims to compare the clinical features of different sizes of deletions in the 3'-flanking SHOX region in order to determine the relevance of the regulatory sequences in this region. Design. We collected DNA from 28 families with deletions in the 3'-PAR1 region. Clinical data were available from 23 index patients and 21 relatives. Results. In 9 families (20 individuals) a large deletion ( ∼ 200-900 kb) was found and in 19 families (35 individuals) a small deletion was demonstrated, equal to the recently described 47.5 kb PAR1 deletion. Median height SDS, sitting height/height ratio SDS and the presence of Madelung deformity in patients with the 47.5 kb deletion were not significantly different from patients with larger deletions. The index patients had a median height SDS which was slightly lower than in their affected family members (p = 0.08). No significant differences were observed between male and female patients. Conclusions. The phenotype of patients with deletions in the 3'-PAR1 region is remarkably variable. Height, sitting height/height ratio and the presence of Madelung deformity were not significantly different between patients with the 47.5 kb recurrent PAR1 deletion and those with larger deletions, suggesting that this enhancer plays an important role in SHOX expression. PMID:23638371

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. Genomic mechanisms underlying PARK2 large deletions identified in a cohort of patients with PD

    PubMed Central

    Morais, Sara; Bastos-Ferreira, Rita; Sequeiros, Jorge

    2016-01-01

    Objectives: To identify the genomic mechanisms that result in PARK2 large gene deletions. Methods: We conducted mutation screening using PCR amplification of PARK2-coding regions and exon-intron boundaries, followed by sequencing to evaluate a large series of 244 unrelated Portuguese patients with symptoms of Parkinson disease. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification, followed by long-range PCR and sequencing to map deletion breakpoints. Results: We identified biallelic pathogenic parkin mutations in 40 of the 244 patients. There were 18 different mutations, some of them novel. This study included mapping of 17 deletion breakpoints showing that nonhomologous end joining is the most common mechanism responsible for these gene rearrangements. None of these deletion breakpoints were previously described, and only one was present in 2 unrelated families, indicating that most of the deletions result from independent events. Conclusions: The c.155delA mutation is highly prevalent in the Portuguese population (62.5% of the cases). Large deletions were present in 42.5% of the patients. We present the largest study on the molecular mechanisms that mediate PARK2 deletions in a homogeneous population. PMID:27182553

  2. Relatively low proportion of dystrophin gene deletions in Israeli Duchenne and Becker muscular dystrophy patients.

    PubMed

    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 to 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. PMID:8160727

  3. 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.

  4. Asian-specific mitochondrial genome polymorphism (9-bp deletion) in Hungarian patients with mitochondrial disease.

    PubMed

    Pentelenyi, Klara; Remenyi, Viktoria; Gal, Aniko; Milley, Gyorgy Mate; Csosz, Aranka; Mende, Balazs Gusztav; Molnar, Maria Judit

    2016-05-01

    A 9-bp deletion of the mtDNA is known as an anthropological marker of people with East-Asian origin. This 9-bp mtDNA deletion was analyzed in 1073 Hungarians with suspected mitochondrial disease and in 468 healthy control individuals. Fourteen cases with the 9-bp deletion were found in the cohort of mitochondrial patients, and one individual from 468 controls. In six cases the 9-bp deletion was present together with pathogenic major deletions in the mitochondrial genome. In one patient we found a frame shift mutation in the D-loop region, and in another family a pathogenic m.8322 A > G mutation in the tRNA(Lys) gene. Although the 9-bp deletion is common in the populations of the Pacific region and Asia, it is present in the Hungarian population as well. This 9-bp deletion may induce instability of the mtDNA and may provoke the introduction of other pathogenic mutations. PMID:25242187

  5. 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. PMID:24290305

  6. 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

  7. Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia.

    PubMed

    Ogura, Kaeko; Takeshita, Kenzo; Arakawa, Chikako; Shimojima, Keiko; Yamamoto, Toshiyuki

    2014-12-01

    Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4. PMID:25329715

  8. 5q11.2 deletion in a patient with tracheal agenesis

    PubMed Central

    de Jong, Elisabeth M; Douben, Hannie; Eussen, Bert H; Felix, Janine F; Wessels, Marja W; Poddighe, Pino J; Nikkels, Peter G J; de Krijger, Ronald R; Tibboel, Dick; de Klein, Annelies

    2010-01-01

    Tracheal agenesis (TA) is a rare congenital anomaly of the respiratory tract. Many patients have associated anomalies, suggesting a syndromal phenotype. In a cohort of 12 patients, we aimed to detect copy number variations. In addition to routine cytogenetic analysis, we applied oligonucleotide array comparative genomic hybridization. Our patient cohort showed various copy number variations, of which many were parentally inherited variants. One patient had, in addition to an inherited 16p12.1 deletion, a 3.6 Mb deletion on chromosomal locus 5q11.2. This patient had a syndromic phenotype, including vertebral, anal, cardiovascular and tracheo-oesophageal associated anomalies, and other foregut-related anomalies, such as cartilage rings in the oesophagus and an aberrant right bronchus. No common deletions or duplications are found in our cohort, suggesting that TA is a genetically heterogeneous disorder. PMID:20551993

  9. 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

  10. 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

  11. 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

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

    PubMed Central

    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. PMID:27274857

  13. 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

  14. 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

  15. 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. PMID:22315192

  16. 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

  17. Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13. 3

    SciTech Connect

    Nesslinger, N.J.; McDermid, H.E. ); Gorski, J.L. ); Kurczynski, T.W.; French, B.N. ); Shapira, S.K. ); Siegel-Bartelt, J. ); Dumanski, J.P.; Cullen, R.F. Jr. )

    1994-03-01

    The authors have studied seven patients who have chromosome 22q13.3 deletions as revealed by high-resolution cytogenetic analysis. Clinical evaluation of the patients revealed a common phenotype that includes generalized developmental delay, normal or accelerated growth, hypotonia, severe delays in expressive speech, and mild facial dysmorphic features. Dosage analysis using a series of genetically mapped probes showed that the proximal breakpoints of the deletions varied over [approximately]13.8 cM, between loci D22S92 and D22S94. The most distally mapped locus, arylsulfatase A (ARSA), was deleted in all seven patients. Therefore, the smallest region of overlap (critical region) extends between locus D22S94 and a region distal to ARSA a distance of >25.5 cM. 38 rfs., 4 figs., 4 tabs.

  18. 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

  19. 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

  20. 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

  1. A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome

    PubMed Central

    GAO, Ying; BAI, Jin-li; LIU, Xiao-yan; QU, Yu-jin; CAO, Yan-yan; WANG, Jian-cai; JIN, Yu-wei; WANG, Hong; SONG, Fang

    2015-01-01

    Kindler syndrome (KS; OMIM 173650) is a rare autosomal recessive skin disorder, which results in symptoms including blistering, epidermal atrophy, increased risk of cancer, and poor wound healing. The majority of mutations of the disease-determining gene (FERMT1 gene) are single nucleotide substitutions, including missense mutations, nonsense mutations, etc. Large deletion mutations are seldom reported. To determine the mutation in the FERMT1 gene associated with a 7-year-old Chinese patient who presented clinical manifestation of KS, we performed direct sequencing of all the exons of FERMT1 gene. For the exons 2–6 without amplicons, we analyzed the copy numbers using quantitative real-time polymerase chain reaction (qRT-PCR) with specific primers. The deletion breakpoints were sublocalized and the range of deletion was confirmed by PCR and direct sequencing. In this study, we identified a new 17-kb deletion mutation spanning the introns 1–6 of FERMT1 gene in a Chinese patient with severe KS phenotypes. Her parents were carriers of the same mutation. Our study reported a newly identified large deletion mutation of FERMT1 gene involved in KS, which further enriched the mutation spectrum of the FERMT1 gene. PMID:26537214

  2. 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

  3. Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients.

    PubMed Central

    Shimkets, R.; Gailani, M. R.; Siu, V. M.; Yang-Feng, T.; Pressman, C. L.; Levanat, S.; Goldstein, A.; Dean, M.; Bale, A. E.

    1996-01-01

    Gorlin syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, medulloblastomas, ovarian fibromas, and a variety of developmental defects. All affected individuals share certain key features, but there is significant phenotypic variability within and among kindreds with respect to malformations. The gene (NBCCS) maps to chromosome 9q22, and allelic loss at this location is common in tumors from Gorlin syndrome patients. Two recessive cancer-predisposition syndromes, xeroderma pigmentosum group A (XPAC) and Fanconi anemia group C (FACC), map to the NBCCS region; and unusual, dominant mutations in these genes have been proposed as the cause of Gorlin syndrome. This study presents cytogenetic and molecular characterization of germ-line deletions in one patient with a chromosome 9q22 deletion and in a second patient with a deletion of 9q22-q3l. Both have typical features of Gorlin syndrome plus additional findings, including mental retardation, conductive hearing loss, and failure to thrive. That Gorlin syndrome can be caused by null mutations (deletions) rather than by activating mutations has several implications. First, in conjunction with previous analyses of allelic loss in tumors, this study provides evidence that associated neoplasms arise with homozygous inactivation of the gene. In addition, dominant mutations of the XPAC and FACC1 genes can be ruled out as the cause of Gorlin syndrome, since the two patients described have null mutations. Finally, phenotypic features that show variable expression must be influenced by genetic background, epigenetic effects, somatic mutations, or environmental factors, since these two patients with identical alterations (deletions) of the Gorlin syndrome gene have somewhat different manifestations of Gorlin syndrome. Images Figure 1 Figure 2 Figure 3 PMID:8755929

  4. Hereditary deletion of the entire FAM20C gene in a patient with Raine syndrome.

    PubMed

    Ababneh, Farouq K; AlSwaid, Abdulrahman; Youssef, Talaat; Al Azzawi, Manaf; Crosby, Andrew; AlBalwi, Mohammed A

    2013-12-01

    Raine syndrome is an autosomal recessive disorder caused by mutations in the FAM20C gene that is characterized by generalized osteosclerosis with periosteal new bone formation and distinctive craniofacial dysmorphism. We report on a child who is homozygous for a 487-kb deletion in 7p22.3 that contains FAM20C. Both parents were heterozygous for the deletion. Our patient had the common craniofacial features as well as, uncommon features such as protruding tongue, short stature, and hypoplastic distal phalanges. In addition, he had wormian bones and pyriform aperture stenosis, features that are usually under diagnosed. It is clear that Raine syndrome has a wide range of expression and may not be lethal in the neonatal period. Furthermore, Raine cases due to whole gene deletion do not seem to have a major difference in the phenotype over those caused by various mutations. PMID:24039075

  5. 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.

  6. Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene.

    PubMed

    Shi, W T; Cai, C Y; Li, M S; Ling, C; Li, W D

    2015-01-01

    We identified three novel mutations of the GTP cyclohydrolase 1 (GCH1) gene in patients with familial dopa-responsive dystonia (DRD), but were unable to identify meaningful sporadic mutations in patients with no obvious family DRD background. To investigate whether GCH1 regional deletions account for the etiology of DRD, we screened for heterozygous exonic deletions in DRD families and in patients with sporadic DRD. Multiple ligation-dependent probe amplification analysis and quantitative real-time polymerase chain reaction amplification was performed in all members of our DRD cohort and in controls to detect exonic deletions in GCH1, tyrosine hydroxylase, and the epsilon-sarcoglycan-encoding (SGCE) genes. Using these techniques, we detected a GCH1 exon 1 heterozygous deletion in 1 of 10 patients with sporadic DRD. Therefore, we concluded that exonic deletion in the GCH1 gene only accounted for the etiology in a small percentage of patients with sporadic DRD in our Han Chinese cohort. PMID:26400349

  7. SHOX gene and conserved noncoding element deletions/duplications in Colombian patients with idiopathic short stature

    PubMed Central

    Sandoval, Gloria Tatiana Vinasco; Jaimes, Giovanna Carola; Barrios, Mauricio Coll; Cespedes, Camila; Velasco, Harvy Mauricio

    2014-01-01

    SHOX gene mutations or haploinsufficiency cause a wide range of phenotypes such as Leri Weill dyschondrosteosis (LWD), Turner syndrome, and disproportionate short stature (DSS). However, this gene has also been found to be mutated in cases of idiopathic short stature (ISS) with a 3–15% frequency. In this study, the multiplex ligation-dependent probe amplification (MLPA) technique was employed to determine the frequency of SHOX gene mutations and their conserved noncoding elements (CNE) in Colombian patients with ISS. Patients were referred from different centers around the county. From a sample of 62 patients, 8.1% deletions and insertions in the intragenic regions and in the CNE were found. This result is similar to others published in other countries. Moreover, an isolated case of CNE 9 duplication and a new intron 6b deletion in another patient, associated with ISS, are described. This is one of the first studies of a Latin American population in which deletions/duplications of the SHOX gene and its CNE are examined in patients with ISS. PMID:24689071

  8. Novel deletions involving the USH2A gene in patients with Usher syndrome and retinitis pigmentosa

    PubMed Central

    García-García, Gema; Jaijo, Teresa; Aparisi, Maria J.; Larrieu, Lise; Faugère, Valérie; Blanco-Kelly, Fiona; Ayuso, Carmen; Roux, Anne-Francoise; Millán, José M.

    2014-01-01

    Purpose The aim of the present work was to identify and characterize large rearrangements involving the USH2A gene in patients with Usher syndrome and nonsyndromic retinitis pigmentosa. Methods The multiplex ligation-dependent probe amplification (MLPA) technique combined with a customized array-based comparative genomic hybridization (aCGH) analysis was applied to 40 unrelated patients previously screened for point mutations in the USH2A gene in which none or only one pathologic mutation was identified. Results We detected six large deletions involving USH2A in six out of the 40 cases studied. Three of the patients were homozygous for the deletion, and the remaining three were compound heterozygous with a previously identified USH2A point mutation. In five of these cases, the patients displayed Usher type 2, and the remaining case displayed nonsyndromic retinitis pigmentosa. The exact breakpoint junctions of the deletions found in USH2A in four of these cases were characterized. Conclusions Our study highlights the need to develop improved efficient strategies of mutation screening based upon next generation sequencing (NGS) that reduce cost, time, and complexity and allow simultaneous identification of all types of disease-causing mutations in diagnostic procedures. PMID:25352746

  9. 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.

  10. 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

  11. 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

  12. MiRNA expression profile of chronic lymphocytic leukemia patients with 13q deletion.

    PubMed

    Hernández-Sánchez, María; Rodríguez-Vicente, Ana E; Hernández, José-Ángel; Lumbreras, Eva; Sarasquete, María-Eugenia; Martín, Ana-África; Benito, Rocío; Vicente-Gutiérrez, Carlos; Robledo, Cristina; Heras, Natalia de Las; Rodríguez, Juan-Nicolás; Alcoceba, Miguel; Coca, Alfonso García de; Aguilar, Carlos; González, Marcos; Hernández-Rivas, Jesús-María

    2016-07-01

    Deletion 13q (13q-) is the most common cytogenetic aberration in chronic lymphocytic leukemia (CLL) and is associated with the most favorable prognosis as the sole cytogenetic abnormality. However, it is heterogeneous whereby CLL patients with higher percentages of 13q- cells (13q-H) have a more aggressive clinical course and a distinct gene expression profile. The microRNA (miRNA) expression profile of CLL gives additional biological and prognostic information, but its expression in 13q- CLL has not been examined in detail. The miRNA expression of clonal B cell lymphocytes (CD19+ cells) of 38 CLL patients and normal B cells of six healthy donors was analyzed. CLL patients with higher percentages of 13q- cells (≥80%) showed a different level of miRNA expression from patients with lower percentages (<80%). Interestingly, miR-143 was downregulated and miR-155 was overexpressed in 13q-H. This deregulation affected important validated target genes involved in apoptosis (BCL2, MDM2, TP53INP1) and proliferation (KRAS, PI3K-AKT signaling), that could lead to decreased apoptosis and increased proliferation in 13q-H patients. This study provides new evidence about the heterogeneity of the 13q deletion in CLL patients, showing that miRNA regulation could be involved in several significant pathways deregulated in CLL patients with a high number of losses in 13q. PMID:27111859

  13. Cytogenetic and clinical findings in a patient with a deletion of 16q23.1: first report of bilateral cataracts and a 16q deletion.

    PubMed

    Monaghan, K G; Van Dyke, D L; Wiktor, A; Feldman, G L

    1997-12-12

    The most commonly reported manifestations of 16q deletions are severe growth and developmental disorders and anomalies of the craniofacial, visceral, and musculoskeletal systems. We reviewed the findings of patients reported with 16q- syndrome and compared them to our patient, a 4 1/2-year-old boy with a deletion of 16q23.1. Findings include psychomotor retardation, hypotonia, high forehead, hypertelorism, upslanting palpebral fissures, low-set abnormally modeled ears, and talipes equinovarus. Anomalies present in our patient not reported in others with 16q- syndrome include bilateral cataracts, iris coloboma, and autistic-like behavior. It is of note that a locus for autosomal dominant congenital cataract, known as Marner cataract, was mapped previously to 16q22. Because our patient has bilateral cataracts and a unilateral iris coloboma, it seems likely that a gene involved in ocular development is located within 16q23.1. Our patient's deletion may also include the gene involved in Marner cataract and may further assist in the isolation of this gene. PMID:9409869

  14. 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.

  15. Increased frequency of minimal homozygous deletions is associated with poor prognosis in primary malignant melanoma patients.

    PubMed

    Boi, Sebastiana; Tebaldi, Toma; Re, Angela; Cantaloni, Chiara; Adami, Valentina; Barbareschi, Mattia; Cristofolini, Mario; Pasini, Luigi; Quattrone, Alessandro

    2014-06-01

    Identification of prognostic melanoma-associated copy number alterations (CNAs) is still an area of active research. Here, we investigated by high-resolution array comparative genomic hybridization (aCGH) a cohort of 31 paraffin-preserved primary malignant melanomas (MMs), whose prognosis was not predictable on the basis of conventional histopathological parameters. Although we identified a variety of highly recurrent sites of genomic lesions, the total number of CNAs per patient was not a discriminator of MM outcome. Furthermore, validation of aCGH by quantitative PCR on an extended population of 65 MM samples confirmed the absence of predictive value for the most recurrent CNA loci. Instead, our analysis revealed specific prognostic potential of the frequency of homozygous deletions (representing less than 3% of the total CNAs on average per sample), which was strongly associated with sentinel lymph node (SLN) invasion (P = 0.003), and distant metastasis (P = 0.003). Increased number of homozygous deletions was also indicative of poor patient survival (P = 0.01), both in our samples and in an independent validation of public dataset of primary and metastatic MMs. Moreover, we identified 77 hotspots of minimal common homozygous deletions, enriched in genes involved in cell adhesion processes and cell-communication functions, which preferentially accumulated in primary MMs showing the most severe outcome. Therefore, specific loss of gene loci in regions of minimal homozygous deletion may represent a pivotal type of genomic alteration accumulating during MM progression with potential prognostic implication. PMID:24615732

  16. Phenotypic and molecular characterization of 19q12q13.1 deletions: a report of five patients.

    PubMed

    Chowdhury, Shimul; Bandholz, Anne M; Parkash, Sandhya; Dyack, Sarah; Rideout, Andrea L; Leppig, Kathleen A; Thiese, Heidi; Wheeler, Patricia G; Tsang, Marilyn; Ballif, Blake C; Shaffer, Lisa G; Torchia, Beth S; Ellison, Jay W; Rosenfeld, Jill A

    2014-01-01

    A syndrome associated with 19q13.11 microdeletions has been proposed based on seven previous cases that displayed developmental delay, intellectual disability, speech disturbances, pre- and post-natal growth retardation, microcephaly, ectodermal dysplasia, and genital malformations in males. A 324-kb critical region was previously identified as the smallest region of overlap (SRO) for this syndrome. To further characterize this microdeletion syndrome, we present five patients with deletions within 19q12q13.12 identified using a whole-genome oligonucleotide microarray. Patients 1 and 2 possess deletions overlapping the SRO, and Patients 3-5 have deletions proximal to the SRO. Patients 1 and 2 share significant phenotypic overlap with previously reported cases, providing further definition of the 19q13.11 microdeletion syndrome phenotype, including the first presentation of ectrodactyly in the syndrome. Patients 3-5, whose features include developmental delay, growth retardation, and feeding problems, support the presence of dosage-sensitive genes outside the SRO that may contribute to the abnormal phenotypes observed in this syndrome. Multiple genotype-phenotype correlations outside the SRO are explored, including further validation of the deletion of WTIP as a candidate for male hypospadias observed in this syndrome. We postulate that unique patient-specific deletions within 19q12q13.1 may explain the phenotypic variability observed in this emerging contiguous gene deletion syndrome. PMID:24243649

  17. 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.

  18. Prevalence of the 4977-bp and 4408-bp mitochondrial DNA deletions in mesenteric arteries from patients with colorectal cancer.

    PubMed

    Li, Tao; Chen, Gui-Lan; Lan, Huan; Mao, Liang; Zeng, Bo

    2016-09-01

    Mitochondrial DNA (mtDNA) deletions are found in many diseased tissues and lead to impairment of mitochondrial functions. In this study, we found wide presence of the common 4977-bp and a novel 4408-bp deletion in the mtDNA of mesenteric arteries from patients with colorectal cancer. These two deletions were also detected in samples from healthy individuals. The content of mtDNA with the 4977-bp deletion was significantly lower in healthy controls than cancer-associated samples, and there was no significant difference for the 4408-bp deletion between the two groups. These results suggest that mtDNA in blood vessels around cancer cells may be strongly affected by oxidative stress and tend to accumulate more large-scale variations. PMID:26332461

  19. 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. PMID:26263419

  20. Clinical implications of cytosine deletion of exon 5 of P53 gene in non small cell lung cancer patients

    PubMed Central

    Mir, Rashid; Masroor, Mirza; Javid, Jamsheed; Ahamad, Imtiyaz; Farooq, Shazia; Yadav, Prasant; Zuberi, Mariyam; Lone, Maqbool; Ray, P. C; Saxena, Alpana

    2016-01-01

    Aim: Lung cancer is considered to be the most common cancer in the world. In humans, about 50% or more cancers have a mutated tumor suppressor p53 gene thereby resulting in accumulation of p53 protein and losing its function to activate the target genes that regulate the cell cycle and apoptosis. Extensive research conducted in murine cancer models with activated p53, loss of p53, or p53 missense mutations have facilitated researchers to understand the role of this key protein. Our study was aimed to evaluate the frequency of cytosine deletion in nonsmall cell lung cancer (NSCLC) patients. Methods: One hundred NSCLC patients were genotyped for P53 (exon5, codon168) cytosine deletion leading to loss of its function and activate the target genes by allele-specific polymerase chain reaction. The P53 cytosine deletion was correlated with all the clinicopathological parameters of the patients. Results and Analysis: 59% cases were carrying P53 cytosine deletion. Similarly, the significantly higher incidence of cytosine deletion was reported in current smokers (75%) in comparison to exsmoker and nonsmoker. Significantly higher frequency of cytosine deletion was reported in adenocarcinoma (68.08%) than squamous cell carcinoma (52.83%). Also, a significant difference was reported between p53 cytosine deletion and metastasis (64.28%). Further, the majority of the cases assessed for response carrying P53 cytosine deletion were found to show faster disease progression. Conclusion: The data suggests that there is a significant association of the P53 exon 5 deletion of cytosine in codon 168 with metastasis and staging of the disease. PMID:27169122

  1. 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

  2. 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.

  3. Two craniosynostotic patients with 11q deletions, and review of 48 cases

    SciTech Connect

    Lewanda, A.F.; Jabs, E.W.; Morsey, S.

    1995-11-06

    Many chromosomal abnormalities have craniofacial manifestations. One such abnormality, partial monosomy of chromosome 11q, is associated with metopic synostosis and resultant trigonocephaly. We reviewed 48 published cases of 11q deletions and translocations. Eighty percent were associated with abnormal head shape. Also commonly found were hypertelorism, ptosis of the eyelids, wide or low nasal bridge, apparently low-set malformed ears, down-turned mouth, micro/retrognathia, digital and cardiac anomalies, and psychomotor retardation. We report on two patients referred for abnormal head shape. The first case had brachycephaly, flat occiput, hypertelorism, and maxillary hypoplasia. Karyotype was 46,XY,del(11)(q24.1{yields}qter). The second patient had trigonocephaly, hypotelorism, posteriorly angulated ears, horizontal crease below his lower lip, syndactyly, shawl scrotum, cryptorchidism, and inguinal hernias. Karyotype showed partial trisomy of chromosome 4q as well as partial monosomy of 11q [46,XY,11,+der(11)t(4;11)(q31.3;q25)], a combination not previously reported. Deletions of 11q appear to produce a wide spectrum of abnormalities. 46 refs., 4 figs., 2 tabs.

  4. Tracking donor-reactive T cells: evidence for clonal deletion in tolerant kidney transplant patients

    PubMed Central

    Morris, Heather; DeWolf, Susan; Robins, Harlan; Sprangers, Ben; LoCascio, Samuel A.; Shonts, Brittany A.; Kawai, Tatsuo; Wong, Waichi; Yang, Suxiao; Zuber, Julien; Shen, Yufeng; Sykes, Megan

    2015-01-01

    T cell responses to allogeneic major histocompatibility (MHC) antigens present a formidable barrier to organ transplantation, necessitating long-term immunosuppression to minimize rejection. Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally induced in humans via combined kidney and bone marrow transplantation (CKBMT), but the mechanisms of tolerance in these patients are incompletely understood. We now establish an assay to identify donor-reactive T cells and test the role of deletion in tolerance after CKBMT. Using high-throughput sequencing of the TCRB chain CDR3 region, we define a fingerprint of the donor-reactive T cell repertoire prior to transplantation and track those clones post-transplant. We observed post-transplant reductions in donor-reactive T cell clones in three tolerant CKBMT patients; such reductions were not observed in a fourth, non-tolerant, CKBMT patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens. T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients; in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in CKBMT patients. The results validate the significance of donor-reactive T cell clones identified pre-transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes. PMID:25632034

  5. 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.

  6. 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.

  7. 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.

  8. Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype.

    PubMed

    Schilter, Kala F; Reis, Linda M; Sorokina, Elena A; Semina, Elena V

    2015-11-01

    Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole-exome sequencing (WES) and whole-genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37-bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled-coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult-onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis-regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss-of-function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu-mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu-mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role

  9. 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

  10. Rare large homozygous CFTR gene deletion in an Iranian patient with cystic fibrosis.

    PubMed

    Farjadian, Shirin; Moghtaderi, Mozhgan; Zuntini, Roberta; Ferrari, Simona

    2014-08-16

    Cystic fibrosis, a common autosomal recessive genetic disorder among Caucasians, is caused by defects in the transmembrane conductance regulatory (CFTR) gene. The analysis of CFTR gene mutations is useful to better characterize the disease, and for preconceptional screening, prenatal and preimplantation genetic diagnosis. Here we report the results of a genetic analysis in a 16-year-old boy from southwestern Iran diagnosed as having cystic fibrosis in infancy based on gastrointestinal and pulmonary manifestations, with positive sweat chloride tests. He lacked both normal and mutant forms of the fragment corresponding to the ∆F508 allele in initial genetic studies. Multiplex ligation-dependent probe amplification-based testing revealed a homozygous deletion spanning exons 4 to 10 of the CFTR gene. We predict an in-frame deletion removing 373 amino acids based on our sequencing results. Determining CFTR gene mutations in patients and their family members would be helpful to prevent the occurrence of new cases, especially in populations in which consanguinity is common. PMID:25133155

  11. 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

  12. De novo deletion of HOXB gene cluster in a patient with failure to thrive, developmental delay, gastroesophageal reflux and bronchiectasis.

    PubMed

    Pajusalu, Sander; Reimand, Tiia; Uibo, Oivi; Vasar, Maire; Talvik, Inga; Zilina, Olga; Tammur, Pille; Õunap, Katrin

    2015-01-01

    We report a female patient with a complex phenotype consisting of failure to thrive, developmental delay, congenital bronchiectasis, gastroesophageal reflux and bilateral inguinal hernias. Chromosomal microarray analysis revealed a 230 kilobase deletion in chromosomal region 17q21.32 (arr[hg19] 17q21.32(46 550 362-46 784 039)×1) encompassing only 9 genes - HOXB1 to HOXB9. The deletion was not found in her mother or father. This is the first report of a patient with a HOXB gene cluster deletion involving only HOXB1 to HOXB9 genes. By comparing our case to previously reported five patients with larger chromosomal aberrations involving the HOXB gene cluster, we can suppose that HOXB gene cluster deletions are responsible for growth retardation, developmental delay, and specific facial dysmorphic features. Also, we suppose that bilateral inguinal hernias, tracheo-esophageal abnormalities, and lung malformations represent features with incomplete penetrance. Interestingly, previously published knock-out mice with targeted heterozygous deletion comparable to our patient did not show phenotypic alterations. PMID:25907420

  13. Deletion of CBFB in a patient with acute myelomonocytic leukemia (AML M4Eo) and inversion 16.

    PubMed

    Egan, Nicole; O'Reilly, John; Chipper, Lucia; Higgins, Melinda; Herrmann, Richard; Cannell, Paul

    2004-10-01

    Acute myelomonocytic leukemia with bone marrow eosinophilia (AML M4Eo) is a subtype of AML with distinct morphological features. Inversion (16)(p13.1q22), t(16;16)(p13.1;q22), and del(16)(q22) are nonrandom abnormalities associated with AML M4Eo and a favorable prognosis, compared with the standard risk group for AML. Deletions of the proximal region of the MYH11 gene located at 16p13.1 have been detected in about 20% of patients with inv(16), with an undetermined effect on patient survival. We present the case of a patient with AML M4Eo and inversion 16 with a distal deletion of the CBFB gene at 16q22 detected with fluorescence in situ hybridization. To our knowledge, only one previous report of a similar deletion has appeared in the literature. PMID:15381374

  14. Typical Renal-coloboma Syndrome Phenotype in a Patient with a Submicroscopic Deletion of the PAX2 Gene

    PubMed Central

    Laimutis, Kucinskas; Jackson, Craig; Xu, Xinjie; Warman, Berta; Sarunas, Rudaitis; Birute, Pundziene; Schimmenti, Lisa A.; Raca, Gordana

    2012-01-01

    We present a patient with optic nerve hypoplasia, secondary strabismus, mild deafness, abnormal external ear helices and renal hypoplasia. The clinical phenotype was consistent with renal-coloboma syndrome, but no point mutation in the PAX2 gene could be identified. High resolution array Comparative Genomic Hybridization (aCGH) analysis showed that this patient has a submicroscopic deletion on chromosome 10, affecting the entire coding region of the PAX2 gene. This finding provided the molecular confirmation of the patient’s clinical diagnosis and showed that, in addition to point mutations, deletions of the PAX2 gene contribute to the etiology of the renal-coloboma syndrome. PMID:22581475

  15. 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

  16. A Deletion Involving CD38 and BST1 Results in a Fusion Transcript in a Patient With Autism and Asthma

    PubMed Central

    Ceroni, Fabiola; Sagar, Angela; Simpson, Nuala H.; Gawthrope, Alex J.T.; Newbury, Dianne F.; Pinto, Dalila; Francis, Sunday M.; Tessman, Dorothy C.; Cook, Edwin H.; Monaco, Anthony P.; Maestrini, Elena; Pagnamenta, Alistair T.; Jacob, Suma

    2015-01-01

    CD38 encodes a ligand in the oxytocin signaling pathway. Some single nucleotide polymorphisms in this gene have been associated with low serum oxytocin levels in autism spectrum disorder (ASD) patients. Oxytocin disruption has been hypothesized to account for features of ASD, including impaired communication and social behavior, based on animal studies. Recent human studies have shown administration of oxytocin improving emotion recognition, promoting social behavior, and improving auditory processing of social stimuli in ASD patients. In addition to its role in oxytocin signaling, CD38 is involved in the regulation of calcium concentration in airway smooth muscle with impairment of CD38 being implicated in airway diseases like asthma. While a number of studies have implicated rare chromosomal deletions and duplications in helping determine genetic risk for autism, there are to our knowledge no reports describing rearrangements involving CD38 or deletions in patients with ASD. Here, we present two sisters diagnosed with autism and with features of regression—previously acquired speech lost in the second year of life. The younger sister, who also had asthma, inherited a maternal deletion of 4p15.32 that results in a BST1-CD38 fusion transcript. Their mother's deletion was mosaic and she was not affected. Although further work is required to assess functional consequences of the fusion transcript, we hypothesize that the proband's deletion may have served as a risk factor for autism that, when combined with other susceptibility variants, resulted in a more severe presentation than her sister. PMID:24634087

  17. Further phenotype description, genotype characterization in patients with de novo interstitial deletion on 2p23.2-24.1.

    PubMed

    Bloch, Mercedes; Leonard, Anissa; Diplas, Andreas A; Pepermans, Xavier; Emanuel, Beverly S; Santa Rocca, Maria; Revencu, Nicole; Sznajer, Yves

    2014-07-01

    Interstitial deletions of the distal part of chromosome 2p seem to be rarely identified or reported: to date, only nine distinct patients have been published. The last three patients were diagnosed with the use of more recent molecular karyotyping technology (SNP array). We report on the natural history of an 8-year-old boy with dysmorphic features, postnatal overgrowth, microcephaly, generalized hypotonia, and global developmental delay. The diagnosis was accomplished by SNP array investigation that led to the identification of a de novo 7.4 Mb deletion of 2p23.2-p24.1. The present patient also developed a nonsyndromic auditory neuropathy. Since the deletion encompassed the OTOF gene, this haploinsufficiency suggests second allele sequencing as a possible cause (DFNB9). We describe the phenotype of the patient and review reports in patients with del 2p23 subsequent to the advent of the genomic era. At the time of identification of "new" micro- deletion and -duplication syndromes, the present report adds to the description of phenotype in patients with del(2)p(23.2;24.1) and the 2p23.2 region in particular. PMID:24700699

  18. 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

  19. Deletion of CFTR Translation Start Site Reveals Functional Isoforms of the Protein in CF Patients

    PubMed Central

    Ramalho, Anabela S.; Lewandowska, Marzena A.; Farinha, Carlos M.; Mendes, Filipa; Gonçalves, Juan; Barreto, Celeste; Harris, Ann; Amaral, Margarida D.

    2009-01-01

    Background/Aims: Mutations in the CFTR gene cause Cystic Fibrosis (CF) the most common life-threatening autosomal recessive disease affecting Caucasians. We identified a CFTR mutation (c.120del23) abolishing the normal translation initiation codon, which occurs in two Portuguese CF patients. This study aims at functionally characterizing the effect of this novel mutation. Methods: RNA and protein techniques were applied to both native tissues from CF patients and recombinant cells expressing CFTR constructs to determine whether c.120del23 allows CFTR protein production through usage of alternative internal codons, and to characterize the putative truncated CFTR form(s). Results: Our data show that two shorter forms of CFTR protein are produced when the initiation translation codon is deleted indicating usage of internal initiation codons. The N-truncated CFTR generated by this mutation has decreased stability, very low processing efficiency, and drastically reduced function. Analysis of mutants of four methionine codons downstream to M1 (M82, M150, M152, M156) revealed that each of the codons M150/M152/M156 (exon 4) can mediate CFTR alternative translation. Conclusions: The CFTR N-terminus has an important role in avoiding CFTR turnover and in rendering effective its plasma membrane traffic. These data correlate well with the severe clinical phenotype of CF patients bearing the c.120del23 mutation. PMID:19910674

  20. GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot–Marie–Tooth disease

    PubMed Central

    Gonzaga-Jauregui, Claudia; Zhang, Feng; Towne, Charles F.; Batish, Sat Dev

    2014-01-01

    The X-linked form of Charcot–Marie–Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations and frameshift deletions that lead to truncated forms of the protein have also been reported to be associated with CMT1X. Previously, there have been reports of patients with deletions of the coding sequence of GJB1; however, the size and breakpoints of these deletions were not assessed. Here, we report five patients with deletions that range in size from 12.2 to 48.3 kb and that completely eliminate the entire coding sequence of the GJB1 gene, resulting in a null allele for this locus. Analyses of the breakpoints of these deletions showed that they are nonrecurrent and that they can be generated by different mechanisms. In addition to PMP22, GJB1 is the second CMT gene for which both point mutations and genomic rearrangements can cause a neuropathy phenotype, stressing the importance of CMT as a genomic disorder. PMID:20532933

  1. Tetralogy of Fallot associated with pulmonary atresia and major aortopulmonary collateral arteries in a patient with interstitial deletion of 16q21-q22.1.

    PubMed

    Yamamoto, Toshiyuki; Dowa, Yuri; Ueda, Hideaki; Kawataki, Motoyoshi; Asou, Toshihide; Sasaki, Yuki; Harada, Naoki; Matsumoto, Naomichi; Matsuoka, Rumiko; Kurosawa, Kenji

    2008-06-15

    A newborn male had an interstitial deletion of 16q21-q22.1 accompanying tetralogy of Fallot associated with pulmonary atresia and major aortopulmonary collateral arteries (MAPCA), dysmorphic craniofacial features, failure to thrive, and severe psychomotor developmental delay. When the deletion in this patient and other reported patients are compared, the 16q22 region appears to be the smallest region for 16q deletion syndrome. Since over 50% of patients with the deletion of 16q22 region have congenital heart disease, there may be a responsible gene in this region. PMID:18470894

  2. Pattern of deletions of the dystrophin gene in Mexican Duchenne/Becker muscular dystrophy patients: the use of new designed primers for the analysis of the major deletion "hot spot" region.

    PubMed

    Coral-Vazquez, R; Arenas, D; Cisneros, B; Peñaloza, L; Salamanca, F; Kofman, S; Mercado, R; Montañez, C

    1997-06-13

    We have analyzed 59 unrelated Mexican Duchenne/Becker muscular dystrophy patients (DMD/BMD) using PCR analysis of the 2 prone deletion regions in the DMD gene. Thirty one (52%) of the patients had a deletion of one or several of the exons. Most of the alterations (87%) were clustered in exons 44-52, this being the highest percentage reported until now. In order to improve the molecular diagnosis in the Mexican population, we designed a new multiplex assay to PCR amplify exons 44-52. This assay allowed for the identification of a greater number of deletions in this region compared with the 9 and 5-plex assays previously described and to determine most of the deletion end boundaries. This is a reliable alternative for the initial screening of the DMD patients in the Mexican population. PMID:9188659

  3. Diagnosis and fine mapping of a deletion in distal 11q in two Chinese patients with developmental delay.

    PubMed

    Ji, Taoyun; Wu, Ye; Wang, Huifang; Wang, Jingmin; Jiang, Yuwu

    2010-08-01

    Jacobsen syndrome (JBS) is a haploinsufficiency syndrome caused by partial deletion of the long arm of chromosome 11. It is characterized by developmental delay (DD)/mental retardation (MR), physical growth retardation, facial dysmorphism, visceral malformations and thrombocytopenia. We report two JBS patients from China out of a total of 451 patients with unexplained DD/MR. The genotypes of these patients were compared with earlier reported patients in North America and Europe. Both patients presented with severe DD, microcephaly and facial dysmorphism; one patient had a low birth weight, congenital heart disease and structural brain abnormalities. Neither patient was thrombocytopenic at the time of diagnosis. The two deletions were 4.1 and 12.8 Mb. The 4.1 Mb deletion is the smallest of all pathogenic regions earlier reported in JBS. Therefore, the critical region underlying DD/MR might be located in the distal portion of the chromosomal segment within 4.1 Mb of the telomere. Candidate genes for DD/MR in this region include SNX19, THYN1, OPCML, NCAPD3 and NTM. One of the critical regions for craniofacial abnormalities may be within 130.3-134.4 Mb in chromosome 11q. Further analysis of Chinese JBS patients would elucidate the relation of phenotype to genotype further. PMID:20520618

  4. 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.

  5. 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.

  6. DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations

    PubMed Central

    Marzese, Diego M.; Scolyer, Richard A.; Roqué, Maria; Vargas-Roig, Laura M.; Huynh, Jamie L.; Wilmott, James S.; Murali, Rajmohan; Buckland, Michael E.; Barkhoudarian, Garni; Thompson, John F.; Morton, Donald L.; Kelly, Daniel F.; Hoon, Dave S. B.

    2014-01-01

    Background The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes. PMID:24968695

  7. PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

    PubMed Central

    Soufir, N; Gerard, B; Portela, M; Brice, A; Liboutet, M; Saiag, P; Descamps, V; Kerob, D; Wolkenstein, P; Gorin, I; Lebbe, C; Dupin, N; Crickx, B; Basset-Seguin, N; Grandchamp, B

    2006-01-01

    The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis ⩽40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common. PMID:16909134

  8. High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome

    PubMed Central

    Parri, Veronica; Katzaki, Eleni; Uliana, Vera; Scionti, Francesca; Tita, Rossella; Artuso, Rosangela; Longo, Ilaria; Boschloo, Renske; Vijzelaar, Raymon; Selicorni, Angelo; Brancati, Francesco; Dallapiccola, Bruno; Zelante, Leopoldo; Hamel, Christian P; Sarda, Pierre; Lalani, Seema R; Grasso, Rita; Buoni, Sabrina; Hayek, Joussef; Servais, Laurent; de Vries, Bert B A; Georgoudi, Nelly; Nakou, Sheena; Petersen, Michael B; Mari, Francesca; Renieri, Alessandra; Ariani, Francesca

    2010-01-01

    Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4–13, 20–30 and 57–60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6–16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome. PMID:20461111

  9. Low frequency of the CYP21A2 deletion in ethnic Chinese (Taiwanese) patients with 21-hydroxylase deficiency.

    PubMed

    Lee, Hsien-Hsiung; Lee, Yann-Jinn; Wang, Yu-Mei; Chao, Hsiang-Tai; Niu, Dau-Ming; Chao, Mei-Chyn; Tsai, Fuu-Jen; Lo, Fu-Sung; Lin, Shio-Jean

    2008-04-01

    Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder which causes more than 90% of CAH cases due to defects in the steroid 21-hydroxylase gene (CYP21A2). The frequency of large mutations was determined in 200 ethnic Chinese (i.e., Taiwanese) CAH patients belonging to 200 families with different clinical forms of CYP21A2 deficiency over 10 years of molecular diagnoses. For a large-gene deletion (or conversion) and the CYP21A2 deletion identification, a PCR product covering the TNXB gene and the 5'-end of the CYP21A2 gene with TaqI endonuclease digestion was analyzed by electrophoresis on agarose gels. For CYP21A2 mutational analysis, secondary PCR amplification of the amplification-created restriction site method was applied. From the results of the analysis, we found that large-gene deletions (or conversions) occurred in 7.5% of the alleles including three different types of the chimeric CYP21A1P/CYP21A2 genes and the haplotype of IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation). The CYP21A2 deletion occurred in 2.0% of the alleles which contained three types of the chimeric TNXA/TNXB genes with two novel ones. We concluded that the CYP21A2 deletion in the ethnic Chinese (Taiwanese) patients exhibits a low occurrence, with the haplotype of the IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation) being prevalent among large gene deletions or conversions. PMID:18039588

  10. Angiotensin-converting enzyme insertion/deletion polymorphism in heterozygous familial hypercholesterolemia patients

    SciTech Connect

    Maslen, C.L.; O`Malley, J.P.; Illingworth, D.R.

    1994-09-01

    The insertion/deletion polymorphism in angiotensin-converting enzyme (ACE/ID) has been shown to be an independent risk factor for myocardial infarction (MI). Patients with heterozygous familial hypercholesterolemia (FH) are known to be at greatly increased risk for heart disease because of their high levels of low density lipoprotein cholesterol. We obtained DNA samples from 105 unrelated FH patients and typed them for ACE/ID by PCR analysis. The frequencies of the DD, DI, and II genotypes were 0.381, 0.390, and 0.229, respectively. The allele frequencies were 0.576 for D and 0.423 for I. This is similar to the allele frequencies observed by Cambien et al. in a control population in Toulouse, France. The relative risk for MI or coronary artery disease (CAD) was assessed in patients who were aged 50 years or older. The criteria for CAD was history of coronary arterial bypass surgery. While the relative risk of having had a myocardial infarction was slightly increased from 0.14 (4/28) in the DI + II group to 0.16 (3/19) in the DD genotype, the differences were not statistically significant. The individual`s risk of CAD increased in the DD genotype, (0.579 of the DD population (n=19) compared to 0.321 of the DI + II population (n=28)). Therefore the ACE/ID polymorphism does appear to interact with FH in increasing a DD individual`s risk of heart disease by a factor of 1.8 relative to the DI and II genotypes.

  11. Muscle hypertrophy as the presenting sign in a patient with a complete FHL1 deletion.

    PubMed

    Willis, T A; Wood, C L; Hudson, J; Polvikoski, T; Barresi, R; Lochmüller, H; Bushby, K; Straub, V

    2016-08-01

    Four and a half LIM protein 1 (FHL1/SLIM1) has recently been identified as the causative gene mutated in four distinct diseases affecting skeletal muscle that have overlapping features, including reducing body myopathy, X-linked myopathy, X-linked dominant scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. FHL1 localises to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation as well as in sarcomere assembly. We describe in this case report a boy with a deletion of the entire FHL1 gene who is now 15 years of age and presented with muscle hypertrophy, reduced subcutaneous fat, rigid spine and short stature. This case is the first, to our knowledge, with a complete loss of the FHL1 protein and MAP7D3 in combination. It supports the theory that dominant negative effects (accumulation of cytotoxic-mutated FHL1 protein) worsen the pathogenesis. It extends the phenotype of FHL1-related myopathies and should prompt future testing in undiagnosed patients who present with unexplained muscle hypertrophy, contractures and rigid spine, particularly if male. PMID:27409453

  12. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing.

    PubMed

    Nectoux, Juliette; de Cid, Rafael; Baulande, Sylvain; Leturcq, France; Urtizberea, Jon Andoni; Penisson-Besnier, Isabelle; Nadaj-Pakleza, Aleksandra; Roudaut, Carinne; Criqui, Audrey; Orhant, Lucie; Peyroulan, Delphine; Ben Yaou, Raba; Nelson, Isabelle; Cobo, Anna Maria; Arné-Bes, Marie-Christine; Uro-Coste, Emmanuelle; Nitschke, Patrick; Claustres, Mireille; Bonne, Gisèle; Lévy, Nicolas; Chelly, Jamel; Richard, Isabelle; Cossée, Mireille

    2015-07-01

    Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment. PMID:25351777

  13. 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.

  14. 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.

  15. 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.

  16. Accuracy in identification of patients with 22q11.2 deletion by likely care providers using facial photographs.

    PubMed

    Becker, Devra B; Pilgram, Thomas; Marty-Grames, Lynn; Govier, Daniel P; Marsh, Jeffrey L; Kane, Alex A

    2004-11-01

    Numerous facial characteristics are associated with velocardiofacial syndrome. Care providers may use these facial characteristics to identify patients who may benefit from fluorescence in situ hybridization genetic testing to determine the presence of the 22q11.2 deletion. The purpose of this study was to test the hypothesis that experienced care providers were able to correctly diagnose the 22q11.2 deletion on the basis of studying frontal facial photographs. After approval was obtained from the human studies committee, patients who had undergone fluorescence in situ hybridization genetics testing for the presence of a 22q11.2 deletion were asked to submit two frontal photographs: one at infancy and one beyond the second birthday. These photographs were randomized, made anonymous, and then placed on a secure Web site. Specialists in the fields of plastic surgery, otolaryngology, genetics, and speech pathology were asked to evaluate their experience and confidence levels in diagnosing a 22q11.2 deletion and were then asked to rate the photographs by likelihood of deletion using a five-point Likert scale. Thirty-two specialists (10 surgeons, nine geneticists, and 13 speech pathologists) participated in the study. On the basis of clear responses, respondents predicted the presence (sensitivity) and absence (specificity) of the 22q11.2 deletion at chance levels. Of the remaining responses, 20 to 25 percent were unsure and 20 to 25 percent were clearly wrong. When an unsure response was treated as a weak positive, the results favored sensitivity slightly, with a sensitivity of 70 percent and a specificity of 50 percent. Sensitivity improved somewhat with experience, as measured by the number of patients seen per year. The prediction of the presence or absence of the 22q11.2 deletion at chance levels suggests that the ability to diagnose on the basis of appearance alone is not a sufficient diagnostic tool. Although the ability does increase with experience, it is of

  17. CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

    PubMed Central

    Xu, Na; Li, Yu-ling; Zhou, Xuan; Cao, Rui; Li, Huan; Lu, Qi-si; Li, Lin; Lu, Zi-yuan; Huang, Ji-xian; Sun, Jing; Liu, Qi-fa; Du, Qing-feng; Liu, Xiao-li

    2015-01-01

    Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes. PMID:26516359

  18. 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.

  19. Characterization of an APC Promoter 1B deletion in a Patient Diagnosed with Familial Adenomatous Polyposis via Whole Genome Shotgun Sequencing

    PubMed Central

    Kalbfleisch, Ted; Brock, Pamela; Snow, Angela; Neklason, Deborah; Gowans, Gordon; Klein, Jon

    2015-01-01

    Recently, deletions have been identified and published as causal for Familial Adenomatous Polyposis in the 1B promoter region of the APC gene.  Those deletions were measured using multiplex ligation-dependent probe amplification.  Here, we present and characterize an ~11kb deletion identified by whole genome shotgun sequencing.  The deletion occurred in a patient diagnosed with Familial Adenomatous Polyposis, and was located on chr5, between bases 112,034,824 and 112,045,845, fully encompassing the 1B promoter region of the APC gene.   Results are presented here that include the sequence evidence supporting the presence of the deletion as well as base level characterization of the deletion site.  These results demonstrate the capacity of whole genome sequencing for the detection of large structural variants in single individuals. PMID:26213617

  20. Characterization of an APC Promoter 1B deletion in a Patient Diagnosed with Familial Adenomatous Polyposis via Whole Genome Shotgun Sequencing.

    PubMed

    Kalbfleisch, Ted; Brock, Pamela; Snow, Angela; Neklason, Deborah; Gowans, Gordon; Klein, Jon

    2015-01-01

    Recently, deletions have been identified and published as causal for Familial Adenomatous Polyposis in the 1B promoter region of the APC gene.  Those deletions were measured using multiplex ligation-dependent probe amplification.  Here, we present and characterize an ~11kb deletion identified by whole genome shotgun sequencing.  The deletion occurred in a patient diagnosed with Familial Adenomatous Polyposis, and was located on chr5, between bases 112,034,824 and 112,045,845, fully encompassing the 1B promoter region of the APC gene.   Results are presented here that include the sequence evidence supporting the presence of the deletion as well as base level characterization of the deletion site.  These results demonstrate the capacity of whole genome sequencing for the detection of large structural variants in single individuals. PMID:26213617

  1. 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

  2. An atypical 7q11.23 deletion in a normal IQ Williams–Beuren syndrome patient

    PubMed Central

    Ferrero, Giovanni Battista; Howald, Cédric; Micale, Lucia; Biamino, Elisa; Augello, Bartolomeo; Fusco, Carmela; Turturo, Maria Giuseppina; Forzano, Serena; Reymond, Alexandre; Merla, Giuseppe

    2010-01-01

    Williams–Beuren syndrome (WBS; OMIM no. 194050) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion of 1.55 Mb on chromosome 7q11.23 spanning 28 genes. Haploinsufficiency of the ELN gene was shown to be responsible for supravalvular aortic stenosis and generalized arteriopathy, whereas LIMK1, CLIP2, GTF2IRD1 and GTF2I genes were suggested to be linked to the specific cognitive profile and craniofacial features. These insights for genotype–phenotype correlations came from the molecular and clinical analysis of patients with atypical deletions and mice models. Here we report a patient showing mild WBS physical phenotype and normal IQ, who carries a shorter 1 Mb atypical deletion. This rearrangement does not include the GTF2IRD1 and GTF2I genes and only partially the BAZ1B gene. Our results are consistent with the hypothesis that hemizygosity of the GTF2IRD1 and GTF2I genes might be involved in the facial dysmorphisms and in the specific motor and cognitive deficits observed in WBS patients. PMID:19568270

  3. Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

    PubMed Central

    Bertelsen, Birgitte; Melchior, Linea; Jensen, Lars R; Groth, Camilla; Glenthøj, Birte; Rizzo, Renata; Debes, Nanette Mol; Skov, Liselotte; Brøndum-Nielsen, Karen; Paschou, Peristera; Silahtaroglu, Asli; Tümer, Zeynep

    2014-01-01

    Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5′-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons. PMID:24549057

  4. 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.

  5. A novel α(0) -thalassemia deletion in a Greek patient with HbH disease and β-thalassemia trait.

    PubMed

    Phylipsen, Marion; Traeger-Synodinos, Jan; van der Kraan, Martijn; van Delft, Peter; Bakker, Greet; Geerts, Mariska; Kanavakis, Emmanuel; Stamoulakatou, Alexandra; Karagiorga, Markissia; Giordano, Piero C; Harteveld, Cornelis L

    2011-12-30

    Objectives:  To determine the molecular basis in a Greek child suspected of having HbH disease and β-thalassemia trait. Methods:  Standard hematology, Hb electrophoresis and HPLC. MLPA, direct sequencing and breakpoint characterization by NimbleGen fine-tiling array analysis. Results:  The index patient showed a moderate microcytic hypochromic anemia with normal ZPP and elevated HbA(2) , indicative for β-thalassemia trait. However the moderate microcytic hypochromic anemia, along with the observation of HbH inclusions in occasional red blood cells suggested a co-existing α-thalassemia. Molecular analysis indicated that the propositus inherited the β(+) -thalassemia mutation IVS2-745 (c>g) and a novel α(0) -thalassemia deletion from the mother, and the common non-deletion α-thalassemia allele α(2) (-5nt)α from the father. The α(0) -thalassemia deletion is approximately 131.6 kb in length. It removes the major regulatory elements along with the functional α-globin genes, but leaves the theta-gene intact. Conclusions:  The compound interaction of a β-thalassemia defect along with a single functional α-globin gene is quite rare. Although patients with HbH/β-thal and simple HbH disease, have comparable levels of Hb, the absence of free β-globin chains and thus detectable non-functional HbH means that in HbH/β-thal the levels of functional Hb are higher, resulting in a better compensated functional anemia. Rare large deletions as the one described here remain undetected by gap-PCR in routine molecular screening. The introduction of MLPA as a diagnostic screening tool may improve laboratory diagnostics for these defects. The use of NimbleGen fine tiling arrays may give additional information about the precise location of breakpoints. © 2011 John Wiley & Sons A/S. PMID:22211883

  6. 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.

  7. 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

  8. Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

    PubMed

    Guilherme, Roberta Santos; Soares, Karina Cunha; Simioni, Milena; Vieira, Tarsis Paiva; Gil-da-Silva-Lopes, Vera Lúcia; Kim, Chong Ae; Brunoni, Décio; Spinner, Nancy Bettina; Conlin, Laura Kathleen; Christofolini, Denise Maria; Kulikowski, Leslie Domenici; Steiner, Carlos Eduardo; Melaragno, Maria Isabel

    2014-07-01

    We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints--unique for each patient--could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder. PMID:24700634

  9. 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. PMID:26508576

  10. 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.

  11. 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.

  12. Distinctive Phenotype in 9 Patients with Deletion of Chromosome 1q24-q25

    PubMed Central

    Burkardt, Deepika D’Cunha; Rosenfeld, Jill A.; Helgeson, Maria; Angle, Brad; Banks, Valerie; Smith, Wendy; Gripp, Karen W.; Moline, Jessica; Moran, Rocio; Niyazov, Dmitriy M.; Stevens, Cathy; Zackai, Elaine; Lebel, Robert Roger; Ashley, Douglas; Kramer, Nancy; Lachman, Ralph S.; Graham, John M.

    2011-01-01

    Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170135865–172099327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. PMID:21548129

  13. Interstitial 1q23.3q24.1 deletion in a patient with renal malformation, congenital heart disease, and mild intellectual disability.

    PubMed

    Mackenroth, Luisa; Hackmann, Karl; Klink, Barbara; Weber, Julia Sara; Mayer, Brigitte; Schröck, Evelin; Tzschach, Andreas

    2016-09-01

    Interstitial deletions including chromosome region 1q23.3q24.1 are rare. Only eight patients with molecularly characterized deletions have been reported to date. Their phenotype included intellectual disability/developmental delay, growth retardation, microcephaly, congenital heart disease, and renal malformations. We report on a female patient with mild developmental delay, congenital heart disease, and bilateral renal hypoplasia in whom an interstitial de novo deletion of approximately 2.7 Mb in 1q23.3q24.1 was detected by array CGH. This is the smallest deletion described in this region so far. Genotype-phenotype comparison with previously published patients allowed us to propose LMX1A and RXRG as potential candidate genes for intellectual disability, PBX1 as a probable candidate gene for renal malformation, and enabled us to narrow down a chromosome region associated with microcephaly. © 2016 Wiley Periodicals, Inc. PMID:27255444

  14. Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome.

    PubMed

    Calì, F; Failla, P; Chiavetta, V; Ragalmuto, A; Ruggeri, G; Schinocca, P; Schepis, C; Romano, V; Romano, C

    2013-01-01

    Rubinstein-Taybi syndrome is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation, psychomotor developmental delay, skeletal anomalies, peculiar facial morphology, and tumorigenesis. Mutations in the gene encoding the cAMP response element-binding protein (CREB, also known as CREBBP or CBP) on chromosome 16p13.3 have been identified. In addition, some patients with low intelligence quotients and autistic features bear large deletions. Based on these observations, we used multiplex ligation-dependent probe amplification to search for large deletions affecting the CREBBP gene in a Rubinstein-Taybi syndrome patient. We identified a novel heterozygote deletion removing five exons (exons 17-21), encoding the histone acetyltransferase domain. We propose the use of multiplex ligation-dependent probe amplification as a fast, accurate and cheap test for detecting large deletions in the CREBBP gene in the sub-group of Rubinstein-Taybi syndrome patients with low intelligence quotients and autistic features. PMID:23315884

  15. 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. PMID:26437767

  16. 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

  17. Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

    SciTech Connect

    Brown, A. |; Phelan, M.C.; Rogers, R.C.

    1996-05-17

    J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magenis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/ duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A). 30 refs., 3 figs., 1 tab.

  18. 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%.

  19. 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.

  20. Screening for mutations in the muscle promoter region and for exonic deletions in a series of 115 DMD and BMD patients.

    PubMed Central

    Vitiello, L; Mostacciuolo, M L; Oliviero, S; Schiavon, F; Nicoletti, L; Angelini, C; Danieli, G A

    1992-01-01

    Mutations in the muscle promoter region and exonic deletions were screened in a series of 115 unrelated DMD and BMD patients from north-east Italy. No gross mutations of the promoter region were found. In three cases in which dystrophin of normal size was expressed at low levels, the analysis of DNA sequences of the promoter region failed to detect abnormalities. The majority of deletions in coding sequences, detected by cDNA probes, occur in the deletion hot spot identified by the probe P20. Intrafamilial variability in the severity of the disease is reported and discussed. Images PMID:1613762

  1. Spontaneous deletion in the FMR-1 gene in a patient with fragile X syndrome and cherubism

    SciTech Connect

    Popovich, B.W.; Anoe, K.S.; Johnson, D.B.

    1994-09-01

    Fragile X mental retardation results from the transcriptional inactivation of the FMR-1 gene and is commonly caused by the expansion of an unstable CGG trinucleotide repeat located in the first exon of the FMR-1 gene. We describe here a two generation fragile X family in which expansion of the CGG repeat may have resulted in a deletion of a least portion of the FMR-1 gene. One member of this family, AB, carries an apparent deletion of the FMR-1 gene and presents with mental retardation and also cherubism, a feature not usually associated with fragile X syndrome. Cherubism is a condition characterized by a swelling of the lower face and is caused by giant cell lesions of the mandible and maxilla, and often the anterior ends of the ribs. The size of the CGG repeat region in this family was determined by Southern analysis of BglII, EcoRI, and PstI digested genomic DNA, isolated from peripheral blood lymphocytes, using a 558 bp PstI-Xhol fragment specific for the 5{prime}-end of the FMR-1 gene. SB and TB, the mother and maternal half-brother of AB, respectively, were both found to carry an expanded FMR-1 allele with greater than 200 CGG repeats. Negligible hybridization was observed in the DNA of AB. In addition, no amplification was observed when the polymerase chain reaction (PCR) was performed using primers flanking the CGG repeat region. These results are consistent with a deletion of at least the 5{prime} portion of the FMR-1 gene in the majority of peripheral blood lymphocytes. Further work is underway using FMR-1 cDNA probes and additional PCR primers to determine the nature of the molecular lesion in AB`s DNA and determine the relationship of this lesion to his cherubism.

  2. 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

  3. 22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization.

    PubMed

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

    2016-02-01

    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

  4. 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

  5. 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

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

    PubMed

    Gangarossa, S; Mattina, T; Romano, V; Milana, G; Mollica, F; Schilirò, 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. PMID:8882392

  7. 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.

  8. 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

  9. The angiotensin-converting enzyme gene insertion–deletion polymorphism in a white British patient cohort with obstetric cholestasis

    PubMed Central

    Müllenbach, Roman; Tetlow, Natasha; Bennett, Amanda; Pipkin, Fiona Broughton; Morgan, Linda; Williamson, Catherine

    2009-01-01

    The DD genotype of the angiotensin-converting enzyme (ACE) gene is over-represented in Finnish patients with obstetric cholestasis (OC). The purpose of this study was to establish whether this genotype is associated with cholestasis in UK cases. In a retrospective case-control study, we determined the ACE insertion/deletion frequencies in 166 British cases and 100 control women by polymerase chain reaction analysis. No significant difference in allele frequencies was found between these groups, but allele frequencies differed significantly between Finnish and UK OC cases (P = 0.0005). The prevalence of the DD genotype is lower in UK cases than in controls (χ2 [1 d.f.] = 4.32, P = 0.05) and the odds ratio for OC associated with the DD genotypeis 0.54, 95% confidence interval 0.30–0.97. In contrast to Finnish OC cases, the DD genotype of the ACE is not increased in UK cases.

  10. 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.

  11. 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

  12. Characterization of chromosome 11 breakpoints and the areas of deletion and amplification in patients with newly diagnosed acute myeloid leukemia.

    PubMed

    Sarova, Iveta; Brezinova, Jana; Zemanova, Zuzana; Bystricka, Dagmar; Krejcik, Zdenek; Soukup, Petr; Vydra, Jan; Cermak, Jaroslav; Jonasova, Anna; Michalova, Kyra

    2013-07-01

    Chromosome 11 abnormalities are found in many hematological malignancies. In acute myeloid leukemia (AML), a proto-oncogene MLL (11q23.3) is frequently altered. However, rearrangements involving other regions of chromosome 11 have been reported. Therefore, we have characterized the chromosome 11 breakpoints and common deleted and amplified areas in the bone marrow or peripheral blood cells of newly diagnosed patients with AML. Using molecular-cytogenetic methods (multicolor fluorescence in situ hybridization (mFISH), multicolor banding (mBAND), microarrays, and FISH with bacterial artificial chromosome (BAC) probes, chromosome 11 abnormalities were delineated in 54 out of 300 (18%) newly diagnosed AML patients. At least 36 different chromosome 11 breakpoints were identified; two were recurrent (11p15.4 in the NUP98 gene and 11q23.3 in the MLL gene), and three were possibly nonrandom: 11p13 (ch11:29.31-31.80 Mb), 11p12 (ch11:36.75-37.49 Mb) and 11q13.2 (68.31-68.52 Mb). One new MLL gene rearrangement is also described. No commonly deleted region of chromosome 11 was identified. However, some regions were affected more often: 11pter-11p15.5 (n = 4; ch11:0-3.52 Mb), 11p14.1-11p13 (n = 4; ch11:28.00-31.00 Mb) and 11p13 (n = 4; ch11:31.00-31.50 Mb). One commonly duplicated (3 copies) region was identified in chromosomal band 11q23.3-11q24 (n = 9; ch11:118.35-125.00 Mb). In all eight cases of 11q amplification (>3 copies), only the 5' part of the MLL gene was affected. This study highlights several chromosome 11 loci that might be important for the leukemogeneic process in AML. PMID:23580398

  13. Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer.

    PubMed

    Ahvenainen, Taru; Lehtonen, Heli J; Lehtonen, Rainer; Vahteristo, Pia; Aittomäki, Kristiina; Baynam, Gareth; Dommering, Charlotte; Eng, Charis; Gruber, Stephen B; Grönberg, Henrik; Harvima, Rauno; Herva, Riitta; Hietala, Marja; Kujala, Minna; Kääriäinen, Helena; Sunde, Lone; Vierimaa, Outi; Pollard, Patrick J; Tomlinson, Ian P M; Björck, Erik; Aaltonen, Lauri A; Launonen, Virpi

    2008-06-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome predisposing to cutaneous and uterine leiomyomatosis as well as renal cell cancer and uterine leiomyosarcoma. Heterozygous germline mutations in the fumarate hydratase (FH, fumarase) gene are known to cause HLRCC. On occasion, no FH mutation is detected by direct sequencing, despite the evident HLRCC phenotype in a family. In the present study, to investigate whole gene or exonic deletions and amplifications in FH mutation-negative patients, we used multiplex ligation-dependent probe amplification technology. The study material comprised 7 FH mutation-negative HLRCC patients and 12 patients affected with HLRCC-associated phenotypes, including papillary RCC, early-onset RCC, uterine leiomyomas, or uterine leiomyosarcoma. A novel FH mutation, a deletion of FH exon 1 that encodes the mitochondrial signal peptide, was detected in one of the HLRCC patients (1/7). The patient with the FH mutation displayed numerous painful cutaneous leiomyomas and papillary type renal cell cancer. Our finding, together with the two patients with whole FH gene deletion who had been detected previously, suggests that exonic or whole-gene FH deletions are not a frequent cause of HLRCC syndrome. PMID:18503824

  14. 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

  15. 9q31.1q31.3 deletion in two patients with similar clinical features: a newly recognized microdeletion syndrome?

    PubMed

    Mucciolo, M; Magini, P; Marozza, A; Mongelli, P; Mencarelli, M A; Hayek, G; Tavalazzi, F; Mari, F; Seri, M; Renieri, A; Graziano, C

    2014-03-01

    Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region. PMID:24376033

  16. Molecular cytogenetic and clinical characterization of a patient with a 5.6-Mb deletion in 7p15 including HOXA cluster.

    PubMed

    Jun, Kyung Ran; Seo, Eul-Ju; Lee, Jin-Ok; Yoo, Han-Wook; Park, In-Sook; Yoon, Hye-Kyung

    2011-03-01

    Here, we describe the clinical features of a boy with a 5.6-Mb deletion at chromosome 7p15.1-p15.3. He has mild facial anomalies, hand-foot abnormalities, hypospadias, congenital heart defects, and supernumerary nipples. This deletion was detected by array comparative genomic hybridization and verified by fluorescence in situ hybridization using BACs selected from the USCS genome browser. This deletion was not found in subsequent FISH analysis of the parental chromosomes. The deleted region contains several genes, including contiguous developmental genes on the HOXA cluster, which play a role in regulating aspects of morphogenesis during normal embryonic development. The patient's limb and urogenital features were similar to those observed in hand-foot-genital syndrome, which is caused by haploinsufficiency of HOXA13, whereas the congenital heart defect may reflect the deletion of HOXA3. We hypothesized that many clinical features of the patient were due to combined haploinsufficiency of the HOXA cluster. Our study also demonstrates the clinical usefulness of a molecular cytogenetic tool that is capable of detecting imbalances in the genome. PMID:21344639

  17. 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.

  18. Deletion of late cornified envelope genes, LCE3C_LCE3B-del, is not associated with psoriatic arthritis in Tunisian patients.

    PubMed

    Chiraz, Bouchlaka Souissi; Myriam, Ammar; Ines, Zarra; Catherine, Jordan; Fatma, Bouazizi; Ilhem, Cheour; Raoudha, Tekaya; Hela, Zeglaoui; Hela, Fourati; Elyes, Bouajina; Nejib, Doss; Cindy, Helms; Amel, Elgaaied; Slaheddine, Sellami

    2014-06-01

    A deletion of two genes from the late cornified envelope (LCE), LCE3B and LCE3C within epidermal differentiation complex on chromosome 1 was shown to be associated with both psoriasis and psoriatic arthritis (PsA) in several populations. To assess whether this deletion may contribute to the genetic predisposition to PsA in Tunisia, a total of 73 patients with PsA and 120 healthy matched controls were screened for the deletion, LCE3C_LCE3B-del, and its tag SNP, rs4112788. We also evaluated a possible relationship between PSORS1 and LCE3C_LCE3B-del through genotyping two proxy markers to HLA-C (rs12191877 and rs2073048). Our results did not provide evidence for association between the LCE3C_LCE3B-del nor the rs4112788 and the PsA. Similarly, no significant epistatic effect was observed. Our data suggest that The LCE deletion, previously identified in patients with psoriasis, is not of a major importance in the development of PsA in Tunisian patients supporting the current perception that different genetic risk factors contribute to skin and joint disease. However, these results need to be confirmed by additional large-scale studies of Tunisian PsA patients and controls. PMID:24566688

  19. 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

  20. Deletion of PREPL, a Gene Encoding a Putative Serine Oligopeptidase, in Patients with Hypotonia-Cystinuria Syndrome

    PubMed Central

    Jaeken, Jaak; Martens, Kevin; François, Inge; Eyskens, François; Lecointre, Claudine; Derua, Rita; Meulemans, Sandra; Slootstra, Jerry W.; Waelkens, Etienne; Zegher, Francis de; Creemers, John W. M.; Matthijs, Gert

    2006-01-01

    In 11 patients with a recessive congenital disorder, which we refer to as “the hypotonia-cystinuria syndrome,” microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Since loss-of-function mutations in SLC3A1 are known to cause isolated cystinuria type I, and since the expression of the flanking genes, C2orf34 and PPM1B, was normal, the extended phenotype can be attributed to the deletion of PREPL. PREPL is localized in the cytosol and shows homology with prolyl endopeptidase and oligopeptidase B. Substitution of the predicted catalytic residues (Ser470, Asp556, and His601) by alanines resulted in loss of reactivity with a serine hydrolase-specific probe. In sharp contrast to prolyl oligopeptidase and oligopeptidase B, which require both aminoterminal and carboxyterminal sequences for activity, PREPL activity appears to depend only on the carboxyterminal domain. Taken together, these results suggest that PREPL is a novel oligopeptidase, with unique structural and functional characteristics, involved in hypotonia-cystinuria syndrome. PMID:16385448

  1. 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

  2. Genome-wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients.

    PubMed

    Nordgard, Silje H; Johansen, Fredrik E; Alnaes, Grethe I G; Bucher, Elmar; Syvänen, Ann-Christine; Naume, Bjørn; Børresen-Dale, Anne-Lise; Kristensen, Vessela N

    2008-08-01

    Breast carcinomas are characterized by DNA copy number alterations (CNAs) with biological and clinical significance. This explorative study integrated CNA, expression, and germline genotype data of 112 early-stage breast cancer patients. Recurrent CNAs differed substantially between tumor subtypes classified according to expression pattern. Deletion of 16q was overrepresented in Luminal A, and a predictor of good prognosis, both overall and for the nonluminal A subgroups. The deleted region most significantly associated with survival mapped to 16q22.2, harboring the genes TXNL4B and DXH38, whose expression was strongly correlated with the deletion. The area most frequently deleted resided on 16q23.1, 3.5 MB downstream of the area most significantly associated with survival, and included the tumor suppressor gene ADAMTS18 and the cell recognition gene CNTNAP4. Whole-genome association analysis identified germline single nucleotide polymorphisms (SNPs) and their corresponding haplotypes, residing on several different chromosomes, to be associated with deletion of 16q. The genes where these SNPs reside encode proteins involved in the extracellular matrix (CHST3 and SPOCK2), in regulation of the cell cycle (JMY, PTPRN2, and Cwf19L2) and chromosome stability (KPNB1). PMID:18398821

  3. Clinical and molecular characterization of a patient with a combination of a deletion and a duplication of 22q13 using array CGH

    PubMed Central

    Ochando, Isabel; Urbano, Antonio; Rubio, Juana; Rueda, Joaquín

    2012-01-01

    Phelan–McDermid syndrome is caused by the loss of terminal regions of different sizes at 22q13. There is a wide range of severity of symptoms in patients with a 22q13 deletion, but these patients usually show neonatal hypotonia, global developmental delay, and dysmorphic traits. We carried out a clinical and molecular characterization of a patient with neonatal hypotonia and dysmorphic features. Array-based comparative genomic hybridization showed an 8.24 Mb terminal deletion associated with a 0.20 Mb duplication. Characterization of patients with Phelan–McDermid syndrome both clinically and at the molecular level allows genotype-phenotype correlations that provide clues to help elucidate the clinical implications. PMID:23776384

  4. 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.

  5. The double polymethylmethacrylate filter (DELETE system) in the removal of light chains in chronic dialysis patients with multiple myeloma.

    PubMed

    Santoro, Antonio; Grazia, Michele; Mancini, Elena

    2013-01-01

    Multiple myeloma (MM) is still one of the most common haematological diseases and is associated with a poor prognosis. It is frequently worsened by acute kidney failure that, in turn, aggravates the risk of death. In the past few years, the idea has made headway that the removal of free light chains (FLC) by means of extracorporeal blood purification systems may facilitate the recovery of renal function. Up to now, many different extracorporeal techniques have been put forward in FLC removal, such as plasma exchange, dialysis with super-flux filters, and adsorption by means of cartridge of resins. In this paper, we illustrate the use of polymethylmethacrylate (PMMA) dialysis membranes with a high adsorptive capacity (Toray BK-F; Toray Industries, Inc., Tokyo, Japan). We have evaluated light chain removal by means of an original dialysis procedure using a double-filter circuit made of PMMA working in sequential dialysis (DELETE system). The system provides satisfactory results in terms of FLC removal and, at the same time, ensures an adequate dialysis treatment (Kt/V >1.5) with significant reduction in urea, creatinine, and β2-microglobulin. The dual PMMA filter system combines an acceptable cost/efficiency ratio when compared with other methods and constitutes a concrete prospect in FLC removal. Its preferential setting of use is in patients with MM or with monoclonal gammopathies, who are on chronic dialysis and maintain high circulating levels of FLC. PMID:23676829

  6. 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. PMID:20334546

  7. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.

    PubMed

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  8. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients

    PubMed Central

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  9. Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients.

    PubMed

    Kamieniak, Marta M; Rico, Daniel; Milne, Roger L; Muñoz-Repeto, Ivan; Ibáñez, Kristina; Grillo, Miguel A; Domingo, Samuel; Borrego, Salud; Cazorla, Alicia; García-Bueno, José M; Hernando, Susana; García-Donas, Jesús; Hernández-Agudo, Elena; Y Cajal, Teresa Ramón; Robles-Díaz, Luis; Márquez-Rodas, Ivan; Cusidó, Maite; Sáez, Raquel; Lacambra-Calvet, Carmen; Osorio, Ana; Urioste, Miguel; Cigudosa, Juan C; Paz-Ares, Luis; Palacios, José; Benítez, Javier; García, María J

    2015-02-01

    Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life. PMID:25454820

  10. Detection of deleted mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome

    SciTech Connect

    Mita, S.; Schmidt, B.; Schon, E.A.; DiMauro, S.; Bonilla, E. )

    1989-12-01

    Using in situ hybridization and immunocytochemistry, the authors studied a muscle biopsy sample from a patient with Kearns-Sayre syndrome (KSS) who had a deletion of mitochondrial DNA (mtDNA) and partial deficiency of cytochrome-c oxidase. They sought a relationship between COX deficiency and abnormalities of mtDNA at the single-fiber level. COX deficiency clearly correlated with a decrease of normal mtDNA and, conversely, deleted mtDNA was more abundant in COX-deficient fibers, especially ragged-red fibers. The distribution of mtRNA has a similar pattern, suggesting that deleted mtDNA is transcribed. Immunocytochemistry showed that the nuclear DNA-encoded subunit IV of COX was present but that the mtDNA-encoded subunit II was markedly diminished in COX-deficient ragged-red fibers. Because the mtDNA deletion in this patient did not comprise the gene encoding COX subunit II, COX deficiency may have resulted from lack of translation of mtRNA encoding all three mtDNA-encoded subunits of COX.

  11. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.

    PubMed

    Gervasini, Cristina; Castronovo, Paola; Bentivegna, Angela; Mottadelli, Federica; Faravelli, Francesca; Giovannucci-Uzielli, Maria Luisa; Pessagno, Alice; Lucci-Cordisco, Emanuela; Pinto, Anna Maria; Salviati, Leonardo; Selicorni, Angelo; Tenconi, Romano; Neri, Giovanni; Larizza, Lidia

    2007-11-01

    Rubinstein-Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5-10 kb. Four of our five intragenic breakpoints cluster at the 5' end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region's vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS. PMID:17855048

  12. Central 22q11.2 deletions.

    PubMed

    Rump, Patrick; de Leeuw, Nicole; van Essen, Anthonie J; Verschuuren-Bemelmans, Corien C; Veenstra-Knol, Hermine E; Swinkels, Mariëlle E M; Oostdijk, Wilma; Ruivenkamp, Claudia; Reardon, Willie; de Munnik, Sonja; Ruiter, Mariken; Frumkin, Ayala; Lev, Dorit; Evers, Christina; Sikkema-Raddatz, Birgit; Dijkhuizen, Trijnie; van Ravenswaaij-Arts, Conny M

    2014-11-01

    22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping deletions distal to the TBX1 locus have been described in the literature. In these patients, the CRKL gene is deleted. Haploinsufficiency of this gene has also been implicated in the pathogenesis of 22q11.2 deletion syndrome. To distinguish these deletions (comprising the LCR22-B to LCR22-D region) from the more distal 22q11.2 deletions (located beyond LCR22-D), we propose the term "central 22q11.2 deletions". In the present study we report on 27 new patients with such a deletion. Together with information on previously published cases, we review the clinical findings of 52 patients. The prevalence of congenital heart anomalies and the frequency of de novo deletions in patients with a central deletion are substantially lower than in patients with a common or distal 22q11.2 deletion. Renal and urinary tract malformations, developmental delays, cognitive impairments and behavioral problems seem to be equally frequent as in patients with a common deletion. None of the patients had a cleft palate. Patients with a deletion that also encompassed the MAPK1 gene, located just distal to LCR22-D, have a different and more severe phenotype, characterized by a higher prevalence of congenital heart anomalies, growth restriction and microcephaly. Our results further elucidate genotype-phenotype correlations in 22q11.2 deletion syndrome spectrum. PMID:25123976

  13. 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.

  14. EGFR exon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients.

    PubMed

    Yang, Shi-Yi; Yang, Tsung-Ying; Li, Yao-Jen; Chen, Kun-Chieh; Liao, Kuo-Meng; Hsu, Kuo-Hsuan; Tsai, Chi-Ren; Chen, Chih-Yi; Hsu, Chung-Ping; Hsia, Jiun-Yi; Chuang, Cheng-Yen; Tsai, Ying-Huang; Chen, Kuan-Yu; Huang, Ming-Shyan; Su, Wu-Chou; Chen, Yuh-Min; Hsiung, Chao A; Shen, Chen-Yang; Chang, Gee-Chen; Yang, Pan-Chyr; Chen, Chien-Jen

    2013-01-15

    We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females. PMID:22573488

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

    PubMed Central

    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

    2010-01-01

    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. PMID:20684015

  16. Identification of novel mutations in CD2BP1 gene in clinically proven rheumatoid arthritis patients of south India.

    PubMed

    Kumar, Bhattaram Siddhartha; Kumar, Pasupuleti Santhosh; Sowgandhi, Nannepaga; Prajwal, Bhattaram Manoj; Mohan, Alladi; Sarma, Kadainti Venkata Subbaraya; Sarma, Potukuchi Venkata Gurunadha Krishna

    2016-08-01

    Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA syndrome) is a rare autosomal dominant, auto-inflammatory disease that affects joints and skin. The disease results due to mutations in the cluster of differentiation 2 binding protein 1 (CD2BP1) gene on chromosome 15q24.3. Rheumatoid arthritis (RA) is a common, genetically complex disease that affects the joints with occasional skin manifestations. Studies related to the pathophysiology of inflammation in these two disorders show a certain degree of overlap at genetic level. The present study was done to confirm the existence of such a genetic overlap between PAPA syndrome and RA in south Indian population. In the present study 100 patients who were clinically diagnosed rheumatoid arthritis and 100 apparently healthy controls were chosen and the 15 exons of CD2BP1 gene were PCR-amplified and sequenced. The sequence analysis showed that in exon 3 thirty eight patients revealed presence of novel heterozygous missense mutations p.Glu51Asp, p.Leu57Arg and p.Ala64Thr. In exons 6, 10 and 14 eight patients showed 44 novel missense mutations and two patients showed novel frame shift mutations p.(Met123_Leu416delinsThr) and p.(Thr337Profs*52) leading to truncated protein formation. Such mutations were not seen in controls. Further, the in silico analysis revealed the mutant CD2BP1 structure showed deletion of Cdc15 and SH3 domains when superimposed with the wild type CD2BP1 structure with variable RMSD values. Therefore, these structural variations in CD2BP1 gene due to the mutations could be one of the strongest reasons to demonstrate the involvement of these gene variations in the patients with rheumatoid arthritis. PMID:27184502

  17. Persistent Production of an Integrase-Deleted HIV-1 Variant with No Resistance Mutation and Wild-Type Proviral DNA in a Treated Patient

    PubMed Central

    Cotte, Laurent; Saison, Julien; Ramière, Christophe; Ronfort, Corinne; Venet, Fabienne; Tardy, Jean-Claude; Monneret, Guillaume; André, Patrice

    2015-01-01

    Abstract An HIV-infected patient presenting an unexpected viral escape under combined antiretroviral treatment is described. The virus isolated from plasma contained a large deletion in the HIV-1 integrase gene but no known resistance mutation. Nested polymerase chain reactions (PCRs) with patient virus integrase-specific primers and probes were developed and used to detect the mutant from plasma, blood, rectal biopsies, and sperm. The variant progressively emerged during a period of therapy-induced virosuppression, and persisted at a low but detectable level for at least 5 years. Surprisingly, proviral DNA from lymphocytes, rectal cells, and sperm cells was, and remained, mainly wild type. Cellular HIV RNA with the deletion was detected only once from the rectum. The origin and mechanisms underlying this so far not described production at a detectable level are largely hypothetical. This observation raised concern about the ability of defective viruses to spread. PMID:25333615

  18. A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient

    SciTech Connect

    Murru, S.; Casula, L.; Moi, P.

    1994-09-15

    In this paper the authors report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In this patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3` breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. 52 refs., 7 figs.

  19. Partial protoporphyrinogen oxidase (PPOX) gene deletions, due to different Alu-mediated mechanisms, identified by MLPA analysis in patients with variegate porphyria

    PubMed Central

    2013-01-01

    Variegate porphyria (VP) is an autosomal dominantly inherited hepatic porphyria. The genetic defect in the PPOX gene leads to a partial defect of protoporphyrinogen oxidase, the penultimate enzyme of heme biosynthesis. Affected individuals can develop cutaneous symptoms in sun-exposed areas of the skin and/or neuropsychiatric acute attacks. The identification of the genetic defect in VP families is of crucial importance to detect the carrier status which allows counseling to prevent potentially life threatening neurovisceral attacks, usually triggered by factors such as certain drugs, alcohol or fasting. In a total of 31 Swedish VP families sequence analysis had identified a genetic defect in 26. In the remaining five families an extended genetic investigation was necessary. After the development of a synthetic probe set, MLPA analysis to screen for single exon deletions/duplications was performed. We describe here, for the first time, two partial deletions within the PPOX gene detected by MLPA analysis. One deletion affects exon 5 and 6 (c.339-197_616+320del1099) and has been identified in four families, most probably after a founder effect. The other extends from exon 5 to exon 9 (c.339-350_987+229del2609) and was found in one family. We show that both deletions are mediated by Alu repeats. Our findings emphasize the usefulness of MLPA analysis as a complement to PPOX gene sequencing analysis for comprehensive genetic diagnostics in patients with VP. PMID:23324528

  20. 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.

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

    PubMed

    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

    2015-05-01

    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

  2. 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. PMID:26486927

  3. 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

  4. A novel mitochondrial DNA deletion in a patient with Pearson syndrome and neonatal diabetes mellitus provides insight into disease etiology, severity and progression.

    PubMed

    Chen, Xin-Yu; Zhao, Si-Yu; Wang, Yan; Wang, Dong; Dong, Chang-Hu; Yang, Ying; Wang, Zhi-Hua; Wu, Yuan-Ming

    2016-07-01

    Pearson syndrome (PS) is a rare, mitochondrial DNA (mtDNA) deletion disorder mainly affecting hematopoietic system and exocrine pancreas in early infancy, which is characterized by multi-organ involvement, variable manifestations and poor prognosis. Since the clinical complexity and uncertain outcome of PS, the ability to early diagnose and anticipate disease progression is of great clinical importance. We described a patient with severe anemia and hyperglycinemia at birth was diagnosed with neonatal diabetes mellitus, and later with PS. Genetic testing revealed that a novel mtDNA deletion existed in various non-invasive tissues from the patient. The disease course was monitored by mtDNA deletion heteroplasmy and mtDNA/nucleus DNA genome ratio in different tissues and at different time points, showing a potential genotype-phenotype correlation. Our findings suggest that for patient suspected for PS, it may be therapeutically important to first perform detailed mtDNA analysis on non-invasive tissues at the initial diagnosis and during disease progression. PMID:26016877

  5. 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

  6. Comparative genomic hybridization of microdissected familial ovarian carcinoma: two deleted regions on chromosome 15q not previously identified in sporadic ovarian carcinoma.

    PubMed

    Zweemer, R P; Ryan, A; Snijders, A M; Hermsen, M A; Meijer, G A; Beller, U; Menko, F H; Jacobs, I J; Baak, J P; Verheijen, R H; Kenemans, P; van Diest, P J

    2001-10-01

    The vast majority of familial ovarian cancers harbor a germline mutation in either the breast cancer gene BRCA1 or BRCA2 tumor suppressor genes. However, mutations of these genes in sporadic ovarian cancer are rare. This suggests that in contrast to hereditary disease, BRCA1 and BRCA2 are not commonly involved in sporadic ovarian cancer and may indicate that there are two distinct pathways for the development of ovarian cancer. To characterize further differences between hereditary and sporadic cancers, the comparative genomic hybridization technique was employed to analyze changes in copy number of genetic material in a panel of 36 microdissected hereditary ovarian cancers. Gains at 8q23-qter (18 of 36, 5 cases with high-level amplifications), 3q26.3-qter (18 of 36, 2 cases with high-level amplifications), 11q22 (11 of 36) and 2q31-32 (8 of 36) were most frequent. Losses most frequently occurred (in decreasing order of frequency) on 8p21-pter (23 of 36), 16q22-pter (19 of 36), 22q13 (19 of 36), 9q31-33 (16 of 36), 12q24 (16 of 36), 15q11-15 (16 of 36), 17p12-13 (14 of 36), Xp21-22 (14 of 36), 20q13 (13 of 36), 15q24-25 (12 of 36), and 18q21 (12 of 36). Comparison with the literature revealed that the majority of these genetic alterations are also common in sporadic ovarian cancer. Deletions of 15q11-15, 15q24-25, 8p21-ter, 22q13, 12q24 and gains at 11q22, 13q22, and 17q23-25, however, appear to be specific to hereditary ovarian cancer. Aberrations at 15q11-15 and 15q24-25 have not yet been described in familial ovarian cancer. In these regions, important tumor suppressor genes, including the hRAD51 gene, are located. These and other yet unknown suppressor genes may be involved in a specific carcinogenic pathway for familial ovarian cancer and may explain the distinct clinical presentation and behavior of familial ovarian cancer. PMID:11598149

  7. Is long-term virological response related to CCR5 Δ32 deletion in HIV-1-infected patients started on highly active antiretroviral therapy?

    PubMed Central

    Laurichesse, Jean-Jacques; Taieb, Audrey; Capoulade-Metay, Corinne; Katlama, Christine; Villes, Virginie; Drobacheff-Thiebaud, Marie-Christine; Raffi, François; Chêne, Genevieve; Theodorou, Ioannis; Leport, Catherine

    2010-01-01

    Objective To examine whether CCR5 Δ32 deletion is associated with long-term response to combination antiretroviral treatment (cART) in HIV-1 infected patients. Methods The genetic sub-study of ANRS CO8 APROCO-COPILOTE cohort included 609 patients who started a protease inhibitor-containing cART in 1997–99. Patients were considered to have a sustained virological response if all plasma HIV-RNA measurements between month 4 and years 3–5 were <500 copies/ml, allowing for a single blip. Virological response was compared between patients heterozygous for CCR5 Δ32 (Δ32/wt) and wild-type patients (wt/wt) from month 4 to year 3 and month 4 to year 5. Logistic regression analysis was used to adjust for baseline demographical data, HIV-RNA, CD4 cell counts, antiretroviral naive status, time spent on antiretroviral therapy at year 3 and 5 and adherence to treatment (month 4 to year 3 and 5). Results Sustained virological response was better in Δ32/wt than in wt/wt patients: 66% versus 52% up to year 3 (p=0.02), nearly significant after adjustment to potential cofounders (p=0.07). Δ32/wt patients had a better virological response, up to year 5, 48% versus 35% (p=0.01), and remained significantly better, after adjustment, associated with a better virological response up to 5 years post initiation of cART (p=0.04). There was no association with CD4 response. Conclusion Δ32/wt deletion is associated with a beneficial virological response to cART on the long-term. Whether this association can be a direct effect of Δ32/wt deletion remains questionable and needs confirmation in other observational studies. PMID:20050936

  8. Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect.

    PubMed

    Cossée, Mireille; Demeer, Bénédicte; Blanchet, Patricia; Echenne, Bernard; Singh, Deepika; Hagens, Olivier; Antin, Manuela; Finck, Sonja; Vallee, Louis; Dollfus, Hélène; Hegde, Sridevi; Springell, Kelly; Thelma, B K; Woods, Geoffrey; Kalscheuer, Vera; Mandel, Jean-Louis

    2006-04-01

    Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR). Clinical features frequently associated with MR were microcephaly and/or short stature. The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon. We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history. We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family. We also found two different 21 bp in-frame deletions (c.334-354del(21 bp) and c.393-413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat. Although such deletions have not been detected in 1180 X chromosomes from European controls, the c. 334-354del(21 bp) was subsequently found in two of 477 Xs from Indian controls. We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function. This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment. PMID:16493439

  9. 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

  10. 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

  11. Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

    PubMed Central

    Santisteban, I; Arredondo-Vega, F X; Kelly, S; Mary, A; Fischer, A; Hummell, D S; Lawton, A; Sorensen, R U; Stiehm, E R; Uribe, L

    1993-01-01

    We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (delta 1019-1020), three missense (Arg156 > His, Arg101 > Leu, Val177 > Met), and three splicing defects (IVS 5, 5'ss T+6 > A; IVS 10, 5'ss G+1 > A; IVS 10, 3'ss G-34 > A). Four of the mutations generated stop signals at codons 131, 321, 334, and 348; transcripts of all but the last, due to delta 1019-1020, were severely reduced. delta 1019-1020 (like delta 955-959, found in one patient and apparently recurrent) is at a short deletional hot spot. Arg156 > His, the product of which had detectable activity, was found in three patients whose second alleles were unlikely to yield active ADA. The oldest patient diagnosed was homozygous for a single base change in intron 10, which activates a cryptic splice acceptor, resulting in a protein with 100 extra amino acids. We speculate that this "macro ADA," as well as the Arg156 > His, Arg101 > Leu, Ser291 > Leu, and delta 1019-1020 products, may contribute to mild phenotype. Tissue-specific variation in splicing efficiency may also ameliorate disease severity in patients with splicing mutations. Images PMID:8227344

  12. 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.

  13. 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…

  14. Bortezomib-based induction improves progression-free survival of myeloma patients harboring 17p deletion and/or t(4;14) and overcomes their adverse prognosis.

    PubMed

    El-Ghammaz, Amro M S; Abdelwahed, Essam

    2016-08-01

    Providing a risk-adapted treatment strategy has been a key goal in the ongoing research efforts aimed at providing treatment tailored to the individual genetic make-up. Eighty myeloma patients have been tested for presence of 17p deletion and/or t(4;14) by fluorescent in situ hybridization (FISH). Based on FISH results, they have been categorized into patients lacking them (standard risk) and those harboring them (high risk). Patients in each category were randomly assigned 1:1 to induction treatment by either vincristine, adriamycin and dexamethasone (VAD), or bortezomib and dexamethasone (VD) followed by autologous stem cell transplantation and thalidomide maintenance and were followed up for 32 months. 32.5 % of patients were high risk. Following induction, there were significantly higher rates of at least very good partial response achievement in VD arms in standard- and high-risk patients. Regarding complete response achievement, there were insignificant differences between VAD and VD arms in standard and high-risk patients. After a median follow-up of 17.5 months, there was insignificant difference in overall survival (OS) between VAD and VD arms in standard and high-risk patients. There was superior progression-free survival (PFS) in VD arms in standard- and high-risk patients. Among patients who received VD, those belonging to standard and high-risk groups had similar PFS. In conclusion, bortezomib-based induction is superior to non-bortezomib-based one in patients harboring 17p deletion and/or t(4;14) in terms of improving PFS but not OS. Also, it reduces progression risk in patients harboring these high risk cytogenetics. PMID:27184486

  15. De novo 9 Mb deletion of 6q23.2q24.1 disrupting the gene EYA4 in a patient with sensorineural hearing loss, cardiac malformation, and mental retardation.

    PubMed

    Dutrannoy, Véronique; Klopocki, Eva; Wei, Ran; Bommer, Christiane; Mundlos, Stefan; Graul-Neumann, Luitgard M; Trimborn, Marc

    2009-01-01

    We report on a patient carrying a de novo interstitial deletion of chromosomal region 6q23.2-24.1. Interstitial deletions of 6q are rarely reported in the literature. Indeed, only four patients with interstitial deletions overlapping partially with the deleted region in our patient are described in the literature. The aberration was detected by GTG-banding. The size of the deletion was further refined by array-CGH and subsequently fine mapped by quantitative real-time PCR. The exact size of the deletion and the sequence composition of the breakpoints were determined by breakpoint spanning PCR and subsequent sequencing. The patient presented with microcephaly, short stature, patent ductus arteriosus, sensorineural hearing loss, mental retardation, reduced speech development, and abnormal behaviour. The deletion disrupts the gene EYA4. Mutations within this gene are associated with postlingual sensorineural hearing loss. The sequencing of the breakpoint indicated non homologous end joining as the most likely mechanism leading to the rearrangement. PMID:19576303

  16. 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.

  17. Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15.

    PubMed

    Siebler, T; Lopaczynski, W; Terry, C L; Casella, S J; Munson, P; De Leon, D D; Phang, L; Blakemore, K J; McEvoy, R C; Kelley, R I

    1995-12-01

    Most patients with deletion of the distal long arm of chromosome 15 have intrauterine growth retardation and postnatal growth deficiency in addition to developmental abnormalities. It has been proposed that the absence of one copy of the insulin-like growth factor I (IGF-I) receptor gene may play a role in the growth deficiency seen in this syndrome. To address this question we examined IGF-I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15 (15q26.1-->qter). Quantitative Southern blot analysis of the IGF-I receptor gene was performed on HindIII digests of fibroblast DNA. Radioactivity in the 1.7-kilobase receptor fragment in the two patients was 55% and 51% of the values in controls, consistent with the absence of one copy of the IGF-I receptor gene. IGF-I receptor messenger ribonucleic acid levels were quantitated by a solution hybridization/nuclease protection assay. Receptor messenger ribonucleic acid levels in the two patients were 45% and 52% of the values in controls. Northern blotting demonstrated normal size IGF-I receptor transcripts and affinity crosslinking of [125I]IGF-I to Triton X-100-solubilized fibroblasts demonstrated a normal size receptor in the patients. Analysis of placental membranes prepared from one patient revealed no difference in [125I]IGF-I binding. In the patients' fibroblasts, however, binding of [125I]long [R3]-IGF-I to the IGF-I receptor was significantly reduced, as assessed by the amount of radioactivity competed by the monoclonal antibody alpha IR-3 or insulin and Scatchard analysis of binding data. To assess IGF-I receptor function, stimulation of [alpha-1-14C]-methylaminoisobutyric acid transport and stimulation of [methyl-3H]thymidine incorporation into DNA by a full range of IGF-I concentrations was examined in patient and control fibroblasts. There was a significant decrease in the maximal response to IGF-I in both assays for one of the two patients when

  18. 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

  19. 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

  20. A Member of a Gene Family on Xp22.3, VCX-A, Is Deleted in Patients with X-Linked Nonspecific Mental Retardation

    PubMed Central

    Fukami, Maki; Kirsch, Stefan; Schiller, Simone; Richter, Alexandra; Benes, Vladimir; Franco, Brunella; Muroya, Koji; Rao, Ercole; Merker, Sabine; Niesler, Beate; Ballabio, Andrea; Ansorge, Wilhelm; Ogata, Tsutomu; Rappold, Gudrun A.

    2000-01-01

    X-linked nonspecific mental retardation (MRX) has a frequency of 0.15% in the male population and is caused by defects in several different genes on the human X chromosome. Genotype-phenotype correlations in male patients with a partial nullisomy of the X chromosome have suggested that at least one locus involved in MRX is on Xp22.3. Previous deletion mapping has shown that this gene resides between markers DXS1060 and DXS1139, a region encompassing ∼1.5 Mb of DNA. Analyzing the DNA of 15 males with Xp deletions, we were able to narrow this MRX critical interval to ∼15 kb of DNA. Only one gene, VCX-A (variably charged, X chromosome mRNA on CRI-S232A), was shown to reside in this interval. Because of a variable number of tandem 30-bp repeats in the VCX-A gene, the size of the predicted protein is 186–226 amino acids. VCX-A belongs to a gene family containing at least four nearly identical paralogues on Xp22.3 (VCX-A, -B, -B1, and -C) and two on Yq11.2 (VCY-D, VCY-E), suggesting that the X and Y copies were created by duplication events. We have found that VCX-A is retained in all patients with normal intelligence and is deleted in all patients with mental retardation. There is no correlation between the presence or absence of VCX-B1, -B, and VCX-C and mental status in our patients. These results suggest that VCX-A is sufficient to maintain normal mental development. PMID:10903929

  1. Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients

    SciTech Connect

    Osborne, L.R.; Rommens, J.; Tsui, Lap-Chee |

    1996-09-01

    Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, a three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding sub-unit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase {delta} and {epsilon}. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients. 56 refs., 4 figs., 3 tabs.

  2. Familial 1.1 Mb deletion in chromosome Xq22.1 associated with mental retardation and behavioural disorders in female patients.

    PubMed

    Grillo, L; Reitano, S; Belfiore, G; Spalletta, A; Amata, S; Bottitta, M; Barone, C; Falco, M; Fichera, M; Romano, C

    2010-01-01

    We report on a 7-year-old girl with severe mental retardation (MR), autism, micro-brachycephaly, generalized muscle hypotonia with distal hypotrophy of lower limbs, scoliosis and facial dysmorphisms. Array-CGH analysis identified a 1.1 Mb deletion of chromosome Xq22.1. Further analysis demonstrated that the deletion was inherited from her mother who showed mild MR, short stature, brachycephaly, epilepsy and a Borderline Personality Disorder. Microsatellite segregation analysis revealed that the rearrangement arose de novo in the mother on the paternal X chromosome. The deleted Xq22.1 region contains part of the NXF gene cluster which is involved in mRNA nuclear export and metabolism. Among them, the NXF5 gene has already been linked to mental retardation whereas NXF2 protein has been recently found to be partner of FMRP in regulating Nxf1 mRNA stability in neuronal cells. The dosage imbalance of NXF5 and NXF2 genes may explain the severe phenotype in our patient. PMID:20096387

  3. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients.

    PubMed Central

    Lubensky, I. A.; Gnarra, J. R.; Bertheau, P.; Walther, M. M.; Linehan, W. M.; Zhuang, Z.

    1996-01-01

    Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8952541

  4. Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements

    PubMed Central

    Whibley, Annabel; Urquhart, Jill; Dore, Jonathan; Willatt, Lionel; Parkin, Georgina; Gaunt, Lorraine; Black, Graeme; Donnai, Dian; Raymond, F Lucy

    2010-01-01

    Monoamine oxidases (MAO-A and MAO-B) have a key role in the degradation of amine neurotransmitters, such as dopamine, norepinephrine and serotonin. We identified an inherited 240 kb deletion on Xp11.3–p11.4, which encompasses both monoamine oxidase genes but, unlike other published reports, does not affect the adjacent Norrie disease gene (NDP). The brothers who inherited the deletion, and thus have no monoamine oxidase function, presented with severe developmental delay, intermittent hypotonia and stereotypical hand movements. The clinical features accord with published reports of larger microdeletions and selective MAO-A and MAO-B deficiencies in humans and mouse models and suggest considerable functional compensation between MAO-A and MAO-B under normal conditions. PMID:20485326

  5. Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients

    PubMed Central

    2012-01-01

    Background Specific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE. Methods A genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR. Results The top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed. Conclusions CNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics. PMID:22748001

  6. 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.

  7. Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement.

    PubMed

    Li, Peining; Zhang, Hui Z; Huff, Shannon; Nimmakayalu, Manjunath; Qumsiyeh, Mazin; Yu, Jingwei; Szekely, Anna; Xu, Tian; Pober, Barbara R

    2006-12-15

    We detected a unique de novo complex chromosome rearrangement (CCR) in a patient with multiple abnormalities including growth retardation, facial anomalies, exudative vitreoretinopathy (EVR), cleft palate, and minor digital anomalies. Cytogenetic analysis, fluorescent in situ hybridization, and microsatellite genotyping showed a reciprocal translocation between chromosomes 5 and 8, and a complex translocation-deletion-inversion process in the formation of derivative chromosomes 11 and 16. High-density whole-genome oligonucleotide array comparative genomic hybridization (oaCGH) defined a 35-megabase interstitial deletion of 11q14.1-q23.2 and a 1 megabase deletion of 16q22.3-q23.1. The Frizzled-4 (FZD4) gene is located within this 11q deletion. Parental studies and sequencing analysis confirmed that the patient was hemizygous for FZD4 due to the loss of a paternal allele on the derivative chromosome 11. Mutations in FZD4 are known to cause autosomal dominant exudative vitreoretinopathy (EVR1). Our patient's findings suggest that haploinsufficiency of the FZD4 gene product can also be a disease-causing mechanism for EVR1. We reviewed the clinical manifestations of 23 cases with 11q14-q23 interstitial deletions, with particular scrutiny of the present case and four reported cases characterized by molecular cytogenetics. These findings were used to construct a regional deletion map consisting of a haplosufficient segment at 11q14.3, a flanking centromeric segment at 11q14.1-q14.2, and a flanking telomeric segment at 11q21-q23.3. We propose that deletions of the FZD4 gene located within the centromeric segment cause retinal dysgenesis, while deletions within the telomeric segment account for dysmorphic craniofacial features, growth and mental retardation, and mild digital anomalies. These results provide insight into karyotype-phenotype correlations and prompt a rational analytic approach to cases with interstitial deletions of the 11q14-q23 region. PMID:17103440

  8. 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

  9. Studies on Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Genotype Distributions in Turkish Preeclampsia Patients

    PubMed Central

    Bereketoğlu, Ceyhun; Kasap, Mülkiye; Pazarbaşı, Ayfer

    2012-01-01

    Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)'s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism (D allele) has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls (P = 0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P = 0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P = 0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls. PMID:22545216

  10. Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis

    PubMed Central

    Greipp, Patricia T.; Smoley, Stephanie A.; Viswanatha, David S.; Frederick, Lori S.; Rabe, Kari G.; Sharma, Ruchi G.; Slager, Susan L.; Van Dyke, Daniel L.; Tschumper, Renee C.; Shanafelt, Tait D.; Zent, Clive S.

    2013-01-01

    Summary Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients. PMID:24032430

  11. A new patient with a terminal de novo 2p25.3 deletion of 1.9 Mb associated with early-onset of obesity, intellectual disabilities and hyperkinetic disorder

    PubMed Central

    2014-01-01

    Terminal and interstitial deletions of 2p25.3 (size < Mb), detected by array-CGH analysis, have been reported in about 18 patients sharing common clinical features represented by early-onset obesity/ overweightness associated with intellectual disabilities (ID) and behavioural troubles. This observations led to hypothesize that 2p subtelomeric deletion should be associated with syndromic obesity and MYT1L became the main candidate gene for ID and obesity since it is deleted or disrupted in all hitherto published cases. Here we described a 2p25.3 de novo terminal deletion of 1.9 Mb, of paternal origin, detected by array-CGH analysis in a girl of 4.4 years with a distinctive phenotype consisting of early-onset of obesity associated with moderate ID, and hyperkinetic disorder. The deletion disrupted MYT1L and encompassed five other OMIM genes, ACP1, TMEM18, SNTG2, TPO, and PXDN. Here, we discuss the combined functional effects of additional haploinsufficient genes, that may concur with heterozygous deletion of MYT1L, in the aetiology for syndromic obesity associated with 2p25.5 subtelomeric deletion. PMID:25126114

  12. A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region.

    PubMed

    Kobayashi, Yusuke; Masuda, Kenta; Kimura, Tokuhiro; Nomura, Hiroyuki; Hirasawa, Akira; Banno, Kouji; Susumu, Nobuyuki; Sugano, Kokichi; Aoki, Daisuke

    2014-02-01

    Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma. PMID:24490603

  13. High-resolution array-CGH in patients with oculocutaneous albinism identifies new deletions of the TYR, OCA2, and SLC45A2 genes and a complex rearrangement of the OCA2 gene.

    PubMed

    Morice-Picard, Fanny; Lasseaux, Eulalie; Cailley, Dorothée; Gros, Audrey; Toutain, Jérome; Plaisant, Claudio; Simon, Delphine; François, Stéphane; Gilbert-Dussardier, Brigitte; Kaplan, Josseline; Rooryck, Caroline; Lacombe, Didier; Arveiler, Benoit

    2014-01-01

    Oculocutaneous albinism (OCA) is caused by mutations in six different genes, and their molecular diagnosis encompasses the search for point mutations and intragenic rearrangements. Here, we used high-resolution array-comparative genome hybridization (CGH) to search for rearrangements across exons, introns and regulatory sequences of four OCA genes: TYR, OCA2, TYRP1, and SLC45A2. We identified a total of ten new deletions in TYR, OCA2, and SLC45A2. A complex rearrangement of OCA2 was found in two unrelated patients. Whole-genome sequencing showed deletion of a 184-kb fragment (identical to a deletion previously found in Polish patients), whereby a large portion of the deleted sequence was re-inserted after severe reshuffling into intron 1 of OCA2. The high-resolution array-CGH presented here is a powerful tool to detect gene rearrangements. Finally, we review all known deletions of the OCA1-4 genes reported so far in the literature and show that deletions or duplications account for 5.6% of all mutations identified in the OCA1-4 genes. PMID:24118800

  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. PMID:25606385

  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. Identification of the -α(2.4) Deletion in One Family and in One Hb H Disease Patient in Guangxi, People's Republic of China.

    PubMed

    Pang, Wanrong; Sun, Lei; Long, Ju; Weng, Xunjin; Ye, Xuehe; Wang, Junjie; Liao, Yan; Tang, Weijun; Fan, Zuqian; Wu, Suping; Song, Chuanlu; Wei, Xiaoying; Zhang, Chenghong

    2016-06-01

    The 2.4 kb (or -α(2.4)) deletion in the α-globin gene cluster (NG_000006.1) is an α(+)-thalassemia (α(+)-thal) allele. The molecular basis of -α(2.4) is a deletion from 36860 to 39251 of the α-globin gene cluster. It was reported by three research groups in 2005, 2012 and 2014, respectively. In routine thalassemia screening studies by this research group, we found an individual with the -α(2.4)/αα genotype and an Hb H (β4) disease patient whose genotype was - -(SEA)/-α(2.4). Samples from the parents of the carrier of the -α(2.4)/αα genotype were collected to perform pedigree analysis, and the proband's mother's genotype was diagnosed to be - -(SEA)/-α(2.4). The research revealed that the -α(2.4) allele exists in the population of southern Guangxi, People's Republic of China. PMID:26984456

  17. Identification of an AluY-mediated deletion of exon 5 in the CPOX gene by MLPA analysis in patients with hereditary coproporphyria.

    PubMed

    Barbaro, M; Kotajärvi, M; Harper, P; Floderus, Y

    2012-03-01

    Hereditary coproporphyria (HCP) is an autosomal dominantly inherited hepatic porphyria, caused by a mutation in the coproporphyrinogen oxidase (CPOX) gene. The genetic defect leads to a partial defect of CPOX, the sixth enzyme involved in haem biosynthesis. Affected individuals can develop acute life-threatening attacks of neurovisceral symptoms and/or more rarely cutaneous symptoms such as skin fragility and blistering. The identification of the genetic defect in HCP families is of crucial importance to detect the carrier status which allows counselling to prevent possible triggering factors, e.g. certain drugs, alcohol, or fasting. In a total of nine Swedish HCP families, routine gene sequence analysis had identified a causative mutation in only five. In the present study, using an in-house developed synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis, we detected a deletion of the fifth exon in the CPOX gene in the remaining four families. The deletion is 3381 bp in size and has originated by an Alu-mediated mechanism. This finding emphasizes the usefulness of MLPA analysis as a complement to gene sequencing for comprehensive genetic diagnostics in HCP patients. PMID:21231929

  18. Haploinsufficiency of XPO1 and USP34 by a de novo 230 kb deletion in 2p15, in a patient with mild intellectual disability and cranio-facial dysmorphisms.

    PubMed

    Fannemel, Madeleine; Barøy, Tuva; Holmgren, Asbjørn; Rødningen, Olaug K; Haugsand, Trine M; Hansen, Børre; Frengen, Eirik; Misceo, Doriana

    2014-09-01

    2p15p16.1-deletion syndrome was first described in 2007 based on the clinical presentation of two patients. The syndrome is characterized by intellectual disability, autism spectrum disorders, microcephaly, dysmorphic facial features and a variety of congenital organ defects. The precise genotype-phenotype correlation in 2p15-deletion syndrome is not understood. However, greater insight can be obtained by thorough clinical investigation of patients carrying deletions, especially those of small size. We report a 21-year-old male patient with features overlapping the clinical spectrum of the 2p15p16.1-deletion syndrome, such as intellectual disability, dysmorphic facial features, and congenital defects. He carried a 230 kb de novo deletion (chr2:61500346-61733075 bp, hg19), which affects the genes USP34, SNORA70B and XPO1. While there is a lack of functional data on SNORA70B, the involvement of USP34 and XPO1 in the regulation of fundamental developmental processes is well known. We suggest that haploinsufficiency of one or both of these genes is likely to be responsible for the disease in our patient. PMID:24911659

  19. The deletion of 22q13 region in both intracranial and spinal meningiomas in a patient (case report).

    PubMed

    Durmaz, R; Arslantaş, A; Artan, S; Ozon, Y H; Işiksoy, S; Başaran, N; Tel, E

    1998-09-01

    We present a 69 year old man with two simultaneous meningiomas in different compartment of neural axis, in both of which 22q13 locus is lost. Histologically the two tumours appeared to be different; meningotheliomatous and transitional with psammoma bodies, respectively. No numerical or structural chromosome abnormalities were seen in karyotype analysis of the cultured spinal and cranial meningioma samples. Since long arm structural aberrations and/or whole loss of chromosome 22 are frequently reported abnormalities of meningiomas, the tumours were also analysed by fluorescence in situ hybridisation (FISH) with different colour-labelled probes in respect to relevant chromosome. The metaphases and interphase nuclei of the samples were evaluated by the combined biotinylated 22q11 and digoxigenin-labelled 22q13 locus specific FISH probes, and 22q13 deletion was revealed in both of spinal and cranial tumour cells. In conclusion, since both tumours from the presented case show the same genetic alterations, multiplicity may be derived from the same clone of cells, and support the theory of development of multiple meningiomas from the spreading of tumour cells via cerebrospinal fluid as a possible mechanism. PMID:9822846

  20. 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

  1. Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay.

    PubMed

    Papoulidis, Ioannis; Paspaliaris, Vassilis; Papageorgiou, Elena; Siomou, Elissavet; Dagklis, Themistoklis; Sotiriou, Sotirios; Thomaidis, Loretta; Manolakos, Emmanouil

    2015-01-01

    A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested. PMID:25925190

  2. A cytogenetic deletion, del(17)(q11.22q21.1), in a patient with sporadic neurofibromatosis type 1 (NF1) associated with dysmorphism and developmental delay.

    PubMed Central

    Upadhyaya, M; Roberts, S H; Maynard, J; Sorour, E; Thompson, P W; Vaughan, M; Wilkie, A O; Hughes, H E

    1996-01-01

    We report the first visible cytogenetic deletion involving the NF1 gene in a patient with sporadic neurofibromatosis, dysmorphic features, and marked developmental delay. The combined evidence of molecular and cytogenetic techniques based on dosage reduction, hemizygosity for microsatellite markers, high resolution G banding, and FISH analysis, predicts this deletion to be approximately 7 Mb in size. Our findings highlight the importance of conducting a detailed cytogenetic and FISH analysis in patients with NF1 who have additional dysmorphic features or particularly severe learning difficulties. Images PMID:8929953

  3. Inversion and deletion of 16q22 defined by array CGH, FISH, and RT-PCR in a patient with AML.

    PubMed

    Dawson, Angelika J; Bal, Shibani; McTavish, Barry; Tomiuk, Michelle; Schroedter, Ingo; Ahsanuddin, Arshad N; Seftel, Matthew D; Vallente, Rhea; Mai, Sabine; Cotter, Philip D; Hovanes, Karine; Gorre, Mercedes; Gunn, Shelly R

    2011-06-01

    Acute myelomonocytic leukemia with eosinophilia is commonly associated with pericentric inversions of chromosome 16, involving the core binding factor beta gene (CBFB) on 16q22 and the myosin heavy chain gene (MYH11) on 16p13. The inv(16)(p13q22) results in a fusion gene comprising the 5'CBFB gene and the 3'MYH11 gene on the short arm of chromosome 16. The fusion gene interferes with the normal transcription of the CBFA/CBFB heterodimer and disrupts myeloid differentiation. The inv(16) is associated with a good prognosis. The inv(16) with deletion of the 3'CBFB region of the gene is a very rare occurrence. Although the number of cases is small, inv(16) with a deleted 3'CBFB seems to be associated with a poorer prognosis than that generally associated with inv(16). Our patient was a 30-year-old man with newly diagnosed acute myeloid leukemia who was found to have a CBFB-MYH11 fusion by reverse transcriptase-polymerase chain reaction. The high blast count and lack of differentiation were not typical for this entity and suggested clonal progression. The initial karyotype by conventional cytogenetic analysis, in all metaphases examined, was 46,XY,del(7)(q32),del(16)(q22). Fluorescence in situ hybridization analysis with a dual-color, break-apart probe corresponding to the CBFB gene locus (Abbott, Des Plaines, IL) showed a derivative chromosome 16 resulting from an inversion of the CBFB gene with a deletion of the 3'CBFB probe region. Oligonucleotide array comparative genetic hybridization analysis was performed on this patient's diagnostic bone marrow DNA referenced to a normal male control DNA by using the DNAarray Heme Profile (CombiMatrix Diagnostics, Irvine, CA) microarray. This analysis showed a 1.2 Mb loss of 16q22.1, which did not include loss of the 3'CBFB gene locus, but rather sequences distal to this locus. The DNAarray Heme Profile results illustrate the importance of microarray in the correct identification of abnormalities that will affect prognosis. PMID

  4. 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.

  5. Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities.

    PubMed

    Frost, Amy R; Böhm, Sabrina V; Sewduth, Raj N; Josifova, Dragana; Ogilvie, Caroline Mackie; Izatt, Louise; Roberts, Roland G

    2010-07-01

    Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin alpha2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a approximately 2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and Warker-Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1(+/-) mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations. PMID:20234391

  6. Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

    PubMed Central

    Frost, Amy R; Böhm, Sabrina V; Sewduth, Raj N; Josifova, Dragana; Ogilvie, Caroline Mackie; Izatt, Louise; Roberts, Roland G

    2010-01-01

    Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin α2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a ∼2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle–eye–brain disease and Warker–Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1+/− mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations. PMID:20234391

  7. Patients with Exon 19 Deletion Were Associated with Longer Progression-Free Survival Compared to Those with L858R Mutation after First-Line EGFR-TKIs for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

    PubMed Central

    Fang, Wenfeng; Yan, Yue; Hu, Zhihuang; Hong, Shaodong; Wu, Xuan; Qin, Tao; Liang, Wenhua; Zhang, Li

    2014-01-01

    Backgrounds It has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered. Methods Subgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively. Results A total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20–0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35–0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation  = 0.59, 95% CI 0.38–0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation  = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies. Conclusions For advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs. PMID:25222496

  8. 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

  9. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival

    PubMed Central

    Rossi, Simona; Shimizu, Masayoshi; Barbarotto, Elisa; Nicoloso, Milena S.; Dimitri, Federica; Sampath, Deepa; Fabbri, Muller; Lerner, Susan; Barron, Lynn L.; Rassenti, Laura Z.; Jiang, Li; Xiao, Lianchun; Hu, Jianhua; Secchiero, Paola; Zauli, Giorgio; Volinia, Stefano; Negrini, Massimo; Wierda, William; Kipps, Thomas J.; Plunkett, William; Coombes, Kevin R.; Abruzzo, Lynne V.

    2010-01-01

    Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients. PMID:20393129

  10. A complex insertion/deletion polymorphism in the compositionally biased region of the ZFHX3 gene in patients with coronary heart disease in a Chinese population

    PubMed Central

    Sun, Shunchang; Zhang, Wenwu; Chen, Xi; Peng, Yunsheng; Chen, Qunrong

    2015-01-01

    Coronary heart disease (CHD) is a leading cause of morbidity and mortality around the world and has both genetic and environmental precipitants. Genetic factors are significant in determining the level of risk factors in individuals. Variants in ZFHX3 gene are associated with atrial fibrillation in individuals of European ancestry. The aim of this study was to analyze the polymorphisms in the compositionally biased region of the ZFHX3 gene in patients with coronary heart disease in a Chinese population, and to explore their associations with coronary heart disease. We recruited 278 CHD patients and 358 age and sex matched healthy controls in a Chinese Han population, polymorphisms in the compositionally biased region of the ZFHX3 gene were determined by polymerase chain reaction followed by DNA sequencing. The genotype frequencies were calculated, and statistical analysis was performed using the non-parametric mood median test. A complex insertion/deletion polymorphism was identified in the compositionally biased region of the ZFHX3 gene in a Chinese population. Six common genotypes (GGC)4GGTGGCAGT(GGC)4GGT(GGC)8, (GGC)4GGTGGCAGT(GGC)5GGT(GGC)8, (GGC)4GGTGGCAGT(GGC)5GGT(GGC)7, (GGC)2GGTGGCAGT(GGC)5GGT(GGC)10, (GGC)4GGTGGCAGT(GGC)5GGT(GGC)5, and (GGC)4GGT(GGC)8 were found in both CHD patients and healthy controls, there was no significant difference in the six genotype frequencies between CHD patients and healthy controls. Rare genotypes (GGC)4GGTGGCAGT(GGC)2GGT(GGC)2GGT(GGC)6, (GGC)4GGTGGCAGT (GGC)8, (GGC)4GGTGGCAGT(GGC)3GGT(GGC)8, and (GGC)6GGT(GGC)8 were only identified in healthy controls. Rare genotypes (GGC)4GGTGGCAGT(GGC)4GGT(GGC)5, (GGC)4GGTGGCAGT(GGC)4GGT(GGC)4, and (GGC)4GGTGGCGGT(GGC)6 were only found in CHD patients. The compositionally biased region of the ZFHX3 gene contains a poly-Gly sequence. A complex insertion/deletion polymorphism exists in this region in a Chinese population, clinical significance of some rare genotypes should be explored for

  11. Angiotensin-converting enzyme gene polymorphism (insertion/deletion) and liver fibrosis in Turkish patients from the western Black Sea region, Turkey.

    PubMed

    Turhan, N K; Ilikhan, S Uygun; Hamamcioglu, A C; Ustundag, Y; Dursun, A; Kokturk, F

    2015-01-01

    Chronic viral hepatitis B, chronic viral hepatitis C, non-alcoholic steatohepatitis, alcoholic liver disease, autoimmune hepatitis, primary biliary cirrhosis, and secondary biliary cirrhosis are important health issues worldwide. While an association between angiotensin-converting enzyme gene insertion/deletion (ACE gene I/D) polymorphism and liver fibrosis has been demonstrated in rat studies, the results of clinical studies area have been contradictory. The aim of this study was to assess the possible association between ACE gene I/D polymorphism and liver fibrosis in a large group of Turkish patients from the western Black Sea region. In 418 patients with different etiologies, ACE gene I/D polymorphism and serum ACE levels were investigated. The distribution of the "DD", "ID", "II" genotypes of the ACE gene were 32.5, 48.8, and 18.7% in the mild to moderate fibrosis group (N = 246, F:1-3 according to Ishak's score) and 39.0, 44.2, and 16.9% in the advanced fibrosis group (N = 172, F:4-6 according to Ishak's score). A significant correlation between serum ACE levels and ACE gene alleles was identified (P < 0.001): serum ACE levels of patients with D alleles were higher than those of patients with I alleles [44 (min 7-max 101) versus 29 (min 7-max 96)]. Patients with advanced fibrosis were also found to be older than those with mild to moderate fibrosis (P < 0.001). No significant association was noted between the patient gender and fibrosis severity. We conclude that ACE I/D polymorphism is not associated with the degree of liver fibrosis. PMID:26681055

  12. NR2F1 Deletion in a Patient with a de novo Paracentric Inversion, inv(5)(q15q33.2), and Syndromic Deafness

    PubMed Central

    Brown, Kerry K.; Alkuraya, Fowzan S.; Matos, Michael; Robertson, Richard L.; Kimonis, Virginia E.; Morton, Cynthia C.

    2009-01-01

    In an effort to discover genes important for human development, we have ascertained patients with congenital anomalies and cytogenetically balanced chromosomal rearrangements. Herein, we report a four year-old girl with profound deafness, a history of feeding difficulties, dysmorphism, strabismus, developmental delay, and an apparently balanced de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2). Molecular cytogenetic analysis of the inversion revealed the presence of microdeletions of approximately 400-500 kb at or near both breakpoints. The 5q15 microdeletion completely removes the nuclear receptor NR2F1 (COUP-TFI) from the inverted chromosome 5. We propose haploinsufficiency of NR2F1 to be the cause of the patient's deafness and many of the other associated anomalies based on striking similarity with the Nr2f1 null mouse. Additionally, this study further highlights the need for high resolution analysis of clinical samples with chromosomal rearrangements as associated deletions may be primarily responsible for the clinical features of these patients. PMID:19353646

  13. Study of two patients with craniosynostosis and deletions of 11q: One with features of Saethre-Chotzen syndrome and the other with concomitant partial trisomy 4q

    SciTech Connect

    Morsey, S. |; Lewanda, A.F. |; Reid, C.S.

    1994-09-01

    Partial monosomy 11q is associated with metopic craniosynostosis and trigonocephaly. Prominant features in the over 30 reported cases include downslanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, wide/depressed nasal bridge, low set malformed ears, downturned mouth, micro/retrognathia, digital and cardiac anomalies and psychomotor retardation. We evaluated two patients referred for abnormal head shape. The first carried a diagnosis of Saethre-Chotzen syndrome due to brachycephaly, facial asymmetry, ptosis, cupped ears, sundactyly of 2nd and 3rd digits, developmental delay, and VSD. Karyotype revealed 46,XY,del(11)(q24.1{yields}qter). No abnormality was noted of chromosome 7p, where the Saethre-Chotzen syndrome locus has been mapped. This suggests genetic heterogeneity for this condition. The second patient had no prior diagnosis. He had trigonocephaly, bilateral cryptorchidism and inguinal hernias. He also had hypotelorism, epicanthal folds, synophrys, posteriorly rotated ears, horizontal crease below his lower lip, unilateral single palmar crease, mild soft tissue syndactyly and a shawl scrotum. His karyotype of 46,XY,-11,+der(11)t(4;11)(q31.3;q25) revealed both partial 11q monosomy and partial 4q trisomy (the latter associated with cryptorchidism, horizontal chin crease and single palmar crease). Deletions of 11q appear to produce a wide spectrum of defects, which may even mimic other known craniosynostotic conditions. Study of these patients may lead to the identification of new genes involved in craniofacial morphogenesis.

  14. Assessment of the Olfactory Function in Italian Patients with Type 3 von Willebrand Disease Caused by a Homozygous 253 Kb Deletion Involving VWF and TMEM16B/ANO2

    PubMed Central

    Cenedese, Valentina; Mezzavilla, Massimo; Morgan, Anna; Marino, Renato; Ettorre, Cosimo Pietro; Margaglione, Maurizio; Gasparini, Paolo; Menini, Anna

    2015-01-01

    Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF). A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16) or anoctamin (ANO). TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT). The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability. PMID:25635880

  15. 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.

  16. 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

  17. 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

  18. The Difference of Clinical Characteristics Between Patients With Exon 19 Deletion and Those With L858R Mutation in Nonsmall Cell Lung Cancer.

    PubMed

    Zhang, Yaxiong; He, Dacheng; Fang, Wenfeng; Kang, Shiyang; Chen, Gang; Hong, Shaodong; Sheng, Jin; Zhan, Jianhua; Chen, Nan; Hu, Zhihuang; Xue, Cong; Yang, Yunpeng; Ma, Yuxiang; Qin, Tao; Zhou, Ting; Huang, Yan; Zhang, Li

    2015-11-01

    Recent studies have demonstrated that exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) are 2 different types of sensitive epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC). However, whether there are some differences between those 2 groups in baseline clinical characteristics is still unclear.We enrolled consecutive 1271 NSCLC patients detected with either 19 Del or L858R and collected their baseline clinical characteristics including age, sex, comorbidity, smoking and drinking status, body mass index (BMI), TNM stage, histologic type, differentiation, tumor maximum diameter (TMD), and CEA level. χ test and multivariate logistic regression analysis were used to compare the difference.We found a higher percentage of 19 Del in younger patients group (< = 50 yr) than L858R (P < 0.001) through χ test. Besides, patients with 19 Del have higher risk of lymph node metastasis (P < 0.001). However, there were no significant differences in other items of clinical characteristics between 19 Del and L858R. Multivariate analysis showed similar significant results. Subgroup analysis in different age groups (10 yr as an interval) and N stages (stratified by N0, N1, N2, and N3) also indicated above-mentioned trends.NSCLC patients with 19 Del are more likely to be young and have lymphatic metastasis than those with L858R. Age and N stage might be considered in predicting EGFR mutation type in NSCLC. PMID:26554801

  19. The Difference of Clinical Characteristics Between Patients With Exon 19 Deletion and Those With L858R Mutation in Nonsmall Cell Lung Cancer

    PubMed Central

    Zhang, Yaxiong; He, Dacheng; Fang, Wenfeng; Kang, Shiyang; Chen, Gang; Hong, Shaodong; Sheng, Jin; Zhan, Jianhua; Chen, Nan; Hu, Zhihuang; Xue, Cong; Yang, Yunpeng; Ma, Yuxiang; Qin, Tao; Zhou, Ting; Huang, Yan; Zhang, Li

    2015-01-01

    Abstract Recent studies have demonstrated that exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) are 2 different types of sensitive epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC). However, whether there are some differences between those 2 groups in baseline clinical characteristics is still unclear. We enrolled consecutive 1271 NSCLC patients detected with either 19 Del or L858R and collected their baseline clinical characteristics including age, sex, comorbidity, smoking and drinking status, body mass index (BMI), TNM stage, histologic type, differentiation, tumor maximum diameter (TMD), and CEA level. χ2 test and multivariate logistic regression analysis were used to compare the difference. We found a higher percentage of 19 Del in younger patients group (< = 50 yr) than L858R (P < 0.001) through χ2 test. Besides, patients with 19 Del have higher risk of lymph node metastasis (P < 0.001). However, there were no significant differences in other items of clinical characteristics between 19 Del and L858R. Multivariate analysis showed similar significant results. Subgroup analysis in different age groups (10 yr as an interval) and N stages (stratified by N0, N1, N2, and N3) also indicated above-mentioned trends. NSCLC patients with 19 Del are more likely to be young and have lymphatic metastasis than those with L858R. Age and N stage might be considered in predicting EGFR mutation type in NSCLC. PMID:26554801

  20. 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.

  1. 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.

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

    PubMed

    Rapini, Novella; Lidano, Roberta; Pietrosanti, Silvia; Vitiello, Giuseppina; Grimaldi, Chiara; Postorivo, Diana; Nardone, Anna Maria; Del Bufalo, Francesca; Brancati, Francesco; Manca Bitti, Maria Luisa

    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

  3. 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

  4. 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

  5. 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.

  6. 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. PMID:15470370

  7. 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.

  8. 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

  9. Loss of heterozygosity on chromosome 10q23 and mutation of the phosphatase and tensin homolog deleted from chromosome 10 tumor suppressor gene in Korean hepatocellular carcinoma patients.

    PubMed

    Bae, Jei-Jun; Rho, Jin-Woo; Lee, Tae-Jin; Yun, Sung-Su; Kim, Hong-Jin; Choi, Joon-Hyuk; Jeong, Daewon; Jang, Byeong-Churl; Lee, Tae-Yoon

    2007-10-01

    Loss of heterozygosity (LOH) in the 10q23 chromosomal region was analyzed in 18 tissue samples from Korean hepatocellular carcinoma (HCC) patients. LOH at the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) region (D10S215, AFMa086wg9 and D10S541) was found in 8 of the 18 (44.4%) HCCs. LOH (20%) and microsatellite instability (26.7%) were also frequently found at the D10S2177 locus, which is located on the telomere side of the PTEN region. LOH was found in other loci, such as AFM280we1 and D10S2281. The presence of LOH in regions other than the PTEN region on chromosome 10q23 suggested the presence of additional tumor suppressor gene(s). PTEN mutation was found in only a subset of HCCs: A single base insertion at the end of the 5'-end splice signal (AG-GUAAGUU) in intron 5 and a silent mutation in exon 6 (codon 188, CTG-Val to CTA). Our data collectively suggest that the genetic alterations of chromosome 10q23, including the PTEN gene, could be important in hepatocarcinogenesis in the Korean population. PMID:17786367

  10. 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

  11. 3p deletion syndrome.

    PubMed

    Kaur, Anupam; Khetarpal, S

    2013-08-01

    3p deletion is a rare cytogenetic finding. Here we describe a 3 months old male with congenital malformations. His karyotype revealed 3p deletion 46,XY,del(3)(p25-pter). The child had flexion deformity of wrist and elbow which has never been reported before. PMID:24036645

  12. 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

  13. [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

  14. Characterization of five partial deletions of the factor VIII gene

    SciTech Connect

    Youssoufian, H.; Antonarakis, S.E.; Aronis, S.; Tsiftis, G.; Phillips, D.G.; Kazazian, H.H. Jr.

    1987-06-01

    Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, the authors have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.

  15. Proper Interval Vertex Deletion

    NASA Astrophysics Data System (ADS)

    Villanger, Yngve

    Deleting a minimum number of vertices from a graph to obtain a proper interval graph is an NP-complete problem. At WG 2010 van Bevern et al. gave an O((14k + 14) k + 1 kn 6) time algorithm by combining iterative compression, branching, and a greedy algorithm. We show that there exists a simple greedy O(n + m) time algorithm that solves the Proper Interval Vertex Deletion problem on \\{claw,net,allowbreak tent,allowbreak C_4,C_5,C_6\\}-free graphs. Combining this with branching on the forbidden structures claw,net,tent,allowbreak C_4,C_5, and C 6 enables us to get an O(kn 6 6 k ) time algorithm for Proper Interval Vertex Deletion, where k is the number of deleted vertices.

  16. Characterization of a Cryptic 3.3 Mb Deletion in a Patient With a “Balanced t(15;22) Translocation” Using High Density Oligo Array CGH and Gene Expression Arrays

    PubMed Central

    Li, Marilyn M.; Nimmakayalu, Manjunath A.; Mercer, Danielle; Andersson, Hans C.; Emanuel, Beverly S.

    2010-01-01

    Patients with an apparently balanced translocation and an abnormal phenotype may carry a cryptic deletion/duplication at their translocation breakpoints that may explain their abnormalities. Using microarray CGH (aCGH) and gene expression arrays we studied a child with t(15;22)(q26.1;q11.2), developmental delay and mild dysmorphic features. A high density aCGH study with 244,000 oligo probes demonstrated a 3.3 Mb deletion immediately adjacent to the 15q breakpoint. Gene expression studies with 44,000 oligos displayed an approximately 50% reduction of the expression of IGF1R gene that was translocated to the der(22). There are 18 known or hypothetical protein coding genes within the deleted region according to UniProt, RefSeq, and GenBank mRNA (UCSC HG17, May 2004). Although two of these genes, RGMA and ST8SIA2, play an important role in neural development, the mild phenotype of our patient indicates that loss of one copy of these genes may not be critical developmentally. The 50% reduction of IGF1R expression could be responsible for the growth deficiency in the patient. Reviewing the few 15q26 microdeletion cases that have been characterized by aCGH, we discovered that deletion of the segment including distal 15q26.2 to the proximal part of 15q26.3 is associated with severe phenotypes. Our experience demonstrates that high-density oligonucleotide-based aCGH is a quick and precise way to identify cryptic copy number changes in “balanced translocations.” Expression studies can also add valuable information regarding gene expression changes due to a chromosomal rearrangement. Both approaches can assist in the elucidation of the etiology of unexplained phenotypic differences in cases such as this one. PMID:18203177

  17. 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.

  18. 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

  19. 109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf-Hirschhorn syndrome.

    PubMed

    Okamoto, Nobuhiko; Ohmachi, Kazumi; Shimada, Shino; Shimojima, Keiko; Yamamoto, Toshiyuki

    2013-06-01

    Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome associated with growth retardation, developmental disabilities, epileptic seizures, and distinct facial features resulting from a deletion of the short arm of chromosome 4. The Wolf-Hirschhorn Syndrome Critical Region WHSCR2 includes the LETM1 gene and 5' end of the WHSC1 gene. A haploinsufficiency of WHSC1 is thought to be responsible for a number of WHS characteristics. We report on a 2-year-old male with severe growth retardation, microcephaly and a characteristic facial appearance. He had no internal anomalies and his developmental milestones were mildly delayed. An array-CGH analysis revealed loss of genomic copy numbers in the region 4p16.3, which included FGFR3, LETM1, and WHSC1. The size of the deletion was only 109 kb. The deletion included the important genes in WHSCR2. We suspect that haploinsufficiency of WHSC1 is the most probable cause of the growth deficiency, microcephaly, and characteristic facial features in WHS. PMID:23637096

  20. 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. PMID:23124039

  1. 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.

  2. 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. PMID:25807935

  3. Molecular analysis of two patients with a duplicated 17p11.2 indicates that this entity may be the reciprocal of the deletion seen in Smith-Magenis syndrome

    SciTech Connect

    Brown, A.; Schwartz, C.; Rogers, R.C.

    1994-09-01

    J.M. and H.G. are two unrelated patients that presented at an early age with developmental delay and failure to thrive. Clinical features specific to J.M. include unusual facies, global developmental delay, and clinodactyly of the fifth toe. A cytogenetic analysis of H.G. was performed on amniocytes obtained due to a low MSAFP conducted as part of a routine screening. In both J.M. and H.G., a duplication of chromosome 17p11.2 was discovered. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-tel. All of the markers were found to be duplicated by dosage analysis except for D17S58. FISH analysis of H.G., using the Smith-Magenis diagnostic probe obtained from ONCOR, also detected a duplication in 17p11.2. The chromosome containing the duplication could be the result of unequal crossing over due to a misalignment of the two chromosomes during meiosis I. It has been shown that the markers deleted in Smith-Magenis syndrome (SMS) patients are the same as those markers duplicated in J.M. and H.G. Therefore, the chromosomal duplication in 17p11.2 observed in these two patients could be the reciprocal of the chromosomal deletion seen in Smith-Magenis syndrome patients. Interestingly, a similar reciprocal duplication/deletion event is observed for CMT1A and HNPP (hereditary neuropathy with liability to pressure palsies) just distal to the SMS region.

  4. New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q.

    PubMed Central

    Petersen, M B; Tranebjaerg, L; Tommerup, N; Nygaard, P; Edwards, H

    1987-01-01

    A karyotype 46,XY,del(20)(q11 X 23q13 X 11) was found in a three year old boy with mental and growth retardation, low set ears, broad nasal bridge, and macrostomia. Adenosine deaminase (ADA) activity was reduced by about 50%, assigning the gene locus to the deleted segment. A review of the previously reported regional assignments suggests that the ADA gene is in the region of band 20q13 X 11. Images PMID:3560174

  5. 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

  6. Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios.

    PubMed

    Mojzikova, Renata; Koralkova, Pavla; Holub, Dusan; Zidova, Zuzana; Pospisilova, Dagmar; Cermak, Jaroslav; Striezencova Laluhova, Zuzana; Indrak, Karel; Sukova, Martina; Partschova, Martina; Kucerova, Jana; Horvathova, Monika; Divoky, Vladimir

    2014-05-01

    Pyruvate kinase (PK) deficiency is an iron-loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease-causing PKLR mutations. Two of these mutations - the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) - have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease-causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK-deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor-15, were increased in PK-deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as-yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency. PMID:24533562

  7. A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation.

    PubMed

    Neri, M; Selvatici, R; Scotton, C; Trabanelli, C; Armaroli, A; De Grandis, D; Levy, N; Gualandi, F; Ferlini, A

    2013-06-01

    Limb girdle muscular dystrophy 2H is a rare autosomal recessive muscular dystrophy, clinically highly variable, caused by mutations in the TRIM32 gene. Here we describe a 35-years-old who experienced progressive muscle weakness. The muscle biopsy revealed an unspecific pattern of atrophic and hypertrophic fibers; the immunohistochemistry for several proteins was normal. Comparative genomic hybridization (CGH) analysis showed a heterozygous deletion of the entire TRIM32 gene. On the other allele we identified the R316X nonsense mutation. The genetic diagnosis of LGMD2H in this case was reached by using a novel high throughput diagnostic tool. PMID:23541687

  8. A submicroscopic deletion involving part of the CREBBP gene detected by array-CGH in a patient with Rubinstein-Taybi syndrome.

    PubMed

    Lai, Angeline H M; Brett, Maggie S; Chin, Wai-Hoe; Lim, Eileen C P; Ng, Jasmine S H; Tan, Ene-Choo

    2012-05-10

    We report a girl with Rubinstein-Taybi syndrome (RSTS) who was found to have copy number loss on 16p13.3 by array-CGH. She has developmental delay and other features of RSTS including downslanting palpebral fissures, a prominent nose with the nasal septum extending below the alae nasi, broad thumbs and big toes, postaxial polydactyly of the right foot and constipation from birth. We report the junction sequence across the breakpoint region for a microdeletion in RSTS. The sequencing results also showed that the deletion was 81.4kb involving three genes DNASE 1, TRAP 1, and CREBBP. PMID:22426292

  9. 22q13.3 Deletion Syndrome: Clinical and Molecular Analysis Using Array CGH

    PubMed Central

    Dhar, S.U.; del Gaudio, D.; German, J.R.; Peters, S.U.; Ou, Z.; Bader, P.I.; Berg, J.S.; Blazo, M.; Brown, C.W.; Graham, B.H.; Grebe, T.A.; Lalani, S.; Irons, M.; Sparagana, S.; Williams, M.; Phillips, J.A.; Beaudet, A.L.; Stankiewicz, P.; Patel, A.; Cheung, S.W.; Sahoo, T.

    2011-01-01

    The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype–phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype–phenotype correlations. PMID:20186804

  10. A patient with both Gilles de la Tourette's syndrome and chromosome 22q11 deletion syndrome: clue to the genetics of Gilles de la Tourette's syndrome?

    PubMed

    Robertson, Mary M; Shelley, Bhaskara Pillai; Dalwai, Suraiya; Brewer, Carole; Critchley, Hugo D

    2006-09-01

    This is the first published case description of the association of Gilles de la Tourette's syndrome (GTS) and chromosome 22q11.2 deletion syndrome (22q11DS; previously referred to as CATCH-22 syndrome). The co-occurrence of GTS, 22q11DS, and their behavioral/neuropsychiatric abnormalities may be due to the common endophenotypic mechanisms shared by these disorders, rather than due to specificity for GTS. Research into this genomic region may lead to advancement in neurobehavioral/neuropsychiatric genetics, which will help us in further explicating a broader perspective of gene-brain-behavior interrelationships and of the genetic underpinnings of various developmental psychopathologies and behavioral/neuropsychiatric disorders that are common to both GTS and 22q11DS. Our report should warrant further genetic investigations of the chromosome 22q11.2 deletion site using alternative strategies to the quantitative trait loci endophenotype-based approach, which would be useful for establishing the biological and molecular underpinnings of obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and GTS. PMID:16938515

  11. 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.

  12. 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.

  13. A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment

    PubMed Central

    2013-01-01

    Background Kearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum. Case presentation Here, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years. Conclusions The response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death. PMID:23421922

  14. 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

  15. Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency.

    PubMed

    Climent, C; García-Pérez, M A; Sanjurjo, P; Ruiz-Sanz, J I; Vilaseca, M A; Pineda, M; Campistol, J; Rubio, V

    1999-10-01

    A deletion of at least 11.5 cM in the paternal X chromosome mapping between microsatellites DXS989 and DXS1003 and encompassing the genes for ornithine transcarbamylase (OTC), retinitis pigmentosa GTPase regulator (RPGR) and dystrophin, was associated with the loss of band Xp21 in a female patient with OTC deficiency. Another four female patients were heterozygous for point mutations in the OTC gene: the nonsense mutation Q69X or the missense mutations I172F, G188V and G197R. In the OTC amino acid sequence, I172 and G197 are proximate to residues involved in catalysis, and G188 is within a loop joining helix 5 and strand 6 in the core of the ornithine-bindingdomain. Therefore, the mutations of these residues may cause structural changes affecting catalysis and/or the architecture of the ornithine domain. The mutation appeared "de novo" in the patients or, in one case, in the mother of the patient, in agreement with the predominance of "de novo" mutations in female patients of OTC deficiency. There was full agreement between the results of mutational analysis and of allopurinol testing in the patients and their female relatives, supporting the value of the allopurinol test in the detection of carriers of OTC deficiency. This deficiency is a genetically heterogeneous X-linked condition. PMID:10502831

  16. 9q22 Deletion - First Familial Case

    PubMed Central

    2011-01-01

    Background Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309). Methods and Results We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. Conclusions This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling. PMID:21693067

  17. 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.

  18. 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.

  19. 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 Central

    AOYAMA, YUKA; YAMAMOTO, TOSHIYUKI; SAKAGUCHI, NAOMI; ISHIGE, MIKA; TANAKA, TOJU; ICHIHARA, TOMOKO; OHARA, KATSUAKI; KOUZAN, HIROKO; KINOSADA, YASUTOMI; FUKAO, TOSHIYUKI

    2015-01-01

    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

  20. 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

  1. Report of limb girdle muscular dystrophy type 2a in 6 Iranian patients, one with a novel deletion in CAPN3 gene.

    PubMed

    Fadaee, Mahsa; Kariminejad, Ariana; Fattahi, Zohreh; Nafissi, Shahriar; Godarzi, Hamed Reza; Beheshtian, Maryam; Vazehan, Raheleh; Akbari, Mohammad Reza; Kahrizi, Kimia; Najmabadi, Hossein

    2016-01-01

    Calpain3 is a calcium-dependent intracellular protease involved in an autosomal recessive form of muscular dystrophy known as limb-girdle muscular dystrophy type 2A. Many pathogenic mutations have been identified in calpain3, encoded by the CAPN3 gene, which leads to weakness of the pelvic and shoulder girdle muscles. In the present study, whole exome sequencing was performed on six unrelated Iranian families who presented with progressive muscle weakness, with a strong suspicion of Calpainopathies. Genetic analysis of CAPN3 gene revealed five causative variants which had not been reported in the Iranian population before including a novel 6 bp deletion (c.795_800delCATTGA) and four previously reported mutations (c.1939G > T, c.2243G > A, c.2257delGinsAA, and c.2380 + 2T > G). Our findings indicate that exome sequencing can be a very effective and affordable method to diagnose heterogeneous muscular dystrophies, especially in consanguineous populations such as Iran. PMID:27020652

  2. Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation.

    PubMed

    Grønskov, Karen; Poole, Rebecca L; Hahnemann, Johanne M D; Thomson, Jennifer; Tümer, Zeynep; Brøndum-Nielsen, Karen; Murphy, Rinki; Ravn, Kirstine; Melchior, Linea; Dedic, Alma; Dolmer, Birgitte; Temple, I Karen; Boonen, Susanne E; Mackay, Deborah J G

    2011-05-01

    Silver-Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35-60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted--that is, hypomethylation affects either H19-ICR or IGF2P0. Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS. This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers. PMID:21278389

  3. 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.

  4. Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome.

    PubMed

    Disciglio, Vittoria; Lo Rizzo, Caterina; Mencarelli, Maria Antonietta; Mucciolo, Mafalda; Marozza, Annabella; Di Marco, Chiara; Massarelli, Antonio; Canocchi, Valentina; Baldassarri, Margherita; Ndoni, Enea; Frullanti, Elisa; Amabile, Sonia; Anderlid, Britt Marie; Metcalfe, Kay; Le Caignec, Cédric; David, Albert; Fryer, Alan; Boute, Odile; Joris, Andrieux; Greco, Donatella; Pecile, Vanna; Battini, Roberta; Novelli, Antonio; Fichera, Marco; Romano, Corrado; Mari, Francesca; Renieri, Alessandra

    2014-07-01

    Phelan-McDermid syndrome (22q13.3 deletion syndrome) is a contiguous gene disorder resulting from the deletion of the distal long arm of chromosome 22. SHANK3, a gene within the minimal critical region, is a candidate gene for the major neurological features of this syndrome. We report clinical and molecular data from a study of nine patients with overlapping interstitial deletions in 22q13 not involving SHANK3. All of these deletions overlap with the largest, but not with the smallest deletion associated with Phelan-McDermid syndrome. The deletion sizes and breakpoints varied considerably among our patients, with the largest deletion spanning 6.9 Mb and the smallest deletion spanning 2.7 Mb. Eight out of nine patients had a de novo deletion, while in one patient the origin of deletion was unknown. These patients shared clinical features common to Phelan-McDermid syndrome: developmental delay (11/12), speech delay (11/12), hypotonia (9/12), and feeding difficulties (7/12). Moreover, the majority of patients (8/12) exhibited macrocephaly. In the minimal deleted region, we identified two candidate genes, SULT4A1 and PARVB (associated with the PTEN pathway), which could be associated in our cohort with neurological features and macrocephaly/hypotonia, respectively. This study suggests that the haploinsufficiency of genes in the 22q13 region beside SHANK3 contributes to cognitive and speech development, and that these genes are involved in the phenotype associated with the larger Phelan-McDermid syndrome 22q13 deletions. Moreover, because the deletions in our patients do not involve the SHANK3 gene, we posit the existence of a new contiguous gene syndrome proximal to the smallest terminal deletions in the 22q13 region. PMID:24700646

  5. Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

    PubMed Central

    de Rooij, Jasmijn D.E.; Beuling, Eva; van den Heuvel-Eibrink, Marry M.; Obulkasim, Askar; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Sonneveld, Edwin; Gibson, Brenda E.S.; Pieters, Rob; Zimmermann, Martin; Zwaan, C. Michel; Fornerod, Maarten

    2015-01-01

    IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1–0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1–4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7 PMID:26069293

  6. Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

    PubMed Central

    HATZIMICHAEL, ELEFTHERIA; LAGOS, KONSTANTINOS; VASSOU, AMALIA; GOUGOPOULOU, DORA; PAPOUDOU-BAI, ALEXANDRA; BRIASOULIS, EVANGELOS

    2016-01-01

    Loss of a section of the long arm of chromosome 5, as a sole cytogenetic abnormality, characterizes a rare type of myelodysplastic syndrome [del(5q) MDS] and the co-existence of the JAK2 V617F mutation occurs in a small subset of these cases. Patients with isolated del(5q) MDS have a relatively favorable prognosis, with transformation to acute myeloid leukemia occurring in <10%, and their disease responds well to lenalidomide. However the optimal therapeutic approach for patients with del(5q) MDS in coexistence with the JAK2 V617F mutation, which is common to myeloproliferative neoplasms, remains to be elucidated. The present study reports a 77-year-old, transfusion-dependent female patient diagnosed with del(5q) MDS and a concomitant JAK2 V617F mutation. The patient was started on 10 mg lenalidomide daily for 21 days in a 28 day-cycle and within the first month of treatment, the patient became transfusion-independent. The only toxicity observed was grade 3 neutropenia, which was managed with transient treatment discontinuation and dose reduction on restart (5 mg). The patient achieved a complete cytogenetic and molecular response (normal karyotype and undetected JAK2 V617F mutation) within 6 months of treatment. However, 12 months post treatment initiation and while on hematological, cytogenetic and molecular response, the patient was unwilling to continue on treatment and lenalidomide was discontinued. The patient remains in hematological response, which lasts for >5 years despite treatment discontinuation. The present case highlights the coexistence of the JAK2 V617F mutation in del(5q) MDS and suggests that lenalidomide treatment is beneficial and effective for these patients, leading to complete hematological, cytogenetic and molecular response. Hematological response may be sustained for long periods of time, even following the discontinuation of the treatment. PMID:27330758

  7. 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.

  8. Molecular characterization of CPS1 deletions by array CGH

    PubMed Central

    Wang, Jing; Shchelochkov, Oleg A.; Zhan, Hongli; Li, Fangyuan; Chen, Li-Chieh; Brundage, Ellen K.; Pursley, Amber N.; Schmitt, Eric S.; Häberle, Johannes; Wong, Lee-Jun C.

    2016-01-01

    CPSI deficiency usually results in severe hyperammonemia presenting in the first days of life warranting prompt diagnosis. Most CPS1 defects are non-recurrent, private mutations, including point mutation, small insertions and deletions. In this study, we report the detection of large deletions varying from 1.4 kb to >130 kb in the CPS1 gene of 4 unrelated patients by targeted array CGH. These results underscore the importance of analysis of large deletions when only one mutation or no mutations are identified in cases where CPSI deficiency is strongly indicated. PMID:20855223

  9. Characterization of large deletions in the DHCR7 gene.

    PubMed

    Lanthaler, B; Hinderhofer, K; Maas, B; Haas, D; Sawyer, H; Burton-Jones, S; Carter, K; Suri, M; Witsch-Baumgartner, M

    2015-08-01

    Pathogenic variants in the DHCR7 gene cause Smith-Lemli-Opitz syndrome (SLOS), a defect of cholesterol biosynthesis resulting in an autosomal recessive congenital metabolic malformation disorder. In approximately 4% of patients, the second mutation remains unidentified. In this study, 12 SLOS patients diagnosed clinically and/or by elevated 7-dehydrocholesterol (7-DHC) have been investigated by customized multiplex ligation-dependent probe amplification (MLPA) analysis, because only one DHCR7 sequence variant has been detected. Two unrelated patients of this cohort carry different large deletions in the DHCR7 gene. One patient showed a deletion of exons 3-6. The second patient has a deletion of exons 1 and 2 (non-coding) and lacks the major part of the promoter. These two patients show typical clinical and biochemical phenotypes of SLOS. Second disease-causing mutations are p.(Arg352Trp) and p.(Thr93Met), respectively. Deletion breakpoints were characterized successfully in both cases. Such large deletions are rare in the DHCR7 gene but will resolve some of the patients in whom a second mutation has not been detected. PMID:25040602

  10. Deletion patterns of Duchenne and Becker muscular dystrophies in Greece.

    PubMed Central

    Florentin, L; Mavrou, A; Kekou, K; Metaxotou, C

    1995-01-01

    We present molecular data from 90 Greek boys with Duchenne or Becker muscular dystrophy using cDNA analysis or multiplex PCR or both. Deletions were detected in 63.3% of patients and were mainly clustered in two areas of the gene, one in the 3' and one in the 5' end of the gene (exons 3-19 and 44-53). Almost 17% of deletion breakpoints lay in intron 44 while 29% of deletions have a breakpoint in intron 50. Thus the distribution of deletions in our DMD/BMD patients differs from that previously reported. Furthermore a 1:4.35 proximal:distal ratio was observed in familial cases and a 1:2.45 ratio in isolated ones. PMID:7897627

  11. 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.

  12. 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

  13. 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.

  14. Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura.

    PubMed

    Paterna, S; Di Pasquale, P; D'Angelo, A; Seidita, G; Tuttolomondo, A; Cardinale, A; Maniscalchi, T; Follone, G; Giubilato, A; Tarantello, M; Licata, G

    2000-01-01

    Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 +/- 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1. 44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies

  15. 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

  16. 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.

  17. 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.

  18. Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations.

    PubMed

    Zhu, Guanshan; Bartsch, Oliver; Skrypnyk, Cristina; Rotondo, Alessandro; Akhtar, Longina A; Harris, Claudia; Virkkunen, Matti; Cassano, Giovanni; Goldman, David

    2004-06-01

    Investigation of the co-occurrence of panic and phobic disorders with joint laxity led to the identification of interstitial duplications involving human chromosome 15q24-26 (named 'DUP25') in a Spanish population. DUP25 was observed in 97% of patients and in 7% of control individuals. In the present study, we used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization (FISH). We evaluated 56 lymphoblastoid cell lines derived from 26 unrelated patients with panic disorder obtained from several European and American populations and 30 normal controls. We could not find any cell line showing a result consistent with DUP25. These data do not support any association of DUP25 with panic disorder. PMID:15054397

  19. Developmental genetics of deleted mtDNA in mitochondrial oculomyopathy.

    PubMed

    Marzuki, S; Berkovic, S F; Saifuddin Noer, A; Kapsa, R M; Kalnins, R M; Byrne, E; Sasmono, T; Sudoyo, H

    1997-02-12

    Heteroplasmic populations of mtDNA, consisting of normal mtDNA and mtDNA with large deletions, are found in the skeletal muscle and other tissues of certain patients with mitochondrial respiratory chain deficiencies, particularly in those with the CPEO (chronic progressive external ophthalmoplegia) phenotype. To study the developmental genetics of this mitochondrial disorder, the distribution of the deleted mtDNA in a wide range of tissues of different embryonic origins (total 34 samples from 27 tissues obtained at autopsy) was investigated in a patient with the CPEO syndrome. Three species of partially deleted mtDNA were observed, with deletions of 2.3 kb, 5.0 kb and 6.4 kb. Their tissue distribution suggests that the mtDNA deletions have occurred very early during embryonic development, prior to the differentiation events that lead to the formation of the three primary embryonic germ layers, and that the partially deleted mtDNA species were segregated during development mainly to the skeletal muscle and to tissues of the central nervous system. PMID:9094043

  20. 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.

  1. 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

  2. Prevalence of βS-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 Central

    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 (βS globin) haplotypes and alpha thalassemia with 3.7 kb deletion (−α3.7kb thalassemia) in the northwest region of Paraná state, and to investigate the oxidative and clinical-hematological profile of βS globin carriers in this population. Of the 77 samples analyzed, 17 were Hb SS, 30 were Hb AS and 30 were Hb AA. The βSglobin haplotypes and −α3.7kb 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 −α3.7kb 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

  3. Chromosome 13q deletion and IgH abnormalities may be both masked by near-tetraploidy in a high proportion of multiple myeloma patients: a combined morphology and I-FISH analysis.

    PubMed

    Koren-Michowitz, Maya; Hardan, Izhar; Berghoff, Janina; Yshoev, Galina; Amariglio, Ninette; Rechavi, Gideon; Nagler, Arnon; Trakhtenbrot, Luba

    2007-10-01

    Ploidy status and chromosomal aberrations involving chromosome 13q and the immunoglobulin heavy chain locus (IgH) are important prognostic features in multiple myeloma (MM). However, conventional cytogenetic studies are often not reveling and determination of plasma cells (PC) ploidy status in MM is technically difficult. We have used a combined cell morphology and interphase FISH (I-FISH) analysis in 184 consecutive BM samples from 136 MM patients for the diagnosis of chromosome 13q deletion [del (13q)] and IgH abnormalities. We have found a high prevalence (37%) of near-tetraploid (NT) PC in the BM samples studied. NT status of PC was verified with DNA index (DI) measurements. del (13q) was found in 69% and a total absence of one IgH copy (loss of IgH) in 20% of NT samples. We have shown that the presence of del (13q) and loss of IgH can be masked in NT cases: in 12 NT samples originally identified as normal for del (13q) the abnormality was obscured in the majority of plasma cells due to the presence of NT. Similarly, loss of IgH was masked in four samples with a large population of NT cells. Moreover, in one case the appearance of a 100% tetraploidy during disease progression masked the presence of del (13q), originally present, and could therefore falsely appear as disappearance of this prognostic marker. In conclusion, we have shown that a combination of three abnormalities, i.e., del (13q), loss of IgH and NT, all of potential prognostic significance, can be overlooked unless NT is specifically searched for and ruled out. Therefore, we suggest that a search for NT should be added to the routine BM assessment in MM patients. PMID:17590504

  4. 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.

  5. 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.

  6. ATLAS DQ2 Deletion Service

    NASA Astrophysics Data System (ADS)

    Oleynik, Danila; Petrosyan, Artem; Garonne, Vincent; Campana, Simone

    2012-12-01

    The ATLAS Distributed Data Management project DQ2 is responsible for the replication, access and bookkeeping of ATLAS data across more than 100 distributed grid sites. It also enforces data management policies decided on by the collaboration and defined in the ATLAS computing model. The DQ2 Deletion Service is one of the most important DDM services. This distributed service interacts with 3rd party grid middleware and the DQ2 catalogues to serve data deletion requests on the grid. Furthermore, it also takes care of retry strategies, check-pointing transactions, load management and fault tolerance. In this paper special attention is paid to the technical details which are used to achieve the high performance of service, accomplished without overloading either site storage, catalogues or other DQ2 components. Special attention is also paid to the deletion monitoring service that allows operators a detailed view of the working system.

  7. Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire.

    PubMed

    Rusconi, Daniela; Negri, Gloria; Colapietro, Patrizia; Picinelli, Chiara; Milani, Donatella; Spena, Silvia; Magnani, Cinzia; Silengo, Margherita Cirillo; Sorasio, Lorena; Curtisova, Vaclava; Cavaliere, Maria Luigia; Prontera, Paolo; Stangoni, Gabriela; Ferrero, Giovanni Battista; Biamino, Elisa; Fischetto, Rita; Piccione, Maria; Gasparini, Paolo; Salviati, Leonardo; Selicorni, Angelo; Finelli, Palma; Larizza, Lidia; Gervasini, Cristina

    2015-06-01

    Rubinstein-Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55% of cases) and EP300 (~8%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30-50 %) and deletions (~10%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype-phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype. PMID:25805166

  8. 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

  9. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran

    PubMed Central

    BARZEGAR, Mohammad; HABIBI, Parinaz; BONYADY, Mortaza; TOPCHIZADEH, Vahideh; SHIVA, Shadi

    2015-01-01

    Objective Duchene and Becker Muscular Dystrophy (DMD/ BMD) are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different populations. This study investigates the deletion rate, type, and distribution of this gene in the Azeri Turk population of North West Iran. Materials &Methods In this study, 110 patients with DMD/ BMD were studied for intragenic deletions in 24 exons and promoter regions of dystrophin genes by using multiplex PCR. Results Deletions were detected in 63 (57.3%) patients, and around 83% localized in the mid-distal hotspot of the gene (on exons 44–52), 21 cases (33.3 %) with single-exon deletions, and 42 cases (66.6%) with multi-exonic deletions. The most frequent deleted exons were exon 50 (15 %) and exon 49 (14%). No deletion was detected in exon 3. Conclusion This study suggests that the frequency and pattern of dystrophin gene deletions in DMD/ BMD in the Azeri Turk population of North West Iran occur in the same pattern when compared with other ethnic groups. PMID:25767538

  10. Prostate cancer and glutathione S-transferase deletions

    PubMed Central

    Malik, Saima Shakil; Masood, Nosheen; Yasmin, Azra

    2015-01-01

    GSTM1 and GSTT1 gene polymorphisms have been studied in many populations to evaluate their association with prostate cancer risk with contrasting results. The current study was aimed to find out the association of GSTM1 and GSTT1 gene polymorphisms with prostate cancer in Pakistani men. This case control study included pathologically confirmed prostate cancer patients and age matched male controls. Epidemiological data was collected by a standard questionnaire and presence or absence of GSTM1 and GSTT1 gene was observed by multiplex PCR using CYP1A1 as housekeeping gene. Prostate cancer was more prevalent in age of >60 years and most of the patients were at stage IV (70 %) and have undergone surgery. Family history of cancer, smoking, metastasis and surgery were found to be significant (P<0.05) risk factors in prostate cancer development. Gleason score 7 was most prevalent (40.5 %) in prostate cancer patients. Source of drinking water, residential area, occupation, eating habits and number of family members had no association (P>0.05) with prostate cancer risk. No significant association was found when comparing GSTM1 (OR=0.78) and GSTT1 (OR=0.89) gene deletions with prostate cancer risk. Smoking and TNM staging were also not associated with deletion of GSTM1 and GSTT1 genes. Comparison of dual null deletion of both genes with prostate cancer also showed non-significant associations. Deletion of GSTM1 gene at stage IV prostate cancer patients was significantly higher compared with other stages of cancer while no significance was shown by GSTT1 gene deletion. GSTM1, GSTT1 and deletion of both GSTM1 and GSTT1 genes do not contribute towards increased risk of prostate cancer in Pakistani population. PMID:26600754

  11. 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.

  12. 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

  13. 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

  14. HMG-CoA lyase (HL) gene: Cloning and characterization of the 5{prime} end of the mouse gene, gene targeting in ES cells, and demonstration of large deletions in three HL-deficient patients

    SciTech Connect

    Wang, S.; Robert, M.F.; Mitchell, G.A.

    1994-09-01

    3-hydroxy-3-methylglutaryl CoA lyase (HL) is a mitochondrial matrix enzyme which catalyzes the last step of leucine catabolism and of ketogenesis. Autosomal recessive HL deficiency in humans results in episodes of hypoglycemia and coma. We are interested in the pathophysiology of HL deficiency as a model for both amino acid and fatty acid inborn errors. We have cloned the human and mouse HL genes. In order to analyze the 5{prime} nontranslated region of mouse HL gene, we cloned and sequenced a 1.8 kb fragment containing the 5{prime} extremity including exon 1 and about 1.6 kb of 5{prime} nontranslated sequence. The region surrounding exon 1 is CpG-rich (66.4%). Using the criteria of West, the Observed/Expected ratio for CpG dinucleotides is 0.7 ({ge}0.6 is consistent with a CpG island). We are carrying out primer extension and RNase protection experiments to determine the transcription initiation site. We constructed a gene targeting vector by introducing the neomycin resistance gene into exon 2 of a 7.5 kb genomic subclone of the mouse HL gene. Targeting was performed by electroporating 10 mg linearized vector into 10{sup 7} ES cells and selecting for 12 days with G418. 5/228 colonies (2.2%) had homologous recombination as shown by PCR screening and Southern analysis. We are microinjecting the 5 targeted clones into blastocysts to create an HL-deficient mouse. To date we have obtained two chimeras with contributions of 95% and 55% from 129, by coat color estimates. Three of 27 (11%) of the HL-deficient patients studied were suggested by genomic Southern analysis to be homozygous for large intragenic deletions. We confirmed this and defined the boundaries using exonic PCR.

  15. Spectrum of phenotypic anomalies in four families with deletion of the SHOX enhancer region

    PubMed Central

    2014-01-01

    Background SHOX alterations have been reported in 67% of patients affected by Léri-Weill dyschondrosteosis (LWD), with a larger prevalence of gene deletions than point mutations. It has been recently demonstrated that these deletions can involve the SHOX enhancer region, rather that the coding region, with variable phenotype of the affected patients. Here, we report a SHOX gene analysis carried out by MLPA in 14 LWD patients from 4 families with variable phenotype. Case presentation All patients presented a SHOX enhancer deletion. In particular, a patient with a severe bilateral Madelung deformity without short stature showed a homozygous alteration identical to the recently described 47.5 kb PAR1 deletion. Moreover, we identified, for the first time, in three related patients with a severe bilateral Madelung deformity, a smaller deletion than the 47.5 kb PAR1 deletion encompassing the same enhancer region (ECR1/CNE7). Conclusions Data reported in this study provide new information about the spectrum of phenotypic alterations showed by LWD patients with different deletions of the SHOX enhancer region. PMID:25056248

  16. 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…

  17. 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 ...

  18. 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.

  19. 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…

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  6. 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

  7. Functional Consequences of Mitochondrial DNA Deletions in Human Skin Fibroblasts

    PubMed Central

    Majora, Marc; Wittkampf, Tanja; Schuermann, Bianca; Schneider, Maren; Franke, Susanne; Grether-Beck, Susanne; Wilichowski, Ekkehard; Bernerd, Françoise; Schroeder, Peter; Krutmann, Jean

    2009-01-01

    Deletions within the mitochondrial DNA (mtDNA) are thought to contribute to extrinsic skin aging. To study the translation of mtDNA deletions into functional and structural changes in the skin, we seeded human skin fibroblasts into collagen gels to generate dermal equivalents. These cells were either derived from Kearns-Sayre syndrome (KSS) patients, who constitutively carry large amounts of the UV-inducible mitochondrial common deletion, or normal human volunteers. We found that KSS fibroblasts, in comparison with normal human fibroblasts, contracted the gels faster and more strongly, an effect that was dependent on reactive oxygen species. Gene expression and Western blot analysis revealed significant upregulation of lysyl oxidase (LOX) in KSS fibroblasts. Treatment with the specific LOX inhibitor β-aminopropionitrile decreased the contraction difference between KSS and normal human fibroblast equivalents. Also, addition of the antioxidant N-tert-butyl-α-phenylnitrone reduced the contraction difference by inhibiting collagen gel contraction in KSS fibroblasts, and both β-aminopropionitrile and N-tert-butyl-α-phenylnitrone diminished LOX activity. These data suggest a causal relationship between mtDNA deletions, reactive oxygen species production, and increased LOX activity that leads to increased contraction of collagen gels. Accordingly, increased LOX expression was also observed in vivo in photoaged human and mouse skin. Therefore, mtDNA deletions in human fibroblasts may lead to functional and structural alterations of the skin. PMID:19661442

  8. 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.

  9. Two interstitial rearrangements (16q deletion and 17p duplication) in a child with MR/MCA

    PubMed Central

    Sanchez-Jimeno, Carolina; Bustamante-Aragonés, Ana; Infantes-Barbero, Fernando; Rodriguez De Alba, Marta; Ramos, Carmen; Trujillo-Tiebas, María Jose; Lorda-Sánchez, Isabel

    2014-01-01

    Key Clinical Meassage Patients with rare deletions in 16q12 and a duplication of 17p, both interstitial and de novo. Only seven cases have been described with these deletions and none of them presented other chromosomal abnormalities. The proband showed a complex phenotype with features found in patients with dup17p11.2 syndrome, deletions in 16q12. PMID:25548634

  10. SNP array mapping of chromosome 20p deletions: genotypes, phenotypes, and copy number variation.

    PubMed

    Kamath, Binita M; Thiel, Brian D; Gai, Xiaowu; Conlin, Laura K; Munoz, Pedro S; Glessner, Joseph; Clark, Dinah; Warthen, Daniel M; Shaikh, Tamim H; Mihci, Ercan; Piccoli, David A; Grant, Struan F A; Hakonarson, Hakon; Krantz, Ian D; Spinner, Nancy B

    2009-03-01

    The use of array technology to define chromosome deletions and duplications is bringing us closer to establishing a genotype/phenotype map of genomic copy number alterations. We studied 21 patients and five relatives with deletions of the short arm of chromosome 20 using the Illumina HumanHap550 SNP array to: 1) more accurately determine the deletion sizes; 2) identify and compare breakpoints; 3) establish genotype/phenotype correlations; and 4) investigate the use of the HumanHap550 platform for analysis of chromosome deletions. Deletions ranged from 95 kb to 14.62 Mb, and all of the breakpoints were unique. Eleven patients had deletions between 95 kb and 4 Mb and these individuals had normal development, with no anomalies outside of those associated with Alagille syndrome (AGS). The proximal and distal boundaries of these 11 deletions constitute a 5.4-Mb region, and we propose that haploinsufficiency for only 1 of the 12 genes in this region causes phenotypic abnormalities. This defines the JAG1-associated critical region, in which deletions do not confer findings other than those associated with AGS. The other 10 patients had deletions between 3.28 Mb and 14.62 Mb, which extended outside the critical region, and, notably, all of these patients had developmental delay. This group had other findings such as autism, scoliosis, and bifid uvula. We identified 47 additional polymorphic genome-wide copy number variants (>20 SNPs), with 0 to 5 variants called per patient. Deletions of the short arm of chromosome 20 are associated with relatively mild and limited clinical anomalies. The use of SNP arrays provides accurate high-resolution definition of genomic abnormalities. PMID:19058200

  11. Detection of a molecular deletion at the DXS732 locus in a patient with X-linked hypohidrotic ectodermal dysplasia (EDA), with the identification of a unique junctional fragment.

    PubMed Central

    Zonana, J; Gault, J; Davies, K J; Jones, M; Browne, D; Litt, M; Brockdorff, N; Rastan, S; Clarke, A; Thomas, N S

    1993-01-01

    X-linked hypohidrotic ectodermal dysplasia (EDA) has been localized to the Xq12-q13.1 region. A panel of genomic DNA samples from 80 unrelated males with EDA has been screened for deletions at seven genetic loci within the Xq12-13 region. A single individual was identified with a deletion at the DXS732 locus by hybridization with the mouse genomic probe pcos169E/4. This highly conserved DNA probe is from locus DXCrc169, which is tightly linked to the Ta locus, the putative mouse homologue of EDA. The proband had the classical phenotype of EDA, with no other phenotypic abnormalities, and a normal cytogenetic analysis. A human genomic DNA clone, homologous to pcos169E/4, was isolated from a human X-chromosome cosmid library. On hybridization with the cosmid, the proband was found to be only partially deleted at the DXS732 locus, with a unique junctional fragment identified in the proband and in three of his maternal relatives. This is the first determination of carrier status for EDA in females, by direct mutation analysis. Failure to detect deletion of the other loci tested in the proband suggests that the DXS732 locus is the closest known locus to the EDA gene. Since the DXS732 locus contains a highly conserved sequence, it must be considered to be a candidate locus for the EDA gene itself. Images Figure 2 Figure 3 PMID:8434608

  12. 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

  13. A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.

    PubMed

    Suzuki-Muromoto, Sato; Hino-Fukuyo, Naomi; Haginoya, Kazuhiro; Kikuchi, Atsuo; Sato, Hiroki; Sato, Yuko; Nakayama, Tojo; Kubota, Yuki; Kakisaka, Yosuke; Uematsu, Mitsugu; Kumabe, Toshihiro; Md, Shigeo Kure

    2016-02-01

    We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24 years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome. PMID:26365017

  14. The rates and patterns of deletions in the human factor IX gene

    SciTech Connect

    Ketterling, R.P.; Vielhaber, E.L.; Lind, T.J.; Thorland, E.C.; Sommer S.S. )

    1994-02-01

    Deletions are commonly observed in genes with either segments of highly homologous sequences or excessive gene length. However, in the factor IX gene and in most genes, deletions (of [ge]21 bp) are uncommon. The authors have analyzed DNA from 290 families with hemophilia B (203 independent mutations) and have found 12 deletions >20 bp. Eleven of these are >2 kb (range >3-163 kb), and one is 1.1 kb. The junctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in patient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For a sample of 203 independent mutations, the authors estimate the [open quotes]baseline[close quotes] rates of deletional mutation per base pair per generation as a function of size. The rate for large (>2 kb)I deletions is exceedingly low. For every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (<20 bp) and 985 single-base substitutions at that base. Analysis of the nine reported deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversion, orphan sequences, or sense strand insertions; (ii) four are simple deletions that display an excess of short direct repeats at their junctions; (iii) there is no dramatic clustering of junctions within the gene; and (iv) with the exception of alternating purines and pyrimidines, deletion junctions are not preferentially associated with repetitive DNA. 58 refs., 5 figs., 5 tabs.

  15. 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.

  16. 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

  17. Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1.

    PubMed Central

    Rasmussen, S A; Colman, S D; Ho, V T; Abernathy, C R; Arn, P H; Weiss, L; Schwartz, C; Saul, R A; Wallace, M R

    1998-01-01

    A set of neurofibromatosis type 1 (NF1) patients was screened for large NF1 gene deletions by comparing patient and parent genotypes at 10 intragenic polymorphic loci. Of 67 patient/parent sets (47 new mutation patients and 20 familial cases), five (7.5%) showed loss of heterozygosity (LOH), indicative of NF1 gene deletion. These five patients did not have severe NF1 manifestations, mental retardation, or dysmorphic features, in contrast to previous reports of large NF1 deletions. All five deletions were de novo and occurred on the maternal chromosome. However, two patients showed partial LOH, consistent with somatic mosaicism for the deletion, suggesting that mosaicism may be more frequent in NF1 than previously recognised (and may have bearing on clinical severity). We suggest that large NF1 deletions (1) are not always associated with unusual clinical features, (2) tend to occur more frequently on maternal alleles, and (3) are an important mechanism for constitutional and somatic mutations in NF1 patients. Images PMID:9643287

  18. Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.

    PubMed

    Lal, Dennis; Pernhorst, Katharina; Klein, Karl Martin; Reif, Philipp; Tozzi, Rossana; Toliat, Mohammad R; Winterer, Georg; Neubauer, Bernd; Nürnberg, Peter; Rosenow, Felix; Becker, Felicitas; Lerche, Holger; Kunz, Wolfram S; Kurki, Mitja I; Hoffmann, Per; Becker, Albert J; Perucca, Emilio; Zara, Federico; Sander, Thomas; Weber, Yvonne G

    2015-09-01

    Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies. PMID:26174448

  19. 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.

  20. Interstitial 11q24 deletion: a new case and review of the literature.

    PubMed

    Tassano, Elisa; Janis, Sara; Canepa, Alberto; Zanotto, Elisabetta; Torello, Corrado; Gimelli, Giorgio; Cuoco, Cristina

    2016-08-01

    We describe a 19-month-old male presenting with right stenotic megaureter, anemia and thrombocytopenia, cardiac and ophthalmologic abnormalities. Analysis with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 2.4 Mb of chromosome 11q24.2q24.3. We compared the phenotype of our patient with that of recently reported patients studied by aCGH, who showed an overlapping deletion. We also analysed the gene content of the deleted region in order to investigate the possible involvement of specific genes in the clinical phenotype. PMID:27020790

  1. Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses.

    PubMed

    Carrozzo, R; Hirano, M; Fromenty, B; Casali, C; Santorelli, F M; Bonilla, E; DiMauro, S; Schon, E A; Miranda, A F

    1998-01-01

    Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from

  2. 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

  3. Prenatal diagnosis and molecular cytogenetic characterization of a de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14).

    PubMed

    Chen, Chih-Ping; Lee, Meng-Ju; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chen, Yu-Ting; Lee, Meng-Shan; Wang, Wayseen

    2013-10-25

    We present prenatal diagnosis of de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14) and molecular cytogenetic characterization of the deletion using uncultured amniocytes. We review the phenotypic abnormalities of previously reported patients with similar proximal interstitial 4p deletions, and we discuss the functions of the genes of RBPJ, CCKAR, STIM2, PCDH7 and ARAP2 that are deleted within this region. PMID:23948085

  4. 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

  5. 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

  6. Deletion analysis of p16(INKa) and p15(INKb) in relapsed childhood acute lymphoblastic leukemia.

    PubMed

    Graf Einsiedel, Hagen; Taube, Tillmann; Hartmann, Reinhard; Wellmann, Sven; Seifert, Georg; Henze, Günter; Seeger, Karl

    2002-06-15

    This study aimed at determining the prevalence of INK4 deletions and their impact on outcome in 125 children with acute lymphoblastic leukemia (ALL) at first relapse using real-time quantitative polymerase chain reaction. Patients were enrolled into relapse trials ALL-REZ BFM (ALL-Relapse Berlin-Frankfurt-Münster) 90 and 96. The prevalence of p16(INK4a) and p15(INK4b) homozygous deletions was 35% (44 of 125) and 30% (38 of 125), respectively. A highly significant association of both gene deletions was found with the 2 major adverse prognostic factors known for relapsed childhood ALL: T-cell immunophenotype and first remission duration. There was no correlation between INK4 deletions and probability of event-free survival. These findings argue against an independent prognostic role of INK4 deletions in relapsed childhood ALL. PMID:12036898

  7. Unbalanced three-way chromosomal translocation leading to deletion 18q and duplication 20p.

    PubMed

    Oegema, Renske; van Zutven, Laura J C M; van Hassel, Daniella A C M; Huijbregts, Guido C M; Hoogeboom, A Jeannette M

    2012-04-01

    In 1980, a case report on a boy with cleft palate, club feet, dysmorphic features, and developmental delay was published by Bijlsma as a possible distinct syndrome. This case is listed in the London Medical Databases version 1.0. We have reevaluated this patient at adult age. Using high resolution karyotyping and Affymetrix 250k SNP array analysis we identified an unbalanced three-way translocation with breakpoints at 17q22, 18q22.1, and 20p12.2 leading to deletion 18q and duplication 20p. Also, a 715 kb duplication in 1p34.2 and a 245 kb deletion at 1p21.1 were found. Mental retardation, cleft palate, and club feet have repeatedly been reported in deletion 18q patients and therefore we conclude that most of the patient's features can be explained by an 18q deletion. PMID:22406089

  8. Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects.

    PubMed Central

    Hennekam, R C; Tilanus, M; Hamel, B C; Voshart-van Heeren, H; Mariman, E C; van Beersum, S E; van den Boogaard, M J; Breuning, M H

    1993-01-01

    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. We 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. Images Figure 1 Figure 2 PMID:8430692

  9. A rare subtelomeric deletion syndrome: Wolf Hirschhorn syndrome.

    PubMed

    Zorlu, P; Eksioglu, A S; Ozkan, M; Tos, T; Senel, S

    2014-01-01

    Wolf-Hirschhorn syndrome is caused by a deletion of the distal portion of the short arm of chromosome 4, and is characterized by psychomotor retardation, seizures, congenital malformations, and typical facial appearance including 'Greek warrior helmet' appearance of the nose. The form and the severity of clinical manifestations vary according to the size and location of the deletion. Major complications are severe growth retardation, developmental delay, seizures, feeding difficulties due to hypotonia, and predisposition to respiratory infections. Patients will benefit from supportive therapy and special education. It is important in terms of prognosis to provide counseling to families in this respect. We present here a case with Wolf-Hirschhorn Syndrome in order to remind its rarity and the ability of the patients' progress in the areas of motor skills, speech, social interaction. PMID:25365852

  10. 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

  11. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.

    PubMed

    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

    2015-08-01

    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

  12. Molecular basis of human growth hormone gene deletions.

    PubMed Central

    Vnencak-Jones, C L; Phillips, J A; Chen, E Y; Seeburg, P H

    1988-01-01

    Crossover sites resulting from unequal recombination within the human growth hormone (GH) gene cluster that cause GH1 gene deletions and isolated GH deficiency type 1A were localized in nine patients. In eight unrelated subjects homozygous for 6.7-kilobase (kb) deletions, the breakpoints are within two blocks of highly homologous DNA sequences that lie 5' and 3' to the GH1 gene. In seven of these eight cases, the breakpoints map within a 1250-base-pair (bp) region composed of 300-bp Alu sequences of 86% homology and flanking non-Alu sequences that are 600 and 300 bp in length and are of 96% and 88% homology, respectively. In the eighth patient, the breakpoints are 5' to these Alu repeats and are most likely within a 700-bp region of 96% homologous DNA sequences. In the ninth patient homozygous for a 7.6-kb deletion, the breakpoints are contained within a 29-bp perfect repeat lying 5' to GH1 and the human chorionic somatomammotropin pseudogene (CSHP1). Together, these results indicate that the presence of highly homologous DNA sequences flanking GH1 predispose to recurrent unequal recombinational events presumably through chromosomal misalignment. Images PMID:2840669

  13. 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:...

  14. Novel features of 3q29 deletion syndrome: Results from the 3q29 registry.

    PubMed

    Glassford, Megan R; Rosenfeld, Jill A; Freedman, Alexa A; Zwick, Michael E; Mulle, Jennifer G

    2016-04-01

    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 Wiley Periodicals, Inc. PMID:26738761

  15. Interstitial deletion of 11(p11.2p12): A newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses

    SciTech Connect

    Potocki, L.; Shaffer, L.G.

    1996-03-29

    Individuals with deletions of the proximal portion of the short arm of chromosome 11 share many manifestations including mental retardation, biparietal foramina, minor facial anomalies, and multiple cartilaginous exostoses. The finding of multiple exostoses in these patients is remarkable as the disorder hereditary multiple exostoses, which is inherited in an autosomal dominant manner, has recently been mapped by linkage to three regions, including proximal 11p. We report the clinical and molecular findings in an additional patient with an 11(p11.2p12) deletion. Cytogenetic and molecular analysis demonstrated a de novo, paternally derived deletion for markers which have been shown to be tightly linked to the 11p locus (EXT2). These data support the location of EXT2 within this region and also provide information regarding the ordering of polymorphic markers on 11p. Deletion 11(p11.2p12) is a rare, yet specific, deletion syndrome involving the EXT2 locus, a gene for parietal foramina, and a mental retardation locus, and therefore can be classified as a contiguous gene deletion syndrome. 24 refs., 4 figs., 1 tab.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Somatic amplifications and deletions in genome of papillary thyroid carcinomas.

    PubMed

    Passon, Nadia; Bregant, Elisa; Sponziello, Marialuisa; Dima, Maria; Rosignolo, Francesca; Durante, Cosimo; Celano, Marilena; Russo, Diego; Filetti, Sebastiano; Damante, Giuseppe

    2015-11-01

    Somatic gene copy number variation contributes to tumor progression. Using comparative genomic hybridization (CGH) array, the presence of genomic imbalances was evaluated in a series of 27 papillary thyroid carcinomas (PTCs). To detect only somatic imbalances, for each sample, the reference DNA was from normal thyroid tissue of the same patient. The presence of the BRAF V600E mutation was also evaluated. Both amplifications and deletions showed an uneven distribution along the entire PTC cohort; amplifications were more frequent than deletions (mean values of 17.5 and 7.2, respectively). Number of aberration events was not even among samples, the majority of them occurring only in a small fraction of PTCs. Most frequent amplifications were detected at regions 2q35, 4q26, and 4q34.1, containing FN1, PDE5A, and GALNTL6 genes, respectively. Most frequent deletions occurred at regions 6q25.2, containing OPMR1 and IPCEF1 genes and 7q14.2, containing AOAH and ELMO1 genes. Amplification of FN1 and PDE5A genomic regions was confirmed by quantitative PCR. Frequency of amplifications and deletions was in relationship with clinical features and BRAF mutation status of tumor. In fact, according to the American Joint Committee on Cancer stage and American Thyroid Association (ATA) risk classification, amplifications are more frequent in higher risk samples, while deletions tend to prevail in the lower risk tumors. Analysis of single aberrations according to the ATA risk grouping shows that amplifications containing PDE5A, GALNTL6, DHRS3, and DOCK9 genes are significantly more frequent in the intermediate/high risk group than in the low risk group. Thus, our data would indicate that analysis of somatic genome aberrations by CGH array can be useful to identify additional prognostic variables. PMID:25863487

  1. 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.

  2. 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.

  3. 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.

  4. Characterization of a 16 Mb interstitial chromosome 7q21 deletion by tiling path array CGH.

    PubMed

    Tzschach, Andreas; Menzel, Corinna; Erdogan, Fikret; Schubert, Marei; Hoeltzenbein, Maria; Barbi, Gotthold; Petzenhauser, Christine; Ropers, Hans-Hilger; Ullmann, Reinhard; Kalscheuer, Vera

    2007-02-15

    We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval. PMID:17230488

  5. Exonic STK11 deletions are not a rare cause of Peutz‐Jeghers syndrome

    PubMed Central

    Hearle, N C M; Rudd, M F; Lim, W; Murday, V; Lim, A G; Phillips, R K; Lee, P W; O'Donohue, J; Morrison, P J; Norman, A; Hodgson, S V; Lucassen, A; Houlston, R S

    2006-01-01

    Background Peutz‐Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro‐facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. Methods Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. Results Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. Conclusions These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients. PMID:16582077

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. Mandibular dysostosis without microphthalmia caused by OTX2 deletion.

    PubMed

    Latypova, Xénia; Bordereau, Sylvain; Bleriot, Alice; Pichon, Olivier; Poulain, Damien; Briand, Annaïg; Le Caignec, Cédric; Isidor, Bertrand

    2016-09-01

    Mutations in OTX2 are mostly identified in patients with anophthalmia/microphthalmia with variable severity. The OTX2 homeobox gene plays a crucial role in craniofacial morphogenesis during early embryo development. We report for the first time a patient with a mandibular dysostosis caused by a 120 kb deletion including the entire coding sequence of OTX2, identified by array CGH. No ocular malformations were identified after extended ophthalmologic examination. Our data refine the clinical spectrum associated with OTX2 mutations and suggests that OTX2 haploinsufficiency should be considered as a possible cause for isolated mandibular dysostosis. © 2016 Wiley Periodicals, Inc. PMID:27378064

  13. 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

  14. Absence of Genomic Ikaros/IKZF1 Deletions in Pediatric B-Precursor Acute Lymphoblastic Leukemia

    PubMed Central

    Qazi, Sanjive; Ma, Hong; Uckun, Fatih M

    2013-01-01

    Here we report the results of gene expression analyses using multiple probesets aimed at determining the incidence of Ikaros/IKZF1 deletions in pediatric B-precursor acute lymphoblastic leukemia (BPL). Primary leukemia cells from 122 Philadelphia chromosome (Ph)+ BPL patients and 237 Ph− BPL patients as well as normal hematopoietic cells from 74 normal non-leukemic bone marrow specimens were organized according to expression levels of IKZF1 transcripts utilizing two-way hierarchical clustering technique to identify specimens with low IKZF1 expression for the 10 probesets interrogating Exons 1 through 4 and Exon 8. Our analysis demonstrated no changes in expression that would be expected from homozygous or heterozygous deletions of IKZF1 in primary leukemic cells. Similar results were obtained in gene expression analysis of primary leukemic cells from 20 Ph+ positive and 155 Ph− BPL patients in a validation dataset. Taken together, our gene expression analyses in 534 pediatric BPL cases, including 142 cases with Ph+ BPL, contradict previous reports that were based on SNP array data and suggested that Ph+ pediatric BPL is characterized by a high frequency of homozygous or heterozygous IKZF1 deletions. Further, exon-specific genomic PCR analysis of primary leukemia cells from 21 high-risk pediatric BPL patients and 11 standard-risk pediatric BPL patients, and 8 patients with infant BPL did not show any evidence for homozygous IKZF1 locus deletions. Nor was there any evidence for homozygous or heterozygous intragenic IKZF1 deletions. PMID:24478816

  15. Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia.

    PubMed

    Kager, Leo; Minkov, Milen; Zeitlhofer, Petra; Fahrner, Bernhard; Ratzinger, Franz; Boztug, Kaan; Dossenbach-Glaninger, Astrid; Haas, Oskar A

    2016-05-01

    We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant. PMID:26728349

  16. 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.

  17. Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene.

    PubMed

    Fridman, C; Hosomi, N; Varela, M C; Souza, A H; Fukai, K; Koiffmann, C P

    2003-06-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11-q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader-Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF-SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hypopigmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region. PMID:12749060

  18. 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.

  19. 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.

  20. Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: Molecular genetic evidence for deletions

    PubMed Central

    Francke, Uta; Harper, John F.; Darras, Basil T.; Cowan, Janet M.; McCabe, Edward R. B.; Kohlschütter, Alfried; Seltzer, William K.; Saito, Fumiko; Goto, Jun; Harpey, Jean-Paul; Wise, Joyce E.

    1987-01-01

    Glycerol kinase deficiency (GKD) is an X-linked recessive trait that occurs in association with congenital adrenal hypoplasia (AH) and developmental delay with or without congenital dystrophic myopathy. Several such patients have recently been reported to have cytological deletions of chromosome region Xp21 and/or of DNA markers that map near the locus for Duchenne muscular dystrophy (DMD) in band Xp21. We have examined the initial family reported in the literature and, using prometaphase chromosome studies and Southern blot analysis with 13 different DNA probes derived from band Xp21, have found no deletions within this region of the X chromosome. When DNA samples from six other unrelated affected males were analyzed, four of them were found to have different-size deletions within Xp21. Thus, the form of GKD associated with AH and dystrophic myopathy exhibits significant genetic heterogeneity at the DNA level. No deletions were detected in two patients with isolated GK deficiency. Comparison of our molecular studies of unrelated patients with deletions of DNA segments allows us to define the region of Xp21 (between probes J-Bir and L1.4) that most likely contains the genes for GKD and AH. This location is distal to the DMD locus. The patients with progressive muscular dystrophy tended to have larger deletions that include markers known to derive from the DMD locus, while GKD/AH/dystrophic-myopathy patients without current evidence of deletion seemed to have a milder, nonprogressive form of congenital myopathy. ImagesFig. 1Fig. 2 PMID:2883886

  1. 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

  2. Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy

    PubMed Central

    Litviakov, Nikolai V.; Cherdyntseva, Nadezhda V.; Tsyganov, Matvey M.; Slonimskaya, Elena M.; Ibragimova, Marina K.; Kazantseva, Polina V.; Kzhyshkowska, Julia; Choinzonov, Eugeniy L.

    2016-01-01

    Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of primary breast cancer. In our previous studies, we reported that clinical tumor response to NAC is associated with the change of multidrug resistance (MDR) gene expression in tumors after chemotherapy. In this study we performed a combined analysis of MDR gene locus deletions in tumor DNA, MDR gene expression and clinical response to NAC in 73 BC patients. Copy number variations (CNVs) in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). 75%–100% persons having deletions of MDR gene loci demonstrated the down-regulation of MDR gene expression. Expression of MDR genes was 2–8 times lower in patients with deletion than in patients having no deletion only in post-NAC tumors samples but not in tumor tissue before chemotherapy. All patients with deletions of ABCB1 ABCB 3 ABCC5 gene loci – 7q21.1, 6p21.32, 3q27 correspondingly, and most patients having deletions in ABCC1 (16p13.1), ABCC2 (10q24), ABCG1 (21q22.3), ABCG2 (4q22.1), responded favorably to NAC. The analysis of all CNVs, including both amplification and deletion showed that the frequency of 13q14.2 deletion was 85% among patients bearing tumor with the deletion at least in one MDR gene locus versus 9% in patients with no deletions. Differences in the frequency of 13q14.2 deletions between the two groups were statistically significant (p = 2.03 ×10−11, Fisher test, Bonferroni-adjusted p = 1.73 × 10−8). In conclusion, our study for the first time demonstrates that deletion MDR gene loci can be used as predictive marker for tumor response to NAC. PMID:26799285

  3. Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements.

    PubMed

    van Zelm, Menno C; Geertsema, Corinne; Nieuwenhuis, Nicole; de Ridder, Dick; Conley, Mary Ellen; Schiff, Claudine; Tezcan, Ilhan; Bernatowska, Ewa; Hartwig, Nico G; Sanders, Elisabeth A M; Litzman, Jiri; Kondratenko, Irina; van Dongen, Jacques J M; van der Burg, Mirjam

    2008-02-01

    Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions ( approximately 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease. PMID:18252213

  4. Gross Deletions Involving IGHM, BTK, or Artemis: A Model for Genomic Lesions Mediated by Transposable Elements

    PubMed Central

    van Zelm, Menno C.; Geertsema, Corinne; Nieuwenhuis, Nicole; de Ridder, Dick; Conley, Mary Ellen; Schiff, Claudine; Tezcan, Ilhan; Bernatowska, Ewa; Hartwig, Nico G.; Sanders, Elisabeth A.M.; Litzman, Jiri; Kondratenko, Irina; van Dongen, Jacques J.M.; van der Burg, Mirjam

    2008-01-01

    Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions (∼60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease. PMID:18252213

  5. 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.

  6. Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms.

    PubMed

    Perier, Celine; Bender, Andreas; García-Arumí, Elena; Melià, Ma Jesus; Bové, Jordi; Laub, Christoph; Klopstock, Thomas; Elstner, Matthias; Mounsey, Ross B; Teismann, Peter; Prolla, Tomas; Andreu, Antoni L; Vila, Miquel

    2013-08-01

    Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA

  7. A New Intergenic α-Globin Deletion (α-α(Δ125)) Found in a Kabyle Population.

    PubMed

    Rabbind Singh, Amrathlal; Lacan, Philippe; Cadet, Estelle; Bignet, Patricia; Dumesnil, Cécile; Vannier, Jean-Pierre; Joly, Philippe; Rochette, Jacques

    2016-03-01

    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. PMID:26911300

  8. Mapping of heteroplasmic mitochondrial DNA deletions in Kearns-Sayre syndrome.

    PubMed Central

    Nelson, I; Degoul, F; Obermaier-Kusser, B; Romero, N; Borrone, C; Marsac, C; Vayssiere, J L; Gerbitz, K; Fardeau, M; Ponsot, G

    1989-01-01

    Kearns-Sayre syndrome (KSS) is a progressive neuromuscular disease characterised by ophtalmoplegia, cardiac bloc branch, pigmentary retinopathy associated with abnormal mitochondrial function. We have studied the mitochondrial DNA organization of patients presenting KSS and have found large deletions ranging from 3 to 8.5 kilobase pairs. DNA molecules containing deletion are accompanied by the presence of the normal sized mtDNA molecule forming heteroplasmic genomes. The deletions always map in the region which is potentially single stranded during mitochondrial DNA replication. The deletions differ in length and position between individuals but are similar within the different tissues of an individual suggesting that they arise during or before embryogenesis. Images PMID:2813058

  9. Molecular dissection of the 5q deletion in myelodysplastic syndrome.

    PubMed

    Ebert, Benjamin L

    2011-10-01

    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 haplo-insufficient 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 haplo-insufficiency of multiple genes. PMID:21943668

  10. Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

    PubMed Central

    Beedle, Aaron M.; Turner, Amy J.; Saito, Yoshiaki; Lueck, John D.; Foltz, Steven J.; Fortunato, Marisa J.; Nienaber, Patricia M.; Campbell, Kevin P.

    2012-01-01

    Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty-week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy. PMID:22922256

  11. 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.

  12. 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

  13. Screening for AZFc Partial Deletions in Dravidian Men with Nonobstructive Azoospermia and Oligozoospermia

    PubMed Central

    Vijesh, Vijayabhavanath Vijayakumaran; Nambiar, Vandana; Mohammed, Surayya I.K.; Sukumaran, Shervin

    2015-01-01

    Context: Dravidians are the predominant population residing in South India with a diverse genetic structure. Considering various genetic discoveries taking place today, it is evident that deletions in the AZFc region are the most common cause of severe spermatogenic failure (SSF) in various populations studied. However, it is significant to note that there is a paucity of scientific literature on AZFc subdeletion screening among the Dravidian population. Objective: To investigate the prevalence and association of AZFc subdeletion patterns among Dravidian men with nonobstructive azoospermia (NOA) and oligozoospermia. Methods: A population of 354 subjects, including 120 patients with NOA, 109 with oligozoospermia, and 125 normal male controls, were screened using locus-specific sequence tag site markers. Results: We found 21 (9.17%) patients with classical AZF deletion, while no deletions were observed in controls. After excluding the samples with AZF deletions, the remaining 208 infertile and 125 control samples were screened for partial AZFc deletions using a standardized multiplex polymerase chain reaction and on analysis revealed that 13 (6.25%) of the infertile samples possessed gr/gr subdeletions and 15 (7.21%) of the infertile samples possessed b2/b3 subdeletions. Six (4.8%) of the normal samples were found to carry gr/gr subdeletions and two (1.6%) had b2/b3 deletions. The b1/b3 deletion was not observed in any of the patient and control samples screened. Conclusion: Our finding shows that there is a strong association between b2/b3 subdeletion and SSF in the Dravidian population (odds ratio, 4.78; 95% confidence interval 1.07–21.26) (p=0.018). Further studies, including gene copy typing for DAZ and CDY genes and a comprehensive haplogrouping analysis, are recommended in a large and well-selected patient group to elude the genetic mechanism behind this association. PMID:25594150

  14. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome

    PubMed Central

    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. PMID:22712005

  15. Delineation of 2q32q35 deletion phenotypes: two apparent "proximal" and "distal" syndromes.

    PubMed

    Mc Cormack, Adrian; Taylor, Juliet; Gregersen, Nerine; George, Alice M; Love, Donald R

    2013-01-01

    We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1-q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6 Mb deletion in patients 1 and 2 and a 24.7 Mb deletion in patient 3. We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2, and CPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene. PMID:23840981

  16. 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.

  17. 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.

  18. Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies

    PubMed Central

    Cho, Sun-Mi; Kim, Yoonjung; Lee, Sang Guk; Yang, Jin-Young

    2014-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22) gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis. PMID:25506001

  19. Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies.

    PubMed

    Cho, Sun-Mi; Hong, Bo Young; Kim, Yoonjung; Lee, Sang Guk; Yang, Jin-Young; Kim, Juwon; Lee, Kyung-A

    2014-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22) gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis. PMID:25506001

  20. 22q11.2 deletion syndrome.

    PubMed

    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

    2015-01-01

    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

  1. 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

  2. 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).

  3. Currarino triad with a terminal deletion 7q35-->qter.

    PubMed

    Masuno, M; Imaizumi, K; Aida, N; Tanaka, Y; Sekido, K; Ohhama, Y; Nishi, T; Kuroki, Y

    1996-10-01

    We describe a de novo terminal deletion of the long arm of chromosome 7 in a 5 year old girl with the Currarino triad, characterised by congenital anorectal stenosis, a sacral defect, and a presacral mass. Recently, this autosomal dominant trait has been shown to be linked to 7q36, the same region as holoprosencephaly (HPE3). The cytogenetic findings in the present patient with the Currarino triad provided further evidence that a gene(s) for the Currarino triad is located in the 7 q terminal segment. PMID:8933345

  4. Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1.

    PubMed

    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

  5. 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

  6. 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.

  7. Congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome due to a 6p deletion.

    PubMed

    Moysés-Oliveira, Mariana; Mancini, Tatiane I; Takeno, Sylvia S; Rodrigues, Andressa D S; Bachega, Tania A S S; Bertola, Debora; Melaragno, Maria Isabel

    2014-01-01

    Cryptic deletions in balanced de novo translocations represent a frequent cause of abnormal phenotypes, including Mendelian diseases. In this study, we describe a patient with multiple congenital abnormalities, such as late-onset congenital adrenal hyperplasia (CAH), primary ovarian failure and Ehlers-Danlos syndrome (EDS), who carries a de novo t(6;14)(p21;q32) translocation. Genomic array analysis identified a cryptic 1.1-Mb heterozygous deletion, adjacent to the breakpoint on chromosome 6, extending from 6p21.33 to 6p21.32 and affecting 85 genes, including CYP21A2,TNXB and MSH5. Multiplex ligation-dependent probe amplification analysis of the 6p21.3 region was performed in the patient and her family and revealed a 30-kb deletion in the patient's normal chromosome 6, inherited from her mother, resulting in homozygous loss of genes CYP21A1P and C4B. CYP21A2 sequencing showed that its promoter region was not affected by the 30-kb deletion, suggesting that the deletion of other regulatory sequences in the normal chromosome 6 caused a loss of function of the CYP21A2 gene. EDS and primary ovarian failure phenotypes could be explained by the loss of genes TNXB and MSH5, a finding that may contribute to the characterization of disease-causing genes. The detection of this de novo microdeletion drastically reduced the estimated recurrence risk for CAH in the family. PMID:24970489

  8. 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.

  9. High resolution mapping of interstitial long arm deletions of chromosome 16: relationship to phenotype.

    PubMed

    Callen, D F; Eyre, H; Lane, S; Shen, Y; Hansmann, I; Spinner, N; Zackai, E; McDonald-McGinn, D; Schuffenhauer, S; Wauters, J

    1993-10-01

    The breakpoints of seven interstitial deletions of the long arm of chromosome 16 and two ring chromosomes of this chromosome were mapped by in situ hybridisation or by analysis of mouse/human somatic cell hybrids containing the deleted chromosome 16. Use of a high resolution cytogenetic based physical map of chromosome 16 enabled breakpoints to be assigned to an average resolution of at least 1.6 Mb. In general, interstitial deletions involving q12 or q22.1 have broadly similar phenotypes though there are differences in specific abnormalities. Deletions involving regions more distal, from 16q22.1 to 16q24.1, were associated with relatively mild dysmorphism. One region of the long arm, q24.2 to q24.3, was not involved in any deletion, either in this study or in any previous report. Presumably, monosomy for this region is lethal. In contrast, patients with deletions of 16q21 have a normal phenotype. These results are consistent with the proposed distribution of genes, frequent in telomeric Giesma light band regions but infrequent in G positive bands. PMID:8230159

  10. 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. PMID:26774077

  11. 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

  12. 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

  13. Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions.

    PubMed

    Steinmann, Katharina; Kluwe, Lan; Cooper, David N; Brems, Hilde; De Raedt, Thomas; Legius, Eric; Mautner, Viktor-Felix; Kehrer-Sawatzki, Hildegard

    2008-05-01

    Gross deletions of the NF1 gene at 17q11.2 belong to the group of 'genomic disorders' characterized by local sequence architecture that predisposes to genomic rearrangements. Segmental duplications within regions associated with genomic disorders are prone to non-allelic homologous recombination (NAHR), which mediates gross rearrangements. Copy number variants (CNVs) without obvious phenotypic consequences also occur frequently in regions of genomic disorders. In the NF1 gene region, putative CNVs have been reportedly detected by array comparative genomic hybridization (array CGH). These variants include duplications and deletions within the NF1 gene itself (CNV1) and a duplication that encompasses the SUZ12 gene, the distal NF1-REPc repeat and the RHOT1 gene (CNV2). To explore the possibility that these CNVs could have played a role in promoting deletion mutagenesis in type-1 deletions (the most common type of gross NF1 deletion), non-affected transmitting parents of patients with type-1 NF1 deletions were investigated by multiplex ligation-dependent probe amplification (MLPA). However, neither CNV1 nor CNV2 were detected. This would appear to exclude these variants as frequent mediators of NAHR giving rise to type-1 deletions. Using MLPA, we were also unable to confirm CNV1 in healthy controls as previously reported. We conclude that locus-specific techniques should be used to independently confirm putative CNVs, originally detected by array CGH, to avoid false-positive results. In one patient with an atypical deletion, a duplication in the region of CNV2 was noted. This duplication could have occurred concomitantly with the deletion as part of a complex rearrangement or may alternatively have preceded the deletion. PMID:18212816

  14. 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

  15. High prevalence of tcdC deletion-carrying Clostridium difficile and lack of association with disease severity.

    PubMed

    Verdoorn, Brandon P; Orenstein, Robert; Rosenblatt, Jon E; Sloan, Lynne M; Schleck, Cathy D; Harmsen, William S; Nyre, Lisa M; Patel, Robin

    2010-01-01

    We assessed the prevalence of tcdC deletion-carrying Clostridium difficile using a stool polymerase chain reaction (PCR) assay that detects previously described 18- and 39-bp deletions (J. Clin. Microbiol. 2008;46:1996). We divided inpatients into 2 groups, those for whom the assay detected a deletion in tcdC and those for whom no deletion was detected. We compared risk factors (antibiotic use, hospitalization, nursing home stay, immunocompromise, age >65 years), complications (pseudomembranous colitis, toxic megacolon, colonic perforation, colectomy, and intensive care unit admission), duration of antibiotic treatment, and 30-day mortality between the groups. Forty-two of 141 patients had deletion-positive C. difficile. Prior nursing home stay and age >65 years were significantly more common in the deletion-positive group. Other risk factors, complications, antibiotic duration, and mortality did not differ significantly. Deletion-carrying C. difficile was commonly present but not associated with more severe disease and not markedly different in terms of risk factor profile. Severity of disease was relatively low, regardless of the presence or absence of a deletion. PMID:19775847

  16. 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

    2015-01-01

    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. PMID:26045207

  17. 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.

  18. 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.

  19. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant

    PubMed Central

    Hannes, F D; Sharp, A J; Mefford, H C; de Ravel, T; Ruivenkamp, C A; Breuning, M H; Fryns, J-P; Devriendt, K; Van Buggenhout, G; Vogels, A; Stewart, H; Hennekam, R C; Cooper, G M; Regan, R; Knight, S J L; Eichler, E E; Vermeesch, J R

    2009-01-01

    Background: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. Methods and Results: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). Conclusion: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients’ phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the

  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. 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.

  2. 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

  3. 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. PMID:27144803

  4. 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.

  5. 78 FR 77106 - Procurement List; Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

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  6. 78 FR 23543 - Procurement List Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-19

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  7. 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.

  8. 76 FR 65501 - Procurement List; Proposed Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-21

    ... 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.... Comments Must Be Received On or Before: 11/21/2011. ADDRESSES: Committee for Purchase From People Who...

  9. 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

  10. RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy.

    PubMed

    Nakayama, Tojo; Saitsu, Hirotomo; Endo, Wakaba; Kikuchi, Atsuo; Uematsu, Mitsugu; Haginoya, Kazuhiro; Hino-fukuyo, Naomi; Kobayashi, Tomoko; Iwasaki, Masaki; Tominaga, Teiji; Kure, Shigeo; Matsumoto, Naomichi

    2014-06-01

    Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9 months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be within RBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case. PMID:23958593

  11. A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome.

    PubMed

    Hannes, Femke; Hammond, Peter; Quarrell, Oliver; Fryns, Jean-Pierre; Devriendt, Koenraad; Vermeesch, Joris R

    2012-05-01

    It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1-2). Here, we identify a 432 kb deletion located 600 kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR1-2 increasing the phenotypic expression. PMID:22438245

  12. CDC73 Intragenic Deletion in Familial Primary Hyperparathyroidism Associated With Parathyroid Carcinoma

    PubMed Central

    Korpi-Hyövälti, Eeva; Cranston, Treena; Ryhänen, Eeva; Arola, Johanna; Aittomäki, Kristiina; Sane, Timo; Thakker, Rajesh V.

    2014-01-01

    Context: CDC73 mutations frequently underlie the hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism (FIHP), and parathyroid carcinoma. It has also been suggested that CDC73 deletion analysis should be performed in those patients without CDC73 mutations. Objective: To investigate for CDC73 deletion in a family with FIHP previously reported not to have CDC73 mutations. Patients and Methods: Eleven members (six affected with primary hyperparathyroidism and five unaffected) were ascertained from the family, and multiplex ligation-dependent probe amplification was performed to detect CDC73 deletion using leukocyte DNA. Results: A previously unreported deletion of CDC73 involving exons 1–10 was detected in five affected members and two unaffected members who were 26 and 39 years of age. Two affected members had parathyroid carcinomas at the ages of 18 and 32 years, and they had Ki-67 proliferation indices of 5 and 14.5% and did not express parafibromin, encoded by CDC73. Primary hyperparathyroidism in the other affected members was due to adenomas and atypical adenomas, and none had jaw tumors. Two affected members had thoracic aortic aneurysms, which in one member occurred with parathyroid carcinoma and renal cysts. Conclusion: A previously unreported intragenic deletion of exons 1 to 10 of CDC73 was detected in a three-generation family with FIHP, due to adenomas, atypical adenomas, and parathyroid carcinomas. In addition, two affected males had thoracic aortic aneurysms, which may represent another associated clinical feature of this disorder. PMID:24823466

  13. Identification and characterization of three large deletions and a deletion/polymorphism in the CFTR gene.

    PubMed

    Chevalier-Porst, F; Souche, G; Bozon, D

    2005-05-01

    Cystic fibrosis (CF) is mainly caused by small molecular lesions of the CFTR gene; mutation detection methods based on conventional PCR do not allow the identification of all CF alleles in a population and large deletions may account for a number of these unidentified molecular lesions. It is only recently that the availability of quantitative PCR methodologies made the search for large gene rearrangements easier in autosomal diseases. Using a combination of different methods, nine of the 37 unidentified CF alleles (24%) were found to harbor large deletions in our cohort of 1600 CF alleles. Three are new deletions, and we report the breakpoints of the previously described EX4_EX10del40kb deletion. An intronic deletion polymorphism affecting intron 17b was also found on almost 1% of "normal" chromosomes. Examination of the breakpoint sequences confirmed that intron 17b is indeed a hot spot for deletions, and that most of these rearrangements are caused by non-homologous recombination. PMID:15841482

  14. 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

  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. Deletion and duplication within the p11.2 region of chromosome 17

    SciTech Connect

    McCorquodale, D.J.; McCorquodale, M.; Bereziouk, O.

    1994-09-01

    A 7 1/2-year-old male patient presented with mild mental retardation, speech delay, hyperactivity, behavioral problems, mild facial hypoplasia, short broad hands, digital anomalies, and self-injurious behavior. Chromosomes obtained from peripheral blood cells revealed a deletion of 17p11.2 in about 40% of the metaphases examined, suggesting that the patient had Smith-Magenis Syndrome. A similar pattern of mosaicism in peripheral blood cells, but not in fibroblasts in which all cells displayed the deletion, has been previously reported. Since some cases of Smith-Magenis Syndrome have a deletion that extends into the region associated with Charcot-Marie-Tooth (CMT) Syndrome, we examined interphase cells with a CMT1A-specific probe by the method of fluorescence in situ hybridization. The CMT1A region was not deleted, but about 40% of the cells gave signals indicating a duplication of the CMT1A region. The patient has not presented neuropathies associated with CMT at this time. Future tracking of the patient should be informative.

  17. 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…

  18. 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…

  19. 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,...

  20. 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…

  1. 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. PMID:22190018

  2. Limits to the role of palindromy in deletion formation.

    PubMed Central

    Weston-Hafer, K; Berg, D E

    1991-01-01

    We tested the effect of palindromy on deletion formation. This involved a study of reversion of insertion mutations in the pBR322 amp gene at a site where deletions end either in 9-bp direct repeats or in adjoining 4-bp direct repeats. Inserts of palindromic DNAs ranging from 10 to more than 26 bp and related nonpalindromic DNAs were compared. The frequency of deletions (selected as Ampr revertants) was stimulated by palindromy only at lengths greater than 26 bp. The 4-bp direct repeats, one component of which is located in the palindromic insert, were used preferentially as deletion endpoints with palindromes of at least 18 bp but not of 16 or 10 bp. We interpret these results with a model of slippage during DNA replication. Because deletion frequency and deletion endpoint location depend differently on palindrome length, we propose that different factors commit a molecule to undergo deletion and determine exactly where deletion endpoints will be. PMID:1846137

  3. 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.

  4. Acute Megakaryoblastic Leukemia with Myelodysplasia-related Changes Associated with ATM Gene Deletion.

    PubMed

    Ureshino, Hiroshi; Tanabe, Momoka; Kurogi, Kazuya; Miyahara, Masaharu; Kimura, Shinya

    2016-01-01

    Ataxia telangiectasia mutated (ATM) is a tumor suppressor gene, and its somatic inactivation plays a role in the pathogenesis of lymphoid malignancies. However, the role of ATM in patients with myeloid malignancies is still unknown. We herein report a case of acute megakaryoblastic leukemia (AMKL) with ATM gene deletion. An 84-year-old Japanese woman presenting with a pale face and pancytopenia was admitted to our institution and diagnosed to have AMKL with ATM gene deletion. She was treated with intravenous azacitidine. The azacitidine treatment was effective for approximately 1 year. Somatic inactivation of the ATM gene may therefore be involved in the pathogenesis of AMKL. PMID:27301517

  5. 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

  6. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.

    PubMed

    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

    2016-08-01

    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

  7. Clinical comparison of 10q26 overlapping deletions: delineating the critical region for urogenital anomalies.

    PubMed

    Vera-Carbonell, Ascensión; López-González, Vanesa; Bafalliu, Juan Antonio; Ballesta-Martínez, María J; Fernández, Asunción; Guillén-Navarro, Encarna; López-Expósito, Isabel

    2015-04-01

    The 10q26 deletion syndrome is a clinically heterogeneous disorder. The most common phenotypic characteristics include pre- and/or postnatal growth retardation, microcephaly, developmental delay/intellectual disability and a facial appearance consisting of a broad nasal bridge with a prominent nose, low-set malformed ears, strabismus, and a thin vermilion of the upper lip. In addition, limb and cardiac anomalies as well as urogenital anomalies are occasionally observed. In this report, we describe three unrelated females with 10q26 terminal deletions who shared clinical features of the syndrome, including urogenital defects. Cytogenetic studies showed an apparently de novo isolated deletion of the long arm of chromosome 10, with breakpoints in 10q26.1, and subsequent oligo array-CGH analysis confirmed the terminal location and defined the size of the overlapping deletions as ∼ 13.46, ∼ 9.31 and ∼ 9.17 Mb. We compared the phenotypic characteristics of the present patients with others reported to have isolated deletions and we suggest that small 10q26.2 terminal deletions may be associated with growth retardation, developmental delay/intellectual disability, craniofacial features and external genital anomalies whereas longer terminal deletions affecting the 10q26.12 and/or 10q26.13 regions may be responsible for renal/urinary tract anomalies. We propose that the haploinsufficiency of one or several genes located in the 10q26.12-q26.13 region may contribute to the renal or urinary tract pathogenesis and we highlight the importance of FGFR2 and probably of CTBP2 as candidate genes. PMID:25655674

  8. 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.

  9. 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

  10. 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

  11. 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 ...

  12. 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 ...

  13. 76 FR 14942 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-18

    ..., XRAW7M8 USPFO Activity IA ARNG, Johnston, IA. ] Deletions On 1/21/2011 (76 FR 3879-3880), the Committee... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Additions and Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletions from...

  14. Human Diallelic Insertion/Deletion Polymorphisms

    PubMed Central

    Weber, James L.; David, Donna; Heil, Jeremy; Fan, Ying; Zhao, Chengfeng; Marth, Gabor

    2002-01-01

    We report the identification and characterization of 2,000 human diallelic insertion/deletion polymorphisms (indels) distributed throughout the human genome. Candidate indels were identified by comparison of overlapping genomic or cDNA sequences. Average confirmation rate for indels with a ⩾2-nt allele-length difference was 58%, but the confirmation rate for indels with a 1-nt length difference was only 14%. The vast majority of the human diallelic indels were monomorphic in chimpanzees and gorillas. The ratio of deletion:insertion mutations was 4.1. Allele frequencies for the indels were measured in Europeans, Africans, Japanese, and Native Americans. New alleles were generally lower in frequency than old alleles. This tendency was most pronounced for the Africans, who are likely to be closest among the four groups to the original modern human population. Diallelic indels comprise ∼8% of all human polymorphisms. Their abundance and ease of analysis make them useful for many applications. PMID:12205564

  15. Deletion of Fanca or Fancd2 dysregulates Treg in mice

    PubMed Central

    Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

    2014-01-01

    Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

  16. 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. PMID:23860047

  17. 78 FR 37525 - Procurement List; Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-21

    ... . SUPPLEMENTARY INFORMATION: Deletions On 4/12/2013 (78 FR 21916); 4/26/2013 (78 FR 24732-24733); 5/3/2013 (78 FR 25970-25971); and 5/10/2013 (78 FR 27368-27369), the Committee for Purchase From People Who Are Blind or..., Black NSN: 7530-01-587-8929L--DAYMAX System, 2012, JR Deluxe Planner, 6- hole, Black w/logo NSN:...

  18. 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.

  19. Conditional Deletion of Pten Causes Bronchiolar Hyperplasia

    PubMed Central

    Davé, Vrushank; Wert, Susan E.; Tanner, Tiffany; Thitoff, Angela R.; Loudy, Dave E.; Whitsett, Jeffrey A.

    2008-01-01

    Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that regulates multiple cellular processes including cell polarity, migration, proliferation, and carcinogenesis. In this work, we demonstrate that conditional deletion of Pten (PtenΔ/Δ) in the respiratory epithelial cells of the developing mouse lung caused epithelial cell proliferation and hyperplasia as early as 4 to 6 weeks of age. While bronchiolar cell differentiation was normal, as indicated by β-tubulin and FOXJ1 expression in ciliated cells and by CCSP expression in nonciliated cells, cell proliferation (detected by expression of Ki-67, phospho-histone-H3, and cyclin D1) was increased and associated with activation of the AKT/mTOR survival pathway. Deletion of Pten caused papillary epithelial hyperplasia characterized by a hypercellular epithelium lining papillae with fibrovascular cores that protruded into the airway lumens. Cell polarity, as assessed by subcellular localization of cadherin, β-catenin, and zonula occludens-1, was unaltered. PTEN is required for regulation of epithelial cell proliferation in the lung and for the maintenance of the normal simple columnar epithelium characteristics of bronchi and bronchioles. PMID:17921358

  20. Carboxyl terminal deletion analysis of tryptophan hydroxylase.

    PubMed

    Mockus, S M; Kumer, S C; Vrana, K E

    1997-10-17

    Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of serotonin and participates (in a non-rate-limiting fashion) in melatonin biosynthesis. In rabbit, TPH exists as a tetramer of four identical 51007 dalton (444 amino acids) protein subunits. An intersubunit binding domain responsible for tetramer formation of TPH was identified by assessing the role of a carboxyl terminal leucine heptad and 4-3 hydrophobic repeat. These repeats are conserved in all of the aromatic amino acid hydroxylases and have been shown to be required for the assembly of tyrosine hydroxylase tetramers. Polymerase chain reaction was utilized to create three TPH carboxyl terminal deletions (C delta8, C delta12 and C delta17) that sequentially remove members of the leucine heptad and 4-3 hydrophobic repeat. Each deletion and full-length recombinant TPH was expressed in bacteria to obtain soluble enzyme extracts for subsequent activity and structural analysis. It was found that removal of 8, 12 or 17 amino acids from the carboxyl terminus of TPH did not significantly alter enzymatic activity when compared to full-length recombinant TPH. However, the macromolecular structure of the deletions was dramatically affected as determined by dimeric and monomeric profiles on size exclusion chromatography. It can be concluded that amino acids 428-444 (the C-terminal 17 amino acids) comprise an intersubunit binding domain that is required for tetramer formation of TPH, but that tetramer assembly is not essential for full enzymatic activity. PMID:9392522

  1. 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

  2. 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

  3. MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions

    PubMed Central

    Garone, Caterina; Rubio, Juan Carlos; Calvo, Sarah E.; Naini, Ali; Tanji, Kurenai; DiMauro, Salvatore; Mootha, Vamsi K.; Hirano, Michio

    2014-01-01

    Objective To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA). Design Case report. Setting University hospitals. Patient A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility. Results Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase–deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions. Conclusions In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions. PMID:22964873

  4. Incidental Radiologic Findings in the 22q11.2 Deletion Syndrome

    PubMed Central

    Schmitt, J.E.; Yi, J.J.; Roalf, D.R.; Loevner, L.A.; Ruparel, K.; Whinna, D.; Souders, M.C.; McDonald-McGinn, D.M.; Yodh, E.; Vandekar, S.; Zackai, E.H.; Gur, R.C.; Emanuel, B.S.; Gur, R.E.

    2015-01-01

    Background and Purpose The 22q11.2 deletion syndrome is a common genetic microdeletion syndrome that results in cognitive delays and an increased risk of several psychiatric disorders, particularly schizophrenia. The current study investigates the prevalence of incidental neuroradiologic findings within this population and their relationships with psychiatric conditions. Materials and Methods Brain MR imaging from 58 individuals with 22q11.2 deletion syndrome was reviewed by board-certified radiologists by using standard clinical procedures. Intracranial incidental findings were classified into 8 categories and compared with a large typically developing cohort. Results The rate of incidental findings was significantly higher (P < .0001) in 22q11.2 deletion syndrome compared with typically developing individuals, driven by a high prevalence of cavum septum pellucidum (19.0%) and white matter abnormalities (10.3%). Both of these findings were associated with psychosis in 22q11.2 deletion syndrome. Conclusions Cavum septum pellucidum and white matter hyperintensities are significantly more prevalent in patients with the 22q11.2 deletion syndrome and may represent biomarkers for psychosis. PMID:24948496

  5. 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.

  6. 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.

  7. 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.

  8. Interstitial deletion of 6q25.2–q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss

    PubMed Central

    Nagamani, Sandesh Chakravarthy Sreenath; Erez, Ayelet; Eng, Christine; Ou, Zhishuo; Chinault, Craig; Workman, Laura; Coldwell, James; Stankiewicz, Pawel; Patel, Ankita; Lupski, James R; Cheung, Sau Wai

    2009-01-01

    Interstitial deletions of 6q are rare. We report a detailed clinical and molecular characterization of four patients with interstitial deletion involving 6q25. All of our patients presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. We determined the size, extent and genomic content of the deletions using high-density array-comparative genomic hybridization (a-CGH), and found that a common segment spanning 3.52 Mb within the 6q25.2–q25.3 region was deleted in all four cases. We hypothesize that a subset of genes in the commonly deleted region are dosage sensitive and that haploinsufficieny of these genes impairs normal development of the brain and hearing. PMID:19034313

  9. Delineation of a recognizable phenotype for the recurrent LCR22-C to D/E atypical 22q11.2 deletion.

    PubMed

    Bengoa-Alonso, Amaya; Artigas-López, Mercè; Moreno-Igoa, María; Cattalli, Claudio; Hernández-Charro, Blanca; Ramos-Arroyo, Maria Antonia

    2016-06-01

    The 22q11.2 deletion syndrome is typically caused by haploinsufficiency of a 3 Mb region that extends from LCR22-A until LCR22-D, while the recurrent recombination between any of the LCR22-D to H causes the 22q11.2 distal deletion syndrome. Here, we describe three patients with a de novo atypical ∼1.4 Mb 22q11.2 deletion that involves LCR22-C to a region beyond D (LCR22-C to D/E), encompassing the distal portion of the typical deleted region and the proximal portion of the distal deletion. We also review six previous published patients with the same rearrangement and compare their features with those found in patients with overlapping deletions. Patients with LCR22-C to D/E deletion present a recognizable phenotype characterized by facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay. Genotype-phenotype analysis of the patients indicates that CRKL and MAPK1 genes play an important role as causative factors for the main clinical features of the syndrome. In particular, CRKL gene seems to be involved in the occurrence of conotruncal cardiac anomalies, mainly tetralogy of Fallot. © 2016 Wiley Periodicals, Inc. PMID:26991864

  10. 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.

  11. High Prevalence of the BIM Deletion Polymorphism in Young Female Breast Cancer in an East Asian Country

    PubMed Central

    Lin, Ching-Hung; Shen, Chen-Yang; Lee, Jih-Hsiang; Huang, Chiun-Sheng; Yang, Chih-Hsin; Kuo, Wen-Hung; Chang, Dwan-Ying; Hsiung, Chia-Ni; Kuo, Kuan-Ting; Chen, Wei-Wu; Chen, I-Chun; Wu, Pei-Fang; Kuo, Sung-Hsin; Chen, Chien-Jen

    2015-01-01

    Background A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians. Method Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs. Results Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort. Conclusions BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians. PMID:25909194

  12. 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.

  13. 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.

  14. ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy.

    PubMed

    Nishigaki, Yutaka; Marti, Ramon; Hirano, Michio

    2004-01-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive multisystem disorder associated with depletion, multiple deletions and site-specific point mutations of mitochondrial DNA (mtDNA). MNGIE is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP; endothelial cell growth factor 1). Deficiency of TP leads to dramatically elevated levels of circulating thymidine and deoxyuridine. The alterations of pyrimidine nucleoside metabolism are hypothesized to cause imbalances of mitochondrial nucleotide pools that, in turn, may cause somatic alterations of mtDNA. We have now identified five major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. While direct repeats and imperfectly homologous sequences appear to mediate the formation of mtDNA deletions, the nicotinamide adenine dinucleotide dehydrogenase 5 gene is a hot-spot for these rearrangements. A novel aspect of the mtDNA deletions in MNGIE is the presence of microdeletions at the imperfectly homologous breakpoints. PMID:14613972

  15. 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

  16. Deletion in the FMR1 gene in a fragile-X male

    SciTech Connect

    Mannermaa, A.; Pulkkinen, L.; Kajanoja, E.

    1996-08-09

    The pathogenesis of fragile-X syndrome is a consequence of absence of the FMR1 gene product associated with expansion of the CGG repeat and abnormal methylation of this and a CpG island 250 hp proximal to the CGG repeat located at exon 1 in the FMR1 gene. While this is usually the case, some suspected fragile-X syndrome patients have been described with a mutation other than CGG expansion. We describe here an affected fragile-X male, who was found to be mosaic of a full mutation of the CGG expansion and a deletion in the FMR1 gene. The patient`s phenotype is probably mainly due to the effect of the full mutation of the repeat sequence. Thus, the influence of the deletion is difficult to evaluate. 20 refs., 2 figs.

  17. 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

  18. [Genetic and clinical characteristics of 22q11.2 deletion syndrome].

    PubMed

    Kozlova, Iu O; Zabnenkova, V V; Shilova, N V; Min'zhenkova, M E; Antonenko, V G; Kotlukova, N P; Simonova, L V; Kazanceva, I A; Levchenko, E G; Bombardirova, T D; Zolotukhina, T V; Poliakov, A V

    2014-05-01

    In a group of 140 patients with typical phenotype, the 22q11.2 microdeletion was detected in 43 patients (32%) using FISH and MLPA methods. There were no deletions of other chromosomal loci leading to phenotypes similar to the 22q11.2 deletion syndrome (22q11.2DS). Sequencing of the TBX1 gene did not detect any mutations, except for some common neutral polymorphisms. For the first time in the Russian Federation, the diagnostic efficiency of 22q11.2DS appeared to be 32%, as a result of the application of a combination of genetic approaches for a large group of patients with suspected 22q11.2DS. PMID:25715476

  19. A New Case of an Extremely Rare 3p21.31 Interstitial Deletion.

    PubMed

    Lovrecic, Luca; Bertok, Sara; Žerjav Tanšek, Mojca

    2016-05-01

    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

  20. A FISH approach to defining the extent and possible clinical significance of deletions at the WAGR locus.

    PubMed Central

    Crolla, J A; Cawdery, J E; Oley, C A; Young, I D; Gray, J; Fantes, J; van Heyningen, V

    1997-01-01

    Nineteen patients were analysed by fluorescence in situ hybridisation (FISH) with selected 11p13 markers. They were examined because they had either isolated sporadic or familial aniridia, or aniridia with one or more of the WAGR (Wilms' tumour, aniridia, genital anomalies, and mental retardation) syndrome anomalies. The FISH markers from distal 11p13 were cosmids FO2121, PAX6 (aniridia), D11S324, and WT1 (Wilms' tumour predisposition). Two of the patients with isolated aniridia were abnormal, one with an apparently balanced reciprocal 7;11 translocation and an 11p13 breakpoint, which by FISH was shown to be approximately 30 kb distal to the aniridia (PAX6) gene, and the other had a submicroscopic deletion involving part of PAX6 that extended distally for approximately 245 kb. Two patients with aniridia together with other WAGR malformations had deletions involving all four cosmids. One case with aniridia associated with developmental and growth delay had a deletion including FO2121 and PAX6 but not D11S324 and WT1, while in a further case the deletion included all four test cosmids. These studies show that a combined conventional and molecular cytogenetic approach to patients presenting with aniridia is a useful method for differentiating between those with deletions extending into and including WT1 and therefore between those with high and low risks of developing Wilms' tumour. Images PMID:9132491

  1. 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

  2. On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis.

    PubMed Central

    Grimm, T; Meng, G; Liechti-Gallati, S; Bettecken, T; Müller, C R; Müller, B

    1994-01-01

    We present the results of a study of the rate and origin of mutations in Duchenne muscular dystrophy (DMD). Depending on the type of mutation (deletion/duplication or point mutation) present in the patient, there are widely varying ratios of male to female mutation rates. In deletions, the male mutation rate is only 30% of the female one. In non-deletional/non-duplicational mutations (presumably containing a high proportion of point mutations) the male mutation rate is at least 2.2 as high as the female one and probably much higher. Allowing for the presence of autosomal recessive phenocopies we find that k in non-deletional/non-duplicational mutations is 40.3. These findings mean that the vast majority of deletions arise in oogenesis, while most point mutations stem from spermatogenesis. Previous investigations have shown that in other diseases and genes, most notably haemophilia B and A, but also the ZFY and ZFX genes, the male mutation rate for point mutations tends to be higher than the female one. Our results can be seen as a confirmation of this for the special case of DMD. The influence on risk figures is considerable. As an example, the risk of the mother of an isolated case of DMD without an apparent structural anomaly of the gene of being a carrier increases from 67% to at least 76%. Given the estimate of 40.3 for k, allowing for the presence of autosomal recessive phenocopies mentioned above, it increases even further to 98%. However, as confidence intervals are still large, more data are needed to improve the estimates. Germinal mosaicism in this context is discussed. PMID:8014964

  3. Deletions in the VPS13B (COH1) gene as a cause of Cohen syndrome.

    PubMed

    Balikova, I; Lehesjoki, A-E; de Ravel, T J L; Thienpont, B; Chandler, K E; Clayton-Smith, J; Träskelin, A-L; Fryns, J-P; Vermeesch, J R

    2009-09-01

    Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation. PMID:19533689

  4. 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

  5. Germ-line deletion in DICER1 revealed by a novel MLPA assay using synthetic oligonucleotides.

    PubMed

    Sabbaghian, Nelly; Srivastava, Archana; Hamel, Nancy; Plourde, François; Gajtko-Metera, Malgorzata; Niedziela, Marek; Foulkes, William D

    2014-04-01

    DICER1 is an endoribonuclease responsible for the production of mature microRNAs which are small, single-stranded RNA molecules that regulate gene expression post-transcriptionally by binding to mRNA and repressing the expression of target genes. Germ-line mutations in DICER1 are responsible for a rare cancer syndrome, including tumors that can co-occur with multinodular goiter (MNG). Using Sanger sequencing, we screened all DICER1 exons and intron boundaries in 20 suspected mutation carriers: nine with ovarian sex cord-stromal tumors (including Sertoli-Leydig cell tumors (SLCTs)), five with pleuropulmonary blastoma, one with cystic nephroma, one with nasal chondromesenchymal hamartoma and four with more than one manifestation suggestive of a germ-line DICER1 mutation. All were negative for any apparently deleterious variants. We developed a Multiplex Ligation-based Probe Amplification assay for DICER1 to screen for large deletions or duplications. Synthetic oligonucleotides were designed to cover all exons in three probe-mixes. In a child with a SLCT and MNG, and in her mother and brother (both diagnosed with MNG), we identified a heterozygous germ-line deletion of approximately 3 kilobases that eliminates exon 21 of DICER1 and two-thirds of intron 21, accompanied by an insertion of a G nucleotide at the 3' end of the deletion (c.3270-6_4051-1280delinsG). This allele is expressed in the patient's cDNA, creating an out-of-frame deletion predicted to result in a truncated protein (r.3270_4050del; p.Tyr1091Ser*28). Our novel finding of a disease-causing large deletion in DICER1 emphasizes the need to include assays that can detect rearrangements, duplications and deletions in any DICER1 screening protocol. PMID:24065110

  6. Germ-line deletion in DICER1 revealed by a novel MLPA assay using synthetic oligonucleotides

    PubMed Central

    Sabbaghian, Nelly; Srivastava, Archana; Hamel, Nancy; Plourde, François; Gajtko-Metera, Malgorzata; Niedziela, Marek; Foulkes, William D

    2014-01-01

    DICER1 is an endoribonuclease responsible for the production of mature microRNAs which are small, single-stranded RNA molecules that regulate gene expression post-transcriptionally by binding to mRNA and repressing the expression of target genes. Germ-line mutations in DICER1 are responsible for a rare cancer syndrome, including tumors that can co-occur with multinodular goiter (MNG). Using Sanger sequencing, we screened all DICER1 exons and intron boundaries in 20 suspected mutation carriers: nine with ovarian sex cord-stromal tumors (including Sertoli–Leydig cell tumors (SLCTs)), five with pleuropulmonary blastoma, one with cystic nephroma, one with nasal chondromesenchymal hamartoma and four with more than one manifestation suggestive of a germ-line DICER1 mutation. All were negative for any apparently deleterious variants. We developed a Multiplex Ligation-based Probe Amplification assay for DICER1 to screen for large deletions or duplications. Synthetic oligonucleotides were designed to cover all exons in three probe-mixes. In a child with a SLCT and MNG, and in her mother and brother (both diagnosed with MNG), we identified a heterozygous germ-line deletion of approximately 3 kilobases that eliminates exon 21 of DICER1 and two-thirds of intron 21, accompanied by an insertion of a G nucleotide at the 3′ end of the deletion (c.3270-6_4051-1280delinsG). This allele is expressed in the patient's cDNA, creating an out-of-frame deletion predicted to result in a truncated protein (r.3270_4050del; p.Tyr1091Ser*28). Our novel finding of a disease-causing large deletion in DICER1 emphasizes the need to include assays that can detect rearrangements, duplications and deletions in any DICER1 screening protocol. PMID:24065110

  7. Marker and real-time quantitative analyses to confirm hemophilia B carrier diagnosis of a complete deletion of the F9 gene.

    PubMed

    Venceslá, Adoración; Barceló, María Jesús; Baena, Manel; Quintana, Manuel; Baiget, Montserrat; Tizzano, Eduardo F

    2007-11-01

    Approximately 3% of hemophilia B patients have major deletions in the F9 gene, half of which are complete. Marker and quantitative PCR analyses were employed for carrier diagnosis in a family of a mentally retarded hemophilia B patient with a total deletion of the F9 gene and neighbor genes. Both methodologies allowed the confirmation of carrier or non-carrier status. PMID:18024414

  8. 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.

  9. 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.

  10. 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.

  11. Gastrointestinal malignancies harbor actionable MET exon 14 deletions

    PubMed Central

    Hong, Mineui; Kim, Sun Young; Jang, Jiryeon; Ahn, Soomin; Kang, So Young; Lee, Sujin; Kim, Seung Tae; Kim, Bogyou; Choi, Jaehyun; Kim, Kyung-Ah; Lee, Jiyun; Park, Charny; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Keunchil; Park, Young Suk; Kim, Kyoung-Mee

    2015-01-01

    Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies. PMID:26375439

  12. Group II Intron-Anchored Gene Deletion in Clostridium

    PubMed Central

    Jia, Kaizhi; Zhu, Yan; Zhang, Yanping; Li, Yin

    2011-01-01

    Clostridium plays an important role in commercial and medical use, for which targeted gene deletion is difficult. We proposed an intron-anchored gene deletion approach for Clostridium, which combines the advantage of the group II intron “ClosTron” system and homologous recombination. In this approach, an intron carrying a fragment homologous to upstream or downstream of the target site was first inserted into the genome by retrotransposition, followed by homologous recombination, resulting in gene deletion. A functional unknown operon CAC1493–1494 located in the chromosome, and an operon ctfAB located in the megaplasmid of C. acetobutylicum DSM1731 were successfully deleted by using this approach, without leaving antibiotic marker in the genome. We therefore propose this approach can be used for targeted gene deletion in Clostridium. This approach might also be applicable for gene deletion in other bacterial species if group II intron retrotransposition system is established. PMID:21304965

  13. Assessing Trace Evidence Left by Secure Deletion Programs

    NASA Astrophysics Data System (ADS)

    Burke, Paul; Craiger, Philip

    Secure deletion programs purport to permanently erase files from digital media. These programs are used by businesses and individuals to remove sensitive information from media, and by criminals to remove evidence of the tools or fruits of illegal activities. This paper focuses on the trace evidence left by secure deletion programs. In particular, five Windows-based secure deletion programs are tested to determine if they leave identifiable signatures after deleting a file. The results show that the majority of the programs leave identifiable signatures. Moreover, some of the programs do not completely erase file metadata, which enables forensic investigators to extract the name, size, creation date and deletion date of the "deleted" files.

  14. Hepatitis B virus: DNA polymerase activity of deletion mutants.

    PubMed

    Kim, Y; Hong, Y B; Jung, G

    1999-02-01

    The hepadnavirus P gene product is a multifunctional protein with priming, DNA- and RNA-dependent DNA polymerase, and RNase H activities. Nested N- or C-terminal deletion mutations and deletions of domain(s) in human HBV polymerase have been made. Wild-type and deletion forms of MBP-fused HBV polymerase were expressed in E. coli, purified by amylose column chromatography, and the DNA-dependent DNA polymerase activities of the purified proteins were compared. Deletion of the terminal protein or spacer regions reduced enzyme activity to 70%, respectively. However, deletion of the RNase H domain affected polymerase activity more than that of the terminal protein or spacer region. The polymerase domain alone or the N-terminal deletion of the polymerase domain still exhibited enzymatic activity. In this report, it is demonstrated that the minimal domain for the polymerizing activity of the HBV polymerase is smaller than the polymerase domain. PMID:10205676

  15. 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%) o