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1

Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter.  

PubMed

Telomeres are gene rich regions with a high recombination rate. Cryptic subtelomeric rearrangements are estimated to account for 5% of mental retardation/malformation syndromes. Here we present the first patient with a deletion of 19p13.3, identified by subtelomeric FISH analysis. His features included a distinctive facial appearance, cleft palate, hearing impairment, congenital heart malformation, keloid scarring, immune dysregulation, and mild learning difficulties. Subtelomeric FISH analysis identified a deletion of 19p13.3-pter. The deletion size was determined to be 1.2 Mb by FISH analysis. It extended from within the chromosomal region covered by BAC RP11-50C6 to 19pter. The deleted area encompassed approximately 60 genes. Fifteen possible candidate genes were considered with respect to the phenotype, including follistatin-related precursor 3 (FSTL3) and serine-threonine kinase 11 (STK-11). PMID:15937949

Archer, H L; Gupta, S; Enoch, S; Thompson, P; Rowbottom, A; Chua, I; Warren, S; Johnson, D; Ledbetter, D H; Lese-Martin, C; Williams, P; Pilz, D T

2005-07-01

2

Prenatal exclusion of subtelomeric deletion 1p by fluorescent in situ hybridization  

Microsoft Academic Search

Background  Subtelomeric deletion 1p is difficult to detect from banded karyotypes. Recent developments in the field of molecular cytogenetics\\u000a have made it possible for submicroscopic rearrangements within chromosomes to be detected using fluorescence in situ hybridization\\u000a (FISH) techniques.\\u000a \\u000a \\u000a \\u000a Materials and methods  We describe prenatal FISH testing of subtelomeric 1p deletion in a fetus of a mother whose previous child had subtelomeric\\u000a 1p

Vorapong Phupong; Verayuth Praphanphoj; Vorasuk Shotelersuk

2007-01-01

3

16p subtelomeric duplication: a clinically recognizable syndrome.  

PubMed

We report on two patients with duplication of the subterminal region of chromosome 16p (dup16p) recognized by fluorescent in situ hybridization (FISH) telomere analysis, presenting with closely overlapping facial features and neurological impairment. Distinct facial anomalies included high forehead, sparse eyebrows, blepharophimosis, short nose, everted upper lip, high-arched palate, wide-spaced teeth, and cupped anteverted ears. Susceptibility to vascular anomalies, in particular pulmonary hypertension and portal cavernoma, was found in one patient. Subtelomeric analysis by FISH demonstrated a de novo duplication of the subtelomeric region of chromosome 16p and a deletion of the subtelomeric region of chromosome 4q in case 1, and duplication of the subtelomeric region of 16p and a deletion of the subtelomeric region of 21q, resulting from malsegregation of a balanced maternal traslocation t(16pter;21qter) in case 2. The extension of duplicated regions measured by array-comparative genome hybridization was about 12 Mb on 16p13.3p13.13 in case 1, and about 8.5 Mb on 16p13.3p13.2 in case 2. In conclusion, we reported a clinically recognizable disorder in two patients with dup16p. Pulmonary hypertension, vascular ring, and manifestations of vascular disruption, as terminal hypoplasia of hands and aplasia cutis, have been previously described in association with dup16p. Thus, susceptibility to pulmonary vascular disease and other vascular anomalies can be a feature of dup16p, suggesting that this subtelomeric region in some respect could be related to vascular anomalies. PMID:19293839

Digilio, Maria Cristina; Bernardini, Laura; Capalbo, Anna; Capolino, Rossella; Gagliardi, Maria Giulia; Marino, Bruno; Novelli, Antonio; Dallapiccola, Bruno

2009-03-18

4

Cryptic subtelomeric 6p deletion in a girl with congenital malformations and severe language impairment  

Microsoft Academic Search

Several cases with microscopically visible, terminal 6p deletions have been described, and a distinct clinical phenotype has emerged, including developmental delay, congenital heart malformations, ocular abnormalities, hearing loss and a characteristic facial appearance. We report a patient with a submicroscopic 6p deletion, detected by subtelomeric screening using fluorescence in situ hybridisation. This girl presented with typical facial dysmorphic features, hearing

Britt-Marie Anderlid; Jacqueline Schoumans; Åsa Hallqvist; Ylva Ståhl; Agneta Wallin; Elisabeth Blennow; Magnus Nordenskjöld; B-M Anderlid

2003-01-01

5

Analysis of myelodysplastic syndromes with complex karyotypes by high-resolution comparative genomic hybridization and subtelomeric CGH array.  

PubMed

Molecular cytogenetic techniques enabled us to clarify numerical and structural alterations previously detected by conventional cytogenetic techniques in 37 patients who had myelodysplastic syndromes with complex karyotypes. Using high-resolution comparative genomic hybridization (HR-CGH), we found the most recurrent alterations to be deletion of 5q (70%), 18q (35%), 7q (32%), 11q (30%), and 20q (24%), gain of 11q (35%) and 8q (24%), and trisomy of chromosome 8 (19%). Furthermore, in 35% of the patients, 20 amplifications were identified. These amplifications were shown by FISH to involve some genes previously described as amplified in hematological malignancies, such as ERBB2, MLL, and RUNX1. In addition, two other genes, BCL6 and BCL2, which are classically related to apoptosis and non-Hodgkin lymphoma, were shown for the first time to be involved in amplification. Genomic alterations involving different subtelomeric regions with losses in 4p16, 5p15.3, 6q27, 18p11.3, and 18q23 and gains in 1p36.3 and 19p13.3 were detected by HR-CGH. Array CGH analysis of the subtelomeric regions in some samples was able to confirm a number of these alterations and found some additional alterations not detected by conventional CGH. PMID:15611930

Martínez-Ramírez, Angel; Urioste, Miguel; Melchor, Lorenzo; Blesa, David; Valle, Laura; de Andrés, Sara Alvarez; Kok, Klaas; Calasanz, Maria José; Cigudosa, Juan Cruz; Benítez, Javier

2005-03-01

6

Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements  

PubMed Central

Chromosome rearrangements are a significant cause of intellectual disability and birth defects. Subtelomeric rearrangements, including deletions, duplications and translocations of chromosome ends, were first discovered over 40 years ago and are now recognized as being responsible for several genetic syndromes. Unlike the deletions and duplications that cause some genomic disorders, subtelomeric rearrangements do not typically have recurrent breakpoints and involve many different chromosome ends. To capture the molecular mechanisms responsible for this heterogeneous class of chromosome abnormality, we coupled high-resolution array CGH with breakpoint junction sequencing of a diverse collection of subtelomeric rearrangements. We analyzed 102 breakpoints corresponding to 78 rearrangements involving 28 chromosome ends. Sequencing 21 breakpoint junctions revealed signatures of non-homologous end-joining, non-allelic homologous recombination between interspersed repeats and DNA replication processes. Thus, subtelomeric rearrangements arise from diverse mutational mechanisms. In addition, we find hotspots of subtelomeric breakage at the end of chromosomes 9q and 22q; these sites may correspond to genomic regions that are particularly susceptible to double-strand breaks. Finally, fine-mapping the smallest subtelomeric rearrangements has narrowed the critical regions for some chromosomal disorders.

Luo, Yue; Hermetz, Karen E.; Jackson, Jodi M.; Mulle, Jennifer G.; Dodd, Anne; Tsuchiya, Karen D.; Ballif, Blake C.; Shaffer, Lisa G.; Cody, Jannine D.; Ledbetter, David H.; Martin, Christa L.; Rudd, M. Katharine

2011-01-01

7

Subtelomeric Deletion of Chromosome 10p15.3: Clinical Findings and Molecular Cytogenetic Characterization  

PubMed Central

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11,), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM# 608668) and DIP2C (OMIM# 611380) (UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.

DeScipio, Cheryl; Conlin, Laura; Rosenfeld, Jill; Tepperberg, James; Pasion, Romela; Patel, Ankita; McDonald, Marie T; Aradhya, Swaroop; Ho, Darlene; Goldstein, Jennifer; McGuire, Marianne; Mulchandani, Surabhi; Medne, Livija; Rupps, Rosemarie; Serrano, Alvaro H.; Thorland, Erik C; Tsai, Anne C-H; Hilhorst-Hofstee, Yvonne; Ruivenkamp, Claudia AL; Van Esch, Hilde; Addor, Marie-Claude; Martinet, Danielle; Mason, Thornton B.A.; Clark, Dinah; Spinner, Nancy B; Krantz, Ian D

2012-01-01

8

Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.  

PubMed

Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b(-/-) mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity. PMID:18558631

Yehezkel, Shiran; Segev, Yardena; Viegas-Péquignot, Evani; Skorecki, Karl; Selig, Sara

2008-06-16

9

Sequential deletion of all the polyketide synthase and nonribosomal peptide synthetase biosynthetic gene clusters and a 900-kb subtelomeric sequence of the linear chromosome of Streptomyces coelicolor.  

PubMed

Streptomyces coelicolor, with its 8 667 507-bp linear chromosome, is the genetically most studied Streptomyces species and is an excellent model for studying antibiotic production and cell differentiation. Here, we report construction of S. coelicolor derivatives containing sequential deletions of all the 10 polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) biosynthetic gene clusters and a 900-kb subtelomeric sequence (total c. 1.22 Mb, 14% of the genome). No obvious differences in growth rates and sporulation of the strains were found. An artificially circularized S. coelicolor genome with deletions of total c. 1.6 Mb segments (840-kb for the left and 761-kb for the right arm of the linear chromosome) was obtained. The actinorhodin biosynthetic gene cluster could be overexpressed in some of the constructed strains. PMID:22670631

Zhou, Min; Jing, Xinyun; Xie, Pengfei; Chen, Weihua; Wang, Tao; Xia, Haiyang; Qin, Zhongjun

2012-06-22

10

Two brothers with 22q13 deletion syndrome and features suggestive of the Clark-Baraitser syndrome.  

PubMed

We report on two brothers with moderate-to-severe mental retardation, severe macrocephaly, obesity, characteristic face, big hands and feet, advanced bone age and brain abnormalities, including frontal cortical atrophy. These two boys resembled the two brothers described by , two maternal cousins subsequently reported by and a Brazilian boy described by . Upon further investigation, we detected a cryptic subtelomeric deletion of chromosome region 22q13, not present in either parent and probably due to a maternal germinal mosaicism. Thus, we describe the first familial case of 22q13 deletion and recommend that patients with a phenotype suggestive of the so-called Clark-Baraitser syndrome be tested for submicroscopic 22qter deletion. PMID:15930901

Tabolacci, Elisabetta; Zollino, Marcella; Lecce, Rosetta; Sangiorgi, Eugenio; Gurrieri, Fiorella; Leuzzi, Vincenzo; Opitz, John M; Neri, Giovanni

2005-07-01

11

Alagille syndrome and deletion of 20p.  

PubMed Central

We add five cases of 20p deletion to the 10 cases already published. Four had craniofacial, vertebral, ocular, and cardiovascular features of Alagille syndrome, which adds weight to the assignment of this disorder to the short arm of chromosome 20. Included in our series is the first report of familial transmission of a 20p deletion. Images

Anad, F; Burn, J; Matthews, D; Cross, I; Davison, B C; Mueller, R; Sands, M; Lillington, D M; Eastham, E

1990-01-01

12

Alagille syndrome and deletion of 20p  

Microsoft Academic Search

We add five cases of 20p deletion to the 10 cases already published. Four had craniofacial, vertebral, ocular, and cardiovascular features of Alagille syndrome, which adds weight to the assignment of this disorder to the short arm of chromosome 20. Included in our series is the first report of familial transmission of a 20p deletion.

F Anad; J Burn; D Matthews; I Cross; B C Davison; R Mueller; M Sands; D M Lillington; E Eastham

1990-01-01

13

A case of an atypically large proximal 15q deletion as cause for Prader-Willi syndrome arising from a de novo unbalanced translocation.  

PubMed

We describe an 11 month old female with Prader-Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype. PMID:23856564

Hickey, Scott E; Thrush, Devon Lamb; Walters-Sen, Lauren; Reshmi, Shalini C; Astbury, Caroline; Gastier-Foster, Julie M; Atkin, Joan

2013-07-13

14

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist  

Microsoft Academic Search

BACKGROUNDSubmicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.METHODSWe studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital

B B A de Vries; S M White; S J L Knight; R Regan; T Homfray; I D Young; M Super; C McKeown; M Splitt; O W J Quarrell; A H Trainer; M F Niermeijer; S Malcolm; J Flint; J A Hurst; R M Winter

2001-01-01

15

Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome  

PubMed Central

Introduction The 22q13.3 deletion syndrome (MIM?606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. Methods The deletions were characterised by FISH, checked for other abnormalities by array?CGH, and confirmed by Real?Time PCR, and finally the breakpoints were cloned, sequenced, and compared. Results Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100?kb of chromosome 22q13.3. The cases show a breakpoint within the same 15?bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. Discussion Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.

Bonaglia, M C; Giorda, R; Mani, E; Aceti, G; Anderlid, B-M; Baroncini, A; Pramparo, T; Zuffardi, O

2006-01-01

16

Deletion 22q13.3 syndrome.  

PubMed

The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy). Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements. Individuals with deletion 22q13 should have routine examinations by the primary care physician as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. No apparent life-threatening organic abnormalities accompany the diagnosis of deletion 22q13. PMID:18505557

Phelan, Mary C

2008-05-27

17

Genetics Home Reference: 16p11.2 deletion syndrome  

MedlinePLUS

... Recent literature OMIM Genetic disorder catalog Conditions > 16p11.2 deletion syndrome On this page: Description Genetic changes ... Glossary definitions Reviewed November 2009 What is 16p11.2 deletion syndrome? 16p11.2 deletion syndrome is a ...

18

Human subtelomeric copy number variations  

Microsoft Academic Search

Copy number variation is a defining characteristic of human subtelomeres. Human subtelomeric segmental duplication regions (‘Subtelomeric Repeats’) comprise about 25% of the most distal 500 kb and 80% of the most distal 100 kb in human DNA. Huge allelic disparities seen in subtelomeric DNA sequence content and organization are postulated to have an impact on the dosage of transcripts embedded

H. Riethman

2008-01-01

19

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome  

Microsoft Academic Search

22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later\\u000a onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the\\u000a deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used\\u000a a real-time quantitative PCR

Rosanna Weksberg; Andrea C. Stachon; Jeremy A. Squire; Laura Moldovan; Jane Bayani; Stephen Meyn; Eva Chow; Anne S. Bassett

2007-01-01

20

Subtelomeric rearrangements in Polish subjects with intellectual disability and dysmorphic features  

Microsoft Academic Search

Fluorescent in situ hybridization (FISH) was performed in 76 patients referred to our department because of intellectual disability\\u000a and dysmorphic features that can be related to subtelomeric microaberrations. In all the patients, conventional cytogenetic\\u000a methods revealed normal karyotype. Four (5.3%) subtelomeric rearrangements were detected by FISH: 2 subtelomeric 1p36 deletions,\\u000a an unbalanced translocation involving chromosomes 1 and 12 with 1p36

J. Bogdanowicz; B. Paw?owska; A. Ilnicka; S. Gawlik-Zawi?lak; A. Jó?wiak; B. Sobiczewska; E. Zdzienicka; L. Korniszewski; J. Zaremba

2010-01-01

21

Large Deletions and Point Mutations Involving DOCK8 in the Autosomal Recessive Form of the Hyper-IgE Syndrome  

PubMed Central

Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60-70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining hyper-IgE syndrome patients, the genetic etiology has not yet been identified. Methods We performed genome-wide single nucleotide polymorphism analysis for nine subjects with autosomal recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with twelve subjects from seven additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal recessive hyper-IgE syndrome. Findings Subtelomeric microdeletions were identified in six subjects at the terminus of chromosome 9p. In all patients the deleted interval involved DOCK8, encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of subjects without large deletions revealed 16 patients from nine unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, single exon- and micro-deletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+ T cells. Interpretation Autosomal recessive mutations in DOCK8 are responsible for many, though not all, cases of autosomal recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T cell activation and TH17 cell differentiation; and impaired eosinophil homeostasis and dysregulation of IgE.

Engelhardt, Karin R.; McGhee, Sean; Winkler, Sabine; Sassi, Atfa; Woellner, Cristina; Lopez-Herrera, Gabriela; Chen, Andrew; Kim, Hong Sook; Lloret, Maria Garcia; Schulze, Ilka; Ehl, Stephan; Thiel, Jens; Pfeifer, Dietmar; Veelken, Hendrik; Niehues, Tim; Siepermann, Kathrin; Weinspach, Sebastian; Reisli, Ismail; Keles, Sevgi; Genel, Ferah; Kutukculer, Necil; Camcioglu, Yildiz; Somer, Ayper; Aydiner, Elif Karakoc; Barlan, Isil; Gennery, Andrew; Metin, Ayse; Degerliyurt, Aydan; Pietrogrande, Maria C.; Yeganeh, Mehdi; Baz, Zeina; Al-Tamemi, Salem; Klein, Christoph; Puck, Jennifer M.; Holland, Steven M.; McCabe, Edward R. B.; Grimbacher, Bodo; Chatila, Talal

2010-01-01

22

DiGeorge Syndrome\\/Velocardiofacial Syndrome: The Chromosome 22q11.2 Deletion Syndrome  

Microsoft Academic Search

\\u000a Chromosome 22q11.2 deletion (CH22qD) syndrome is also known as DiGeorge syndrome or velocardiofacial syndrome. This deletion\\u000a syndrome is extremely common with nearly one in 4000 children being affected. Recent advances and a holistic approach to patients\\u000a have improved the care and well-being of these patients. This review will summarize advances in understanding the health needs\\u000a and immune system of patients

Kathleen E. Sullivan

23

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.  

PubMed

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8?Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1. PMID:23073310

Leroy, Camille; Landais, Emilie; Briault, Sylvain; David, Albert; Tassy, Olivier; Gruchy, Nicolas; Delobel, Bruno; Grégoire, Marie-José; Leheup, Bruno; Taine, Laurence; Lacombe, Didier; Delrue, Marie-Ange; Toutain, Annick; Paubel, Agathe; Mugneret, Francine; Thauvin-Robinet, Christel; Arpin, Stéphanie; Le Caignec, Cedric; Jonveaux, Philippe; Beri, Mylène; Leporrier, Nathalie; Motte, Jacques; Fiquet, Caroline; Brichet, Olivier; Mozelle-Nivoix, Monique; Sabouraud, Pascal; Golovkine, Nathalie; Bednarek, Nathalie; Gaillard, Dominique; Doco-Fenzy, Martine

2012-10-17

24

Olfactory Disorder in Children With 22q11 Deletion Syndrome  

PubMed Central

OBJECTIVE 22q11 deletion syndrome, a common human interstitial deletion syndrome (1:5000), is associated with a heterogeneous physical phenotype, including several factors that markedly increase the risk for olfactory disorder. Despite its potential consequences, pediatric studies of impaired olfaction are rare, and odor detection in children with 22q11 deletion syndrome has not yet been examined. METHODS The University of Pennsylvania Smell Identification Test was administered to 62 children, including 39 with 22q11 deletion syndrome and 23 neurotypical control siblings who ranged in age from 5.3 to 14.8 years. Lowered smell detection accuracy among affected children was predicted. RESULTS Substantially more children with 22q11 deletion syndrome (68%) as compared with neurotypical control subjects (13%) had University of Pennsylvania Smell Identification Test scores ?2 SDs below the standardization sample mean. Frequency of impairment in younger versus older children did not differ. The score distributions of children with and without velopharyngeal insufficiency did not differ; however, markedly lower score variance among children with velopharyngeal insufficiency suggested its negative impact on olfaction. Posthoc error analyses revealed that affected children had special difficulty detecting smells that are associated with fumes and smoke. CONCLUSIONS Odor detection failures are ubiquitous among children with 22q11 deletion syndrome and are not associated with developmental delay or performance characteristics of younger affected children. Additional studies are needed to examine further the impact on olfaction of velopharyngeal insufficiency and compromised nasal airway patency. Children with 22q11 deletion syndrome should be evaluated routinely for olfactory disorder. When deficits are identified, caregivers should be warned of potential dangers that are associated with this type of sensory impairment.

Sobin, Christina; Kiley-Brabeck, Karen; Dale, Kathryn; Monk, Samantha H.; Khuri, Jananne; Karayiorgou, Maria

2009-01-01

25

Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter  

PubMed Central

Background Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. Methods We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. Results We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Conclusion Subtelomeric screening is a useful adjunct to conventional cytogenetic analyses, and should be considered in mentally retarded subjects with dysmorphic features and unknown cause.

Sogaard, Marie; Tumer, Zeynep; Hjalgrim, Helle; Hahnemann, Johanne; Friis, Birgitte; Ledaal, Paal; Pedersen, Vibeke Faurholt; Baekgaard, Peter; Tommerup, Niels; Cingoz, Sultan; Duno, Morten; Brondum-Nielsen, Karen

2005-01-01

26

Large SGCE deletion contributes to Taiwanese myoclonus-dystonia syndrome.  

PubMed

We report three novel deletions of the SGCE gene in three families with myoclonus-dystonia (M-D) syndrome in Taiwan. Their clinical characteristics included: early onset, dominant myoclonus and dystonia in the neck, trunk and upper limbs. By direct sequencing of the SGCE gene coding regions, we identified a small heterozygous deletion (c.842delA) in exon 7 of the three sibs and asymptomatic father in the first family and an eight-base heterozygous deletion (c.524_531del) in exon 5 of the mother and a daughter in the second family. Using multiple ligation-dependent probe amplification (MLPA), a large heterozygous deletion of 2-11 exons was identified in the father and a son in the third family which was undetected by initial sequencing. It is the largest intragenic deletion ever reported. In conclusion, we have identified three novel mutations of SGCE in the respective three M-D families. The large deletion was responsible for one third of these M-D families which might implicate an important contribution to Taiwanese M-D syndrome. We suggest that the contribution of large deletion should be further verified in a large cohort of patients with M-D syndrome in Han Chinese. PMID:20800530

Huang, Chia-Ling; Lan, Min-Yu; Chang, Yung-Yee; Hsu, Chia-Yu; Lai, Szu-Chia; Chen, Rou-Shayn; Chang, Hsiu-Chen; Lu, Chin-Song; Wu-Chou, Yah-Huei

2010-08-30

27

Narrowing the candidate region of Albright hereditary osteodystrophy-like syndrome by deletion mapping in a patient with an unbalanced cryptic translocation t(2;6)(q37.3;q26).  

PubMed

We here describe a submicroscopic translocation affecting the subtelomeric regions of chromosomes 2q and 6q identified in a patient referred to us because of mental retardation, obesity, brachydactyly, and short stature. FISH analysis using subtelomeric probes showed a 46,XY,der(2)t(2;6)(q37.3;q26) in the propositus, and a balanced t(2;6) in his father and sister. FISH with region-specific genomic clones made it possible to map the 2q37.3 breakpoint precisely to the region covered by BAC 585E12, and the 6q26 breakpoint to between the regions encompassed by 414A5 and 480A20. The 2q subtelomeric deletion has often been found in patients with Albright hereditary osteodystrophy (AHO)-like syndrome but, to the best of our knowledge, the 2q37.3-qter monosomy ascertained in our patient is the smallest so far described within the syndrome's critical interval, and may thus enhance the search for the responsible genes. PMID:12966529

Giardino, Daniela; Finelli, Palma; Gottardi, Giulietta; De Canal, Gabriella; Della Monica, Matteo; Lonardo, Fortunato; Scarano, Gioacchino; Larizza, Lidia

2003-10-15

28

Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation  

PubMed Central

Background Subtelomeric imbalance is widely accepted as related to developmental delay/mental retardation (DD/MR). Fine mapping of aberrations in gene-enriched subtelomeric regions provides essential clues for localizing critical regions, and provides a strategy for identifying new candidate genes. To date, no large-scale study has been conducted on subtelomeric aberrations in DD/MR patients in mainland China. Methods This study included 451 Chinese children with moderate to severe clinically unexplained DD/MR. The subtelomere-MLPA (multiplex ligation dependent probe amplification) and Affymetrix human SNP array 6.0 were used to determine the subtelomeric copy number variations. The exact size and the breakpoint of each identified aberration were well defined. Results The submicroscopic subtelomeric aberrations were identified in 23 patients, with a detection rate of 5.1%. 16 patients had simple deletions, 2 had simple duplications and 5 with both deletions and duplications. The deletions involved 14 different subtelomeric regions (1p, 2p, 4p, 6p, 7p, 7q, 8p, 9p, 10p, 11q, 14q, 15q, 16p and 22q), and duplications involved 7 subtelomeric regions (3q, 4p, 6q, 7p, 8p, 12p and 22q). Of all the subtelomeric aberrations found in Chinese subjects, the most common was 4p16.3 deletion. The sizes of the deletions varied from 0.6 Mb to 12 Mb, with 5-143 genes inside. Duplicated regions were 0.26 Mb to 11 Mb, with 6-202 genes inside. In this study, four deleted subtelomeric regions and one duplicated region were smaller than any other previously reported, specifically the deletions in 11q25, 8p23.3, 7q36.3, 14q32.33, and the duplication in 22q13. Candidate genes inside each region were proposed. Conclusions Submicroscopic subtelomeric aberrations were detected in 5.1% of Chinese children with clinically unexplained DD/MR. Four deleted subtelomeric regions and one duplicated region found in this study were smaller than any previously reported, which will be helpful for further defining the candidate dosage sensitive gene associated with DD/MR.

2010-01-01

29

Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay  

PubMed Central

Background Subtelomeric regions are gene rich and deletions in these chromosomal segments have been demonstrated to account for approximately 2.5% of patients displaying mental retardation with or without association of dysmorphic features. However, cases that report de novo terminal deletions on chromosome arm 15q are rare. Methods In this study we present the first example of a detailed molecular genetic mapping of a de novo deletion in involving 15q26.2-qter, caused by the formation of a dicentric chromosome 15, using metaphase FISH and tiling resolution (32 k) genome-wide array-based comparative genomic hybridization (CGH). Results After an initial characterization of the dicentric chromosome by metaphase FISH, array CGH analysis mapped the terminal deletion to encompass a 6.48 megabase (Mb) region, ranging from 93.86–100.34 Mb on chromosome 15. Conclusion In conclusion, we present an additional case to the growing family of reported cases with 15q26-deletion, thoroughly characterized at the molecular cytogenetic level. In the deleted regions, four candidate genes responsible for the phenotype of the patient could be delineated: IGFR1, MEF2A, CHSY1, and TM2D3. Further characterization of additional patients harboring similar 15q-aberrations might hopefully in the future lead to the description of a clear cut clinically recognizable syndrome.

Davidsson, Josef; Collin, Anna; Bjorkhem, Gudrun; Soller, Maria

2008-01-01

30

18q deletion syndrome - A case report  

PubMed Central

ABSTRACT We report on a 3 years old boy with severe mental retardation, hypotonia, deafness, cerebral dysmyelination, low levels of immunoglobulin A and dysmorphic features, bearing a distal deletion of 18q: 18q21-qter. Karyotype analysis by GTG banding was performed, revealing a deletion of the distal fragment of chromosome 18q, ranging from band q21 to qter, later confirmed by Fluorescence In Situ Hybridization (FISH). Whole chromosome painting for chromosome 18 ruled out any cryptic rearrangements involving other chromosomes. An attempted therapy with growth hormone did not bring any improvement and was discontinued due to an unexplained febrile episode and overall regress of the patient.

BUDISTEANU, Magdalena; ARGHIR, Aurora; CHIRIEAC, Sorina Mihaela; TUTULAN-CUNITA, Andreea; LUNGEANU, Agripina

2010-01-01

31

Array-CGH in a series of 30 patients with mental retardation, dysmorphic features, and congenital malformations detected an interstitial 1p22.2-p31.1 deletion in a patient with features overlapping the Goldenhar syndrome.  

PubMed

Genosensor Array 300 (Abbott) is a multiplex platform for array-based comparative genomic hybridization that detects unbalanced genomic aberrations including whole chromosome gains/losses, microdeletions, duplications and unbalanced subtelomeric rearrangements. A series of 30 patients with unexplained mental retardation, dysmorphic features, congenital abnormalities and normal high resolution karyotype and FISH subtelomeric studies were analyzed using Genosensor Array 300 array-CGH. We identified a chromosomal aberration in one patient with an interstitial 1p31.1 deletion. FISH analysis with BACs specific probes of the 1p region confirmed the interstitial 1p22.2-p31.1 deletion. The patient was a 20-year-old man with short stature, facial dysmorphism including asymmetry, scoliosis, severe psychomotor delay and an epibulbar dermoid cyst. The phenotype was compatible with Goldenhar syndrome despite the absence of asymmetric ears. This observation is of interest since it could be a clue in the search for the genes responsible for Goldenhar syndrome. This study demonstrates the utility of the array-CGH technology in detecting interstitial deletions. PMID:18629884

Callier, P; Faivre, L; Thauvin-Robinet, C; Marle, N; Mosca, A L; D'Athis, P; Guy, J; Masurel-Paulet, A; Joly, L; Guiraud, S; Teyssier, J R; Huet, F; Mugneret, F

2008-08-15

32

Co-occurrence of 22q11 deletion syndrome and hdr syndrome.  

PubMed

22q11 deletion syndrome is one of the most common chromosomal deletion syndromes and is usually caused by a 1.5-3.0?Mb deletion at chromosome 22q11.2. It is characterized by hypocalcemia resulting from hypoplasia of the parathyroid glands, hypoplasia of the thymus, and defects of the cardiac outflow tract. We encountered a Japanese boy presenting with an unusually severe phenotype of 22q11 deletion syndrome, including progressive renal failure and severe intellectual disabilities. Diagnostic testing using fluorescent in situ hybridization revealed deletion of the 22q11 region, but this did not explain the additional complications. Copy number analysis was therefore performed using whole genome single nucleotide polymorphism (SNP) assay, which identified an additional de novo deletion at 10p14. This region is the locus for hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome caused by haploinsufficiency of GATA3. Together, these two syndromes sufficiently explain the patient's phenotype. This is the first known case report of the co-occurrence of 22q11 deletion syndrome and HDR syndrome. As the two syndromes overlap clinically, this study indicates the importance of carrying out careful clinical and genetic assessment of patients with atypical clinical phenotypes or unique complications. Unbiased genetic analysis using whole genome copy number SNP arrays is especially useful for detecting such rare double mutations. © 2013 Wiley Periodicals, Inc. PMID:23918631

Fukai, Ryoko; Ochi, Nobuhiko; Murakami, Akira; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Matsumoto, Naomichi; Miyake, Noriko

2013-08-05

33

A deletion in chromosome 22 can cause digeorge syndrome  

Microsoft Academic Search

An association between DiGeorge's syndrome and an unbalanced chromosomal rearrangement leading to trisomy 20pter?20q11 and monosomy 22pter?22q11 was found in four individuals belonging to one family. These and other data from the literature are interpreted to suggest that DiGeorge's syndrome can be caused by deletion of a gene located in chromosome 22, probably in band 22q11.

Albert de la Chapelle; Riitta Herva; Maila Koivisto; Pertti Aula

1981-01-01

34

Proton Magnetic Resonance Spectroscopy in 22q11 Deletion Syndrome  

Microsoft Academic Search

ObjectivePeople with velo-cardio-facial syndrome or 22q11 deletion syndrome (22q11DS) have behavioral, cognitive and psychiatric problems. Approximately 30% of affected individuals develop schizophrenia-like psychosis. Glutamate dysfunction is thought to play a crucial role in schizophrenia. However, it is unknown if and how the glutamate system is altered in 22q11DS. People with 22q11DS are vulnerable for haploinsufficiency of PRODH, a gene that

Fabiana da Silva Alves; Erik Boot; Nicole Schmitz; Aart Nederveen; Jacob Vorstman; Christina Lavini; Petra Pouwels; Lieuwe de Haan; Don Linszen; Therese van Amelsvoort; Takeo Yoshikawa

2011-01-01

35

Large contiguous gene deletions in Sjögren-Larsson syndrome.  

PubMed

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis. PMID:21684788

Engelstad, Holly; Carney, Gael; S'aulis, Dana; Rise, Janae; Sanger, Warren G; Rudd, M Katharine; Richard, Gabriele; Carr, Christopher W; Abdul-Rahman, Omar A; Rizzo, William B

2011-05-30

36

Developmental Trajectories in Syndromes with Intellectual Disability, with a Focus on Wolf-Hirschhorn and Its Cognitive-Behavioral Profile  

ERIC Educational Resources Information Center

|Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn…

Fisch, Gene S.; Carpenter, Nancy; Howard-Peebles, Patricia N.; Holden, Jeanette J. A.; Tarleton, Jack; Simensen, Richard; Battaglia, Agatino

2012-01-01

37

Del 1p36 syndrome: a newly emerging clinical entity  

Microsoft Academic Search

Monosomy 1p36 is a recently delineated contiguous gene syndrome, which is now considered to be the most common subtelomeric microdeletion syndrome. From the recent literature it appears as if 1p36 deletions account for 0.5–1.2% of idiopathic mental retardation. The deletions can be detected by high resolution cytogenetic studies in a minority of patients, and fluorescence in situ hybridisation (FISH) is

Agatino Battaglia

2005-01-01

38

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

SciTech Connect

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.

Michaelis, R.C.; Skinner, S.A.; Lethco, B.A. [Greenwood Genetic Center, SC (United States)] [and others

1995-01-02

39

Mutator phenotype of Werner syndrome is characterized by extensive deletions.  

PubMed Central

Werner syndrome (WS) is a rare autosomal-recessive disorder characterized by the premature appearance of features of normal aging in young adults. The extensive phenotypic overlap between WS and normal aging suggests they may also share pathogenetic mechanisms. We reported previously that somatic cells from WS patients demonstrate a propensity to develop chromosomal aberrations, including translocations, inversions, and deletions, and that WS cell lines demonstrate a high spontaneous mutation rate to 6-thioguanine resistance. We report here the biochemical and molecular characterization of spontaneous mutations at the X chromosome-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 6-thioguanine-resistant WS and control cells. Blot hybridization analysis of 89 independent spontaneous HPRT mutations in WS and control mutants lacking HPRT activity revealed an unusually high proportion of HPRT deletions in WS as compared with control cells (76% vs. 39%). Approximately half (58%) of the deletions in WS cells consisted of the loss of greater than 20 kilobases of DNA from the HPRT gene. These results suggest that an elevated somatic mutation rate, and particularly deletions, may play pathogenetically important roles in WS and in several associated age-dependent human disease processes. Images

Fukuchi, K; Martin, G M; Monnat, R J

1989-01-01

40

Cardiac Defects and Results of Cardiac Surgery in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

|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…

Carotti, Adriano; Digilio, Maria Cristina; Piacentini, Gerardo; Saffirio, Claudia; Di Donato, Roberto M.; Marino, Bruno

2008-01-01

41

Cardiac Defects and Results of Cardiac Surgery in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

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…

Carotti, Adriano; Digilio, Maria Cristina; Piacentini, Gerardo; Saffirio, Claudia; Di Donato, Roberto M.; Marino, Bruno

2008-01-01

42

Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities  

PubMed Central

Background Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2–29% because of different inclusion criteria. Methods This study presents data compiled from 11?688 cases referred for subtelomere FISH testing in three clinical cytogenetic laboratories. Results In this study population, the detection rate for clinically significant subtelomere abnormalities was approximately 2.5%, with an additional 0.5% detection of presumed familial variants. Approximately half of the clinically significant abnormalities identified were terminal deletions, the majority of which were de novo. Most of the remaining cases were unbalanced translocations between two chromosomes or two arms of the same chromosome. Approximately 60% of the unbalanced translocations were inherited from a parent carrying a balanced form of the rearrangement. Other abnormalities identified included tandem duplications, apparently balanced translocations, partial deletions, and insertions. Interestingly, 9 cases (0.08%) were found to have interstitial deletions of non?telomeric control loci, either BCR on 22q or PML on 15q. The most common clinically significant imbalances found were deletions of 1p, 22q, 4p, 9q, 8p, 2q and 20p. The most common familial variants were a deletion or duplication of 10q, deletion of 4q, deletion of Yq, and duplication of X/Yp onto Xq. Conclusions This study of subtelomere rearrangements is a 20 fold increase in number over the previously reported largest study and represents an unbiased analysis of subtelomere rearrangements in a large, unselected patient population.

Ravnan, J B; Tepperberg, J H; Papenhausen, P; Lamb, A N; Hedrick, J; Eash, D; Ledbetter, D H; Martin, C L

2006-01-01

43

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event  

PubMed Central

Subtelomeres are concentrations of interchromosomal segmental duplications capped by telomeric repeats at the ends of chromosomes. The nature of the segments shared by different sets of human subtelomeres reflects their high rate of recent interchromosomal exchange. Here, we characterize the rearrangements incurred by the 15q subtelomere after it arose from a chromosome fission event in the common ancestor of great apes. We used FISH, sequencing of genomic clones, and PCR to map the breakpoint of this fission and track the fate of flanking sequence in human, chimpanzee, gorilla, orangutan, and macaque genomes. The ancestral locus, a cluster of olfactory receptor (OR) genes, lies internally on macaque chromosome 7. Sequence originating from this fission site is split between the terminus of 15q and the pericentromere of 14q in the great apes. Numerous structural rearrangements, including interstitial deletions and transfers of material to or from other subtelomeres, occurred subsequent to the fission, such that each species has a unique 15q structure and unique collection of ORs derived from the fission locus. The most striking rearrangement involved transfer of at least 200 kb from the fission-site region to the end of chromosome 4q, where much still resides in chimpanzee and gorilla, but not in human. This gross structural difference places the subtelomeric defect underlying facioscapulohumeral muscular dystrophy (FSHD) much closer to the telomere in human 4q than in the hybrid 4q–15q subtelomere of chimpanzee.

Rudd, M. Katharine; Endicott, RaeLynn M.; Friedman, Cynthia; Walker, Megan; Young, Janet M.; Osoegawa, Kazutoyo; de Jong, Pieter J.; Green, Eric D.; Trask, Barbara J.

2009-01-01

44

Classical Noonan syndrome is not associated with deletions of 22q11  

SciTech Connect

Deletions of 22q11 cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22q11 deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22q11 deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22q11 deletion. A 2-month-old infant with several findings suggestive of NS did have a 22q11 deletion, suggesting that a small number of 22q11 deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. 10 refs., 1 fig.

Robin, N.H.; Sellinger, B.; McDonald-McGinn, D. [Children`s Hospital of Philadelphia, PA (United States)] [and others

1995-03-13

45

Autism, ADHD, Mental Retardation and Behavior Problems in 100 Individuals with 22q11 Deletion Syndrome  

ERIC Educational Resources Information Center

|This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens. Autism spectrum disorders (ASDs) and/or attention…

Niklasson, Lena; Rasmussen, Peder; Oskarsdottir, Solveig; Gillberg, Christopher

2009-01-01

46

[TSC2/PKD1 contiguous gene deletion syndrome].  

PubMed

The TSC2 gene responsible for Tuberous Sclerosis, is located in chromosome 16p 13.3, adjacent to the gene for autosomal dominant polycystic kidney disease. A large deletion can involve both genes, causing the so-called TSC2/PKD1 contiguous gene syndrome (MIM#600273). It is characterized by congenital renal cysts, or their early onset in patients with tuberous sclerosis, and implies a worst prognosis in renal disease. We report the case of a five year-old boy with tuberous sclerosis, who presented with multiple large bilateral renal cysts in the neonatal period. A genetic confirmation study was later performed using the multiple ligation probe amplification (MLPA) technique. PMID:23402778

Llamas Velasco, S; Camacho Salas, A; Vidales Moreno, C; Ceballos Rodríguez, R M; Murcia García, F J; Simón de la Heras, R

2013-02-09

47

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA  

PubMed Central

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed.

Barbaro, Michela; Balsamo, Antonio; Anderlid, Britt Marie; Myhre, Anne Grethe; Gennari, Monia; Nicoletti, Annalisa; Pittalis, Maria Carla; Oscarson, Mikael; Wedell, Anna

2009-01-01

48

Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.  

PubMed

Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement. PMID:21187929

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

2010-12-20

49

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated  

PubMed Central

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

Corsten-Janssen, N.; Saitta, S.C.; Hoefsloot, L.H.; McDonald-McGinn, D.M.; Driscoll, D.A.; Derks, R.; Dickinson, K.A.; Kerstjens-Frederikse, W.S.; Emanuel, B.S.; Zackai, E.H.; van Ravenswaaij-Arts, C.M.A.

2013-01-01

50

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

SciTech Connect

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.

Shashi, V.; Golden, W.L.; Fryburg, J.S. [Univ. of Virginia, Charlottesville, VA (United States)

1994-01-01

51

Detection of deleted mitochondrial DNA in Kearns-Sayre syndrome using laser capture microdissection  

Microsoft Academic Search

A novel 4949-base pair mitochondrial DNA (mtDNA) deletion was detected in various tissues in a postmortem study of a patient with Kearns-Sayre syndrome (KSS). Deleted mtDNA levels were higher in skeletal muscle and brain and lower in kidney, working myocardium, and endocrine tissues (thyroid, parathyroids, pancreas, and adrenal glands). The distribution of the deletion in skeletal muscle and conducting myocardium

Daniela Pistilli; Cira R. T di Gioia; Giulia D’Amati; Salvatore Sciacchitano; Raffaele Quaglione; Raffaella Quitadamo; Carlo Casali; Pietro Gallo; Filippo M Santorelli

2003-01-01

52

Characterization of a 5025 base pair mitochondrial DNA deletion in Kearns-Sayre syndrome  

Microsoft Academic Search

We characterized a mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome. Southern blot hybridization showed that 86 to 93% of the mitochondrial genome harbored a 5.0 kb deletion. The percentage of affected genomes is higher than in previously described cases. Direct sequencing of the breakpoint region revealed that the deletion extended 5025 by from nt 10050 in the tRNA

Miriam Vázquez-Acevedo; Roberto Coria; Adalberto González-Astiazarán; Violeta Medina-Crespo; Cecilia Ridaura-Sanz; Diego González-Halphen

1995-01-01

53

Language Skills in 5-8-Year-Old Children with 22q11 Deletion Syndrome  

ERIC Educational Resources Information Center

|Background: Language impairment and delayed language onset have been described, although not investigated in detail, in children with 22q11 deletion syndrome. Aims: To investigate different areas of language: the ability to retell a narrative, phonology, syntax and receptive vocabulary in a group of 5-8-year-old children with 22q11 deletion

Persson, Christina; Niklasson, Lena; Oskarsdottir, Solveig; Johansson, Susanne; Jonsson, Radi; Soderpalm, Ewa

2006-01-01

54

Social skills of children with 22q11 Deletion Syndrome: A social cognitive neuroscience approach  

Microsoft Academic Search

The 22q11 DS is the most common genetic deletion syndrome. The deletion is believed to result in the dysregulation of the dopamine, GABA, and glutamate systems which, in turn, affects the prefrontal cortex, associated circuitry, and cognitive abilities governed by these brain regions. Research suggests that 22q11 DS children experience attention and executive function deficits; clinical observation also suggests impaired

Karen Kiley-Brabeck

2004-01-01

55

A large family with subtelomeric translocation t(18;21)(q23;q22.1) and molecular breakpoint in the Down syndrome critical region  

Microsoft Academic Search

We describe a 17-month-old infant with clinical features of Down syndrome and a normal karyotype by standard chromosomal analysis,\\u000a her two uncles aged 28 and 30 years, respectively, with reduced intelligence and unusual appearance but not apparent Down\\u000a syndrome, and a severely retarded 6-year-old girl with dysmorphy and epilepsy from the same family. Cytogenetic studies of\\u000a patients and normal intervening

Oliver Bartsch; Georg K. Hinkel; Michael B. Petersen; Ulrich König; Merete Bugge; Margareta Mikkelsen; Dimitris Avramopoulos; Michael Morris; Stylianos E. Antonarakis

1997-01-01

56

Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?  

PubMed

We report a full-term male infant born to nonconsanguinous parents who had clinical features of Goldenhar syndrome and cri du chat syndrome. At birth, the infant was noted to have dysmorphic features with bilateral preauricular tags, rotated ears, bilateral epicanthic folds, a left epibulbar lipodermoid, and an accessory left nipple. After he was assessed for feeding difficulty and tachypnea, he was found to have esophageal atresia with tracheoesophageal fistula. In addition, he had a high-pitched, cat-like cry, characteristic of cri-du-chat syndrome. He also failed a hearing test. Chromosomal analysis and fluorescence in situ hybridisation studies showed an unbalanced karyotype with a terminal deletion of the segment p14 on the short arm of chromosome 5, which is consistent with the cri-du-chat locus. The association of Goldenhar syndrome and cri-du-chat syndrome in this patient suggests that the chromosome 5p14 locus may harbor a gene implicated with Goldenhar syndrome. PMID:12825068

Choong, Yee Fong; Watts, Patrick; Little, Elizabeth; Beck, Lyn

2003-06-01

57

Nasal dimple as part of the 22q11.2 deletion syndrome  

SciTech Connect

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.

Gripp, K.W.; Reed, L.A. [Children`s Hospital of Philadelphia, PA (United States); Emanuel, B.S. [Children`s Hospital of Philadelphia, PA (United States)]|[Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

1997-03-31

58

Beckwith-Wiedemann syndrome in a child with chromosome 18q deletion.  

PubMed Central

Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy. In addition, a deletion of chromosome 18q22.1 was identified in this infant without clinical features of 18q-syndrome (microcephaly, short stature, hypotonia). The association of a chromosome 18 deletion and BWS may be coincidental or may indicate the location of a trans activating regulator element for maintenance of IGF2 imprinting. Images

Brewer, C M; Lam, W W; Hayward, C; Grace, E; Maher, E R; FitzPatrick, D R

1998-01-01

59

Recurrent interstitial 1p36 deletions: evidence for germline mosaicism and complex rearrangement breakpoints  

PubMed Central

Deletions of chromosome 1p36 are one of the most frequently encountered subtelomeric alterations. Clinical features of monosomy 1p36 include neurocognitive impairment, hearing loss, seizures, cardiac defects, and characteristic facial features. The majority of cases have occurred sporadically, implying that genomic instability plays a role in the prevalence of the syndrome. Here we report two siblings with mild phenotypic features of the deletion syndrome, including developmental delay, hearing loss and left ventricular noncompaction (LVNC). Microarray analysis using bacterial artificial chromosome and oligonucleotide microarrays indicated the deletions were identical, suggesting germline mosaicism. Parental phenotypes were normal, and analysis by fluorescence in situ hybridization (FISH) did not show mosaicism. These small interstitial deletions were not detectable by conventional subtelomeric FISH analysis. To investigate the mechanism of deletion further, the breakpoints were cloned and sequenced, demonstrating the presence of a complex rearrangement. Sequence analysis of genes in the deletion interval did not reveal any mutations on the intact homologue that may have contributed to the LVNC seen in both children. This is the first report of apparent germline mosaicism for this disorder. Thus, our findings have important implications for diagnostic approaches and for recurrence risk counseling in families with a child with monosomy 1p36. In addition, our results further refine the minimal critical region for LVNC and hearing loss.

Gajecka, Marzena; Saitta, Sulagna C.; Gentles, Andrew J.; Campbell, Lindsey; Ciprero, Karen; Geiger, Elizabeth; Catherwood, Anne; Rosenfeld, Jill A.; Shaikh, Tamim; Shaffer, Lisa G.

2010-01-01

60

Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome  

SciTech Connect

Mendelian inherited disorders to deletions of adjacent genes on a chromosome have been described as contiguous gene syndromes. Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome have been found as isolated entities or associated in various combination in 27 patients with interstitial and terminal deletions involving the distal short are of the X chromosome. The use of cDNA and genomic probes from the Xp22-pter region allowed us to identify 12 different deletion intervals and to confirm, and further refine, the chromosomal assignment of X-linked recessive chondrodysplasia punctata and Kallmann syndrome genes. A putative pseudoautosomal gene affecting height and an X-linked nonspecific mental retardation gene have been tentatively assigned to specific intervals. The deletion panel described is a useful tool for mapping new sequences and orienting chromosome walks in the region.

Ballabio, A.; Andria, G. (Univ. of Reggio Calabria, Catanzaro (Italy)); Bardoni, B.; Fraccaro, M.; Maraschio, P.; Zuffardi, O.; Guioli, S.; Camerino, G. (Univ. of Pavia (Italy)); Carrozzo, R. (Univ. of Naples (Italy)); Bick, D.; Campbell, L. (Univ. of Texas, San Antonio (USA)); Hamel, B. (Univ. of Nijmegen (Netherlands)); Ferguson-Smith, M.A. (Univ. of Cambridge (England)); Gimelli, G. (G. Gaslini Institute, Genoa (Italy))

1989-12-01

61

Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review  

PubMed Central

Lynch syndrome (clinically referred to as HNPCC – Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3’end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.

2013-01-01

62

Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review.  

PubMed

Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition. PMID:23938213

Tutlewska, Katarzyna; Lubinski, Jan; Kurzawski, Grzegorz

2013-08-12

63

The Neural Correlates of Non-Spatial Working Memory in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)  

ERIC Educational Resources Information Center

|Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant…

Kates, Wendy R.; Krauss, Beth R.; AbdulSabur, Nuria; Colgan, Deirdre; Antshel, Kevin M.; Higgins, Anne Marie; Shprintzen, Robert J.

2007-01-01

64

Mapping Cortical Morphology in Youth with Velocardiofacial (22q11.2 Deletion) Syndrome  

ERIC Educational Resources Information Center

|Objective: Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) represents one of the highest known risk factors for schizophrenia. Insofar as up to 30% of individuals with this genetic disorder develop schizophrenia, VCFS constitutes a unique, etiologically homogeneous model for understanding the pathogenesis of schizophrenia. Method:…

Kates, Wendy R.; Bansal, Ravi; Fremont, Wanda; Antshel, Kevin M.; Hao, Xuejun; Higgins, Anne Marie; Liu, Jun; Shprintzen, Robert J.; Peterson, Bradley S.

2011-01-01

65

A case report of 22q11 deletion syndrome confirmed by array-CGH method.  

PubMed

Velo-cardio-facial syndrome (VCFS) is caused by a submicroscopic deletion on the long arm of chromosome 22 and affects approximately 1 in 4000 persons, making it the second most prevalent genetic syndrome after Down syndrome and the most common genetic syndrome associated with cleft palate. Most of the 22q11.2 deletion cases are new occurrences or sporadic; however, in about 10 % of families, the deletion is inherited and other family members are affected or at risk for passing this deletion to their children. This report describes a 1.5 years-old male child with clinical signs of velo-cardio-facial syndrome (VCFS) presented with heart defect, soft cleft palate, developmental delay, acrocephaly, seizure, MRI abnormalities and descriptive facial feature, such as hypertelorism. Array-CGH test was done to confirm the diagnosis; the result revealed a 2.6 Mbp deletion in 22q11.2 chromosome that containing TBX1 and COMT genes. Our data suggest that haploinsufficiency of TBX1 gene is probably a major contributor to some of the syndrome characteristic signs, such as heart defect. Because of developmental delay and dysmorphic facial feature were observed in the index's mother and relatives, inherited autosomal dominant form of VCF is probable, and MLPA (multiplex ligation-dependent probe amplification) test should be performed for parents to estimate the recurrent risk in next pregnancy. PMID:23267387

Sedghi, Maryam; Nouri, Narges; Abdali, Hossein; Memarzadeh, Mehrdad; Nouri, Nayereh

2012-03-01

66

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

PubMed Central

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

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

67

Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene  

PubMed Central

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.

2012-01-01

68

A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp  

Microsoft Academic Search

Imprinting on human chromosome 15q11-q13 is controlled by a bipartite imprinting center (IC) that maps to the SNRPN locus. Deletions of the IC result in an imprinting defect and Prader-Willi syndrome or Angelman syndrome (AS). We have now identified a 5-kb IC deletion in an English AS patient (AS-LO); this represents the smallest microdeletion found in AS and narrows down

Karin Buiting; Christina Lich; Sally Cottrell; Angela Barnicoat; Bernhard Horsthemke

1999-01-01

69

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes  

Microsoft Academic Search

Prader–Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1–BP3

Soo-Jeong Kim; Jennifer L Miller; Paul J Kuipers; Jennifer Ruth German; Arthur L Beaudet; Trilochan Sahoo; Daniel J Driscoll

2012-01-01

70

Candidate Genes and the Behavioral Phenotype in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

|There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk…

Prasad, Sarah E.; Howley, Sarah; Murphy, Kieran C.

2008-01-01

71

Otolaryngologic Manifestations of the 22q11.2 Deletion Syndrome  

Microsoft Academic Search

Background: The 22q11.2 chromosome deletion syn- drome occurs at a frequency of 1 in 4000 live births. Fluo- rescent in situ hybridization is a reliable means of test- ing for this genetic abnormality. Objective: To describe the otolaryngologic manifesta- tions of the 22q11.2 deletion syndrome to improve rec- ognition and management of these disorders. Patients and Design: A retrospective medical

Orville Dyce; Donna McDonald-McGinn; Richard E. Kirschner; Elaine Zackai; Kathleen Young; Ian N. Jacobs

2002-01-01

72

Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes  

Microsoft Academic Search

Six genes in the 1.5 Mb region of chromosome 22 deleted in DiGeorge\\/22q11 deletion syndrome–Mrpl40, Prodh, Slc25a1, Txnrd2, T10, and Zdhhc8–encode mitochondrial proteins. All six genes are expressed in the brain, and maximal expression coincides with peak forebrain synaptogenesis shortly after birth. Furthermore, their protein products are associated with brain mitochondria, including those in synaptic terminals. Among the six, only Zddhc8

T. M. Maynard; D. W. Meechan; M. L. Dudevoir; D. Gopalakrishna; A. Z. Peters; C. C. Heindel; T. J. Sugimoto; Y. Wu; J. A. Lieberman; A.-S. LaMantia

2008-01-01

73

Severe craniosynostosis in an infant with deletion 22q11.2 syndrome.  

PubMed

We report a male infant with 22q11.2 deletion syndrome and very severe multi-sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni- or bi-sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi-sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder. PMID:23239640

Al-Hertani, W; Hastings, V A; McGowan-Jordan, J; Hurteau, J; Graham, Gail E

2012-12-13

74

A Patient with 22q11.2 Deletion Syndrome: Case Report  

PubMed Central

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. Conflict of interest:None declared.

Bas, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Ruveyde; Gunoz, Hulya; Saka, Nurcin

2009-01-01

75

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

PubMed

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

Ery?lmaz, Sema Kabata?; Ba?, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin

2009-02-06

76

Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome.  

PubMed

Cardiovascular anomalies are present in 80% of neonates with 22q11.2 deletion syndrome. Three genes in chromosome 22q11.2 (TBX1, CRKL, and ERK2) have been identified whose haploinsufficiency causes dysfunction of the neural crest cell and anterior heart field and anomalies of 22q11.2 deletion syndrome. The most common diseases are conotruncal anomalies, which include tetralogy of Fallot (TF), TF with pulmonary atresia, truncus arteriosus, and interrupted aortic arch. A high prevalence of the deletion is noted in patients with TF with absent pulmonary valve, TF associated with pulmonary atresia and major aortopulmonary collateral arteries, truncus arteriosus, and type B interruption of aortic arch. Right aortic arch, aberrant subclavian artery, cervical origin of the subclavian artery, crossing pulmonary arteries, and major aortopulmonary collateral arteries are frequently associated with cardiovascular anomalies associated with 22q11.2 deletion syndrome. Virtually every type of congenital heart defect has been described early in the context of a 22q11.2 deletion. In conclusion, conotruncal anomaly associated with aortic arch and ductus arteriosus anomalies should increase the suspicion of 22q11.2 deletion. PMID:20494672

Momma, Kazuo

2010-06-01

77

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes  

SciTech Connect

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.

Teshima, I.; Chadwick, D.; Chitayat, D. [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)

1996-03-29

78

Autosomal dominant {open_quotes}Opitz{close_quotes} GBBB syndrome due to a 22q11.2 deletion  

SciTech Connect

The classification of Opitz GBBB syndrome has been associated with the deletion of the DiGeorge chromosome region on human chromosome 22q11.2. The broad phenotype involved in this deletion syndrome has been referred to as the DiGeorge/velocardiofacial syndrome. The clinical description of the patient will influence the diagnosis of the syndrome. More cooperation between the clinicians and the molecular researchers is necessary in order to locate the gene(s) for these disorders. 11 refs.

McDonald-McGinn, D.M.; Emanuel, B.S.; Zackai, E.H. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)

1996-08-23

79

Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment  

PubMed Central

Background Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. Methods We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. Results Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. Conclusions Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

Gould, Douglas B; Jaafar, Mohamad S; Addison, Mark K; Munier, Francis; Ritch, Robert; MacDonald, Ian M; Walter, Michael A

2004-01-01

80

Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria.  

PubMed

Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region. PMID:23794250

Bartholdi, Deborah; Asadollahi, Reza; Oneda, Beatrice; Schmitt-Mechelke, Thomas; Tonella, Paolo; Baumer, Alessandra; Rauch, Anita

2013-06-21

81

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

PubMed Central

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

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

1996-01-01

82

Genotype-phenotype correlation in 22q11.2 deletion syndrome  

PubMed Central

Background The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

2012-01-01

83

A novel mitochondrial DNA deletion in a Chinese girl with Kearns-Sayre syndrome.  

PubMed

Kearns-Sayre syndrome is a rare disorder often caused by mitochondrial DNA rearrangement. The most commonly reported mitochondrial DNA deletion is 4977 bp in size spanning nucleotides 8469 and 13447. The clinical signs of Kearns-Sayre syndrome include chronic progressive external ophthalmoplegia, retinitis pigmentosa, heart block and cerebellar ataxia, as well as other heterogeneous manifestations including neuromuscular problems and endocrine disorders. Cardiac conduction defects can develop insidiously, leading to sudden death sometimes if not promptly recognised. This report focuses on the diagnosis of Kearns-Sayre syndrome in a Chinese girl who presented initially with short stature, delayed puberty, insidious onset of ptosis and later with typical features of Kearns-Sayre syndrome including complete heart block. Genetic analysis disclosed a novel 7.2 kilobases deletion in muscle tissue. Mitochondrial diseases have heterogeneous phenotypes and mutational analysis has proven to be an effective tool for confirming the diagnosis. PMID:19801695

Yau, Eric K C; Chan, K Y; Au, K M; Chow, T C; Chan, Y W

2009-10-01

84

A Nuclear Defect in the 4p16 Region Predisposes to Multiple Mitochondrial DNA Deletions in Families with Wolfram Syndrome  

Microsoft Academic Search

Wolfram syndrome is a progressive neurodegenerative dis- order transmitted in an autosomal recessive mode. We re- port two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached per- centages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members

Antoni Barrientos; Víctor Volpini; Jordi Casademont; David Genís; Josep-Maria Manzanares; Isidre Ferrer; Jordi Corral; Francesc Cardellach; Alvaro Urbano-Márquez; Xavier Estivill; Virginia Nunes

85

Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study  

Microsoft Academic Search

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leigh's syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion,

M. Brockington; N. Alsanjari; M. G. Sweeney; J. A. Morgan-Hughes; F. Scaravilli; A. E. Harding

1995-01-01

86

22q11 Deletion Syndrome: A Role for TBX1 in Pharyngeal and Cardiovascular Development  

Microsoft Academic Search

Tbx1 is a member of the Tbox family of binding domain transcription factors. TBX1 maps within the region of 22q11 deleted in humans with DiGeorge or velocardiofacial syndrome. Mice haploinsufficient for\\u000a Tbx1 have phenotypes that recapitulate major features of the syndrome, notably abnormal growth and remodelling of the pharyngeal\\u000a arch arteries. The Tbx1 haploinsufficiency phenotype is modified by genetic background

Peter J. Scambler

2010-01-01

87

Cognitive, Behavioural and Psychiatric Phenotype in 22q11.2 Deletion Syndrome  

Microsoft Academic Search

22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions,\\u000a particularly schizophrenia which develops in about 20–25% of individuals with a chromosome 22q11.2 microdeletion. From the\\u000a initial discovery of the syndrome, associated developmental delays made it clear that changes in brain development were a\\u000a key part of the expression. Once patients were followed through childhood

Nicole Philip; Anne Bassett

2011-01-01

88

Screening for minute deletions in patients with suspected cri-du-chat syndrome and apparently normal karyotype  

Microsoft Academic Search

Measurement studies were carried out on the B-group chromosomes in three patients with suspected cri-du-chat syndrome, four karyotypically confirmed cases of the syndrome and three normal subjects. None of the propositi showed a detectable short-arm deletion. Within the four cases with obvious short arm deletion the amount of the deletion varies to a high degree. In addition to the technique

H. Hoehn; W. Engel

1969-01-01

89

Molecular Characterization of a Deletion in the HPRT1 Gene in a Patient with Lesch–Nyhan Syndrome  

Microsoft Academic Search

Lesch–Nyhan syndrome is caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT) encoded by HPRT1. About 20% of patients have a deletion of HPRT1 and large deletions of HPRT1 are not always fully characterized at the molecular level. Here, we report on a case of Lesch–Nyhan syndrome with a 33-kb deletion involving exon 1 of HPRT1. This novel mutation is caused

A. Taniguchi; Y. Yamada; M. Hakoda; C. Sekita; M. Kawamoto; H. Kaneko; H. Yamanaka

2011-01-01

90

Is the autosomal dominant Opitz GBBB syndrome part of the DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2?  

SciTech Connect

The classification of Opitz GBBB syndrome has been associated with the deletion of the DiGeorge chromosome region on human chromosome 22q11.2. The broad phenotype involved in this deletion syndrome is usually referred to as the DiGeorge/velocardiofacial syndrome. The clinical description of the patient will influence the diagnosis of the syndrome. More exact descriptions are necessary in order to locate the gene(s) for these disorders. 13 refs.

Wulfsberg, E.A. [Univ. of Maryland School of Medicine, Baltimore, MD (United States)

1996-08-23

91

Subtypes in 22q11.2 Deletion Syndrome Associated with Behaviour and Neurofacial Morphology  

ERIC Educational Resources Information Center

|22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis…

Sinderberry, Brooke; Brown, Scott; Hammond, Peter; Stevens, Angela F.; Schall, Ulrich; Murphy, Declan G. M.; Murphy, Kieran C.; Campbell, Linda E.

2013-01-01

92

22q11.2 deletion syndrome with life-threatening adenovirus infection.  

PubMed

Adenovirus causes significant morbidity and mortality in immunocompromised children. We report how an infusion of HLA-matched sibling donor T lymphocytes rapidly eradicated life-threatening, high-level adenoviremia in a child with complete DiGeorge syndrome (22q11.2 deletion) who went on to reconstitute a diverse, donor-derived, postthymic T-cell repertoire. PMID:23660376

Ip, Winnie; Zhan, Hong; Gilmour, Kimberly C; Davies, E Graham; Qasim, Waseem

2013-05-06

93

Prenatal diagnosis of the 22q11.2 deletion syndrome.  

PubMed

The development of fluorescence in situ hybridization (FISH)- and polymerase chain reaction (PCR)-based assays for the detection of deletions of chromosome 22q11.2 has enabled the medical community to offer couples at risk prenatal diagnostic testing. Current indications for testing include a previous child with a 22q11.2 deletion or DiGeorge/velocardiofacial syndrome, an affected parent with a 22q11.2 deletion, and in utero detection of a conotruncal cardiac defect. Antenatal knowledge of the deletion status provides couples and clinicians with an accurate diagnosis, prognostic information, and recurrence risk, which may assist couples with their reproductive decisions. However, there are limitations to prenatal testing, which should be reviewed prior to testing. PMID:11339370

Driscoll, D A

94

EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients.  

PubMed

The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-five cases with MSH2 loss were identified: 10 had mutations of MSH2, five had mutations of MSH6, and 10 did not show MSH2/MSH6 mutations. These 25 cases were analyzed for EPCAM deletions using multiplex ligation-dependent probe amplification, and deletions were mapped using long-range PCR analysis. One subject with no MSH2/MSH6 mutations had a large deletion in the EPCAM locus that extended for 8.7 kb and included exons 8 and 9. The tumor exhibited MSH2 promoter hypermethylation. EPCAM deletion analysis followed by MSH2 methylation testing of the tumor is a fast low-cost procedure that can be used to identify mutations that cause LS. We propose that this procedure be incorporated into clinical genetic analysis strategies and present a decision-support flow diagram for the diagnosis of LS. PMID:20864635

Guarinos, Carla; Castillejo, Adela; Barberá, Víctor-Manuel; Pérez-Carbonell, Lucía; Sánchez-Heras, Ana-Beatriz; Segura, Angel; Guillén-Ponce, Carmen; Martínez-Cantó, Ana; Castillejo, María-Isabel; Egoavil, Cecilia-Magdalena; Jover, Rodrigo; Payá, Artemio; Alenda, Cristina; Soto, José-Luís

2010-09-23

95

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

SciTech Connect

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.

Blok, R.B.; Thorburn, D.R.; Danks, D.M. [Royal Children`s Hospital, Melbourne (Australia)] [and others

1994-09-01

96

Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions.  

PubMed

CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype. PMID:12673657

Lalani, Seema R; Stockton, David W; Bacino, Carlos; Molinari, Laura M; Glass, Nancy L; Fernbach, Susan D; Towbin, Jeffrey A; Craigen, William J; Graham, John M; Hefner, Margaret A; Lin, Angela E; McBride, Kim L; Davenport, Sandra L; Belmont, John W

2003-04-30

97

Genotype/phenotype correlation in women with nonmosaic X chromosome deletions and Turner syndrome  

SciTech Connect

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.

Zinn, A.R. [Univ. of Texas Southwestern Medical School, Dallas, TX (United States)

1994-09-01

98

EPCAM germline and somatic rearrangements in lynch syndrome: identification of a novel 3'EPCAM deletion.  

PubMed

3'EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3'EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis. A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3'EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556-531_*872del) and one known EPCAM deletion (c.859-689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM-MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI-high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM-MSH2 region in the other tumor. This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors. PMID:23801599

Spaepen, Marijke; Neven, Esther; Sagaert, Xavier; De Hertogh, Gert; Beert, Eline; Wimmer, Katharina; Matthijs, Gert; Legius, Eric; Brems, Hilde

2013-06-26

99

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

PubMed

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

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

100

Twelve new patients with 13q deletion syndrome: genotype-phenotype analyses in progress.  

PubMed

13q deletion is characterized by a wide phenotypic spectrum resulting from a partial deletion of the long arm of chromosome 13. The main clinical features are mental retardation, growth retardation, craniofacial dysmorphy and various congenital defects. Only one recent Italian study was aimed at determining genotype-phenotype correlations among 13q deletions from a group of mainly live born children, using array-CGH and FISH. In order to improve the molecular characterization of 13q monosomy, 12 new patients (9 foetuses and 3 children) were collected based on a cohort of holoprosencephaly (HPE) linked to ZIC2 gene deletion and/or patients with 13q deletion diagnosed by standard karyotype. First, quantitative gene screening using MLPA (Multiplex Ligation dependent Probe Amplification) was performed to look for ZIC2 gene deletion and then, CGH array analysis was carried out using the Agilent Human Genome CGH microarray 4x44K (Agilent Technologies, Santa Clara, USA). All the foetuses had severe cerebral midline malformations associated with a deletion including the ZIC2 gene. We report one patient with Steinfeld phenotype linked to this chromosomal anomaly, and suggest that some of the associations between cerebral midline malformation and limb defects might be related to 13q deletion. Further candidate genes are suspected to explain the malformations associated with cerebral anomalies in the hypothesis of a contiguous gene syndrome: SPRY2 in 13q31.1 is implicated in lens cell proliferation and differentiation for congenital cataract; GPC5 in 13q32 is mainly expressed in the mesenchyme of the developing limb bud for upper limb anomalies. PMID:19022413

Quélin, Chloé; Bendavid, Claude; Dubourg, Christèle; de la Rochebrochard, Céline; Lucas, Josette; Henry, Catherine; Jaillard, Sylvie; Loget, Philippe; Loeuillet, Laurence; Lacombe, Didier; Rival, Jean-Marie; David, Véronique; Odent, Sylvie; Pasquier, Laurent

2008-10-31

101

An Fgf8 Mouse Mutant Phenocopies Human 22q11 Deletion Syndrome  

PubMed Central

SUMMARY Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.

Frank, Deborah U.; Fotheringham, Lori K.; Brewer, Judson A.; Muglia, Louis J.; Tristani-Firouzi, Martin; Capecchi, Mario R.; Moon, Anne M.

2006-01-01

102

A new case with 10q23 interstitial deletion encompassing both PTEN and BMPR1A narrows the genetic region deleted in juvenile polyposis syndrome.  

PubMed

We report on a patient with a contiguous interstitial germline deletion of chromosome 10q23, encompassing BMPR1A and PTEN, with clinical manifestations of juvenile polyposis and minor symptoms of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The patient presented dysmorphic features as well as developmental delay at the age of 5 months. Multiple polyps along all parts of the colon were diagnosed at the age of 3 years, following an episode of a severe abdominal pain and intestinal bleeding. The high-resolution comparative genomic hybridisation revealed a 3.7-Mb deletion within the 10q23 chromosomal region: 86,329,859-90,035,024. The genotyping with four polymorphic microsatellite markers confirmed a de novo 10q deletion on the allele with a paternal origin, encompassing both PTEN and BMPR1A genes. The karyotype analysis additionally identified a balanced translocation involving chromosomes 5q and 7q, and an inversion at chromosome 2, i.e. 46,XY,t(5;7)(q13.3-q36), inv(2)(p25q34). Although many genetic defects were detected, it is most likely that the 10q23 deletion is primarily the cause for the serious phenotypic manifestations. The current clinical findings and deletion of BMPR1A indicate a diagnosis of severe juvenile polyposis, but the existing macrocephaly and PTEN deletion also point to either CS or BRRS, which cannot be ruled out at the moment because of their clinical manifestation later in life and the de novo character of the deletion. The deletion detected in our patient narrows the genetic region deleted in all reported cases with juvenile polyposis by 0.04 Mb from the telomeric side, mapping it to the region chr10:88.5-90.03Mb (GRCh37/hg19), with an overall length of 1.53 Mb. PMID:22993021

Hiljadnikova Bajro, Marija; Sukarova-Angelovska, Elena; Adélaïde, Jose; Chaffanet, Max; Dimovski, Aleksandar J

2012-09-21

103

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

SciTech Connect

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.

McCabe, E.R.B.; Towbin, J.A. (Baylor College of Medicine, Houston, TX (United States)); Engh, G. van den; Trask, B.J. (Lawrence Livermore National Lab., CA (United States))

1992-12-01

104

Velopharyngeal, speech and dental characteristics as diagnostic aids in 22q11.2 deletion syndrome.  

PubMed

This study examines velopharyngeal, speech, and dental parameters as possible diagnostic aids in 22q11.2 deletion syndrome. It is a retrospective study on 56 individuals. Twenty-one percent had a submucous cleft palate and 41 percent required palate surgery for speech. Common dental findings included poor oral hygiene, multiple carious lesions, congenitally missing teeth, class II malocclusion, and open bite.There are common findings that can aid the dental practitioner in recognizingthe syndrome and make appropriate referrals. PMID:21721477

Oberoi, Snehlata; Huynh, Linda; Vargervik, Karin

2011-05-01

105

22q11 deletions in isolated and syndromic patients with tetralogy of Fallot  

Microsoft Academic Search

Tetralogy of Fallot (TF) is a congenital conotruncal heart defect commonly found in DiGeorge (DGS) and velo-cardio-facial (VCFS) syndromes. The deletion of chromosome 22q11 (de122q11) is a well established cause of DGS and VCFS, and it has been demonstrated also in sporadic or familial cases of TF. In order to investigate the prevalence of de122q11 in patients with TF, we

Francesca Amati; Aldo Mari; Maria Cristina Digilio; Rita Mingarelli; Bruno Marino; Aldo Giannotti; Giuseppe Novelli; Bruno Dallapiccola

1995-01-01

106

Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B  

Microsoft Academic Search

.   Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement,\\u000a including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation,\\u000a polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described\\u000a as causative in more than 80%

Friedhelm Hildebrandt; Hans Gerd Nothwang; Urs Vossmerbäumer; Cornelia Springer; Brigitte Strahm; Bernd Hoppe; Burkhard Keuth; Arno Fuchshuber; Uwe Querfeld; Thomas J Neuhaus; Matthias Brandis

1998-01-01

107

Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome  

Microsoft Academic Search

Williams-Beuren syndrome (WBS) is generally the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene, thus causing hemizygosity at the elastin gene locus. The origin of the deletion has been reported by many authors to be maternal in ~60% and paternal in 40% of cases. Segregation analysis of grandparental markers flanking the microdeletion region in WBS patients

Fabrizio Dutly; Albert Schinzel

1996-01-01

108

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

PubMed

Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene. PMID:21932316

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

2011-09-19

109

Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease  

Microsoft Academic Search

Kearns Sayre syndrome (KSS) is a multisystem disorder with a confounding variety of clinical manifestations, including ocular\\u000a myopathy, pigmentary retinopathy, heart block and ataxia. Endocrinopathies are common in KSS, including growth hormone deficiency,\\u000a hypogonadism, diabetes mellitus and hypoparathyroidism. ?A variety of deletions of mitochondrial DNA (mtDNA) are found in\\u000a most cases. We report on a 5-year-old boy with Addison disease

R. G. Boles; T. Roe; D. Senadheera; V. Mahnovski; L. J. C. Wong

1998-01-01

110

Induced Chromosome Deletion in a Williams-Beuren Syndrome Mouse Model Causes Cardiovascular Abnormalities  

Microsoft Academic Search

Aims: The Williams-Beuren syndrome (WBS) is a genetic disorder caused by a heterozygous ?1.5-Mb deletion. The aim of this study was to determine how the genetic changes in a Wbs mouse model alter Eln expression, blood pressure, vessel structure, and abdominal aortic wall dynamics in vivo. Methods: Elastin (ELN) transcript levels were quantified by qRT-PCR and blood pressure was measured

Craig J. Goergen; Hong-Hua Li; Uta Francke; Charles A. Taylor

2011-01-01

111

The Neuropsychology of 22q11 Deletion Syndrome. A Neuropsychiatric Study of 100 Individuals  

ERIC Educational Resources Information Center

|The primary objective of this study was to study the impact of ASD/ADHD on general intellectual ability and profile, executive functions and visuo-motor skills in children and adults with 22q11 deletion syndrome (22q11DS). A secondary aim was to study if gender, age, heart disease, ASD, ADHD or ASD in combination with ADHD had an impact on…

Niklasson, Lena; Gillberg, Christopher

2010-01-01

112

Greig cephalopolysyndactyly syndrome: Altered phenotype of a contiguous gene syndrome by the presence of a chromosomal deletion  

SciTech Connect

Greig cephalopolysyndactyly syndrome (GCPS) is characterized by craniofacial anomalies, broad thumbs and halluces, polydactyly of the hands and feet, and variable syndactyly. Intellectual abilities are usually normal. Inheritance is in an autosomal dominant fashion. The disorder has been mapped to chromosome 7p13, suggesting that the condition represents a contiguous gene syndrome (CGS). A male infant presented with multiple congenital anomalies, including omphalocele, dysgenesis of the corpus callosum, hydrocephalus, esotropia, broad thumbs and halluces, syndactyly, polydactyly of one foot, hypotonia and developmental delay. A de novo interstitial deletion of chromosome 7p was detected, 46,XY,del(7)(p13p15). Although clinical findings in this case were reminiscent of GCPS, and the chromosomal abnormality included the region assigned to the candidate gene for this syndrome, additional physical abnormalities were present, as well as cognitive deficits. Some of these features have been previously described in patients with chromosomal deletions of 7p. The chromosomal abnormality in our case provides supportive evidence of the gene locus in GCPS, and that GCPS represents a new CGS. However, a larger deletion, extending beyond the limits of the gene, significantly altered the phenotype. Isolation of the gene responsible for GCPS, and identification of additional patients with chromosomal abnormalities in this region of chromosome 7, should help to provide more accurate genotype-phenotype correlations.

Hersh, J.H.; Williams, P.G.; Yen, F.F. [Univ. of Louisville, KY (United States)] [and others

1994-09-01

113

Histology of the Pharyngeal Constrictor Muscle in 22q11.2 Deletion Syndrome and Non-Syndromic Children with Velopharyngeal Insufficiency  

Microsoft Academic Search

Plastic surgeons aim to correct velopharyngeal insufficiency manifest by hypernasal speech with a velopharyngoplasty. The functional outcome has been reported to be worse in patients with 22q11.2 deletion syndrome than in patients without the syndrome. A possible explanation is the hypotonia that is often present as part of the syndrome. To confirm a myogenic component of the etiology of velopharyngeal

Josine C. C. Widdershoven; Nicole E. Spruijt; Wim G. M. Spliet; Corstiaan C. Breugem; Moshe Kon; Samuel J. Lin

2011-01-01

114

Detection of Gene Deletions in Children with Chondrodysplasia Punctata, Ichthyosis, Kallmann Syndrome, and Ocular Albinism by FISH Studies  

Microsoft Academic Search

Background: Contiguous gene syndrome (CGS) is characterized by a series of clinical fea- tures resulting from interstitial or terminal deletions of various adjacent genes. Several important genes have been identified in the Xp22.3 region to be responsible for genetically heterogeneous diseases. In this study, fluores- cence in situ hybridization (FISH) methods were used to detect the extent of gene deletion

Jia-Woei Hou

115

Diagnosis of distal 22q11.2 deletion syndrome in a patient with a teratoid/rhabdoid tumour.  

PubMed

We report an 18 year old patient with mild intellectual disability who was diagnosed with a late onset teratoid/rhabdoid tumour by histological and immunohistochemical studies. Array-CGH studies, performed on a peripheral blood sample, showed a 3.4Mb deletion of chromosome 22q11.2, distal to the common DiGeorge syndrome (DGS) or Velocardiofacial syndrome (VCFs) region. This deletion is consistent with a diagnosis of distal 22q11.2 deletion syndrome. The deletion encompasses the INI1/SMARCB1 tumour suppressor gene. Biallelic inactivation of this gene is characteristic of atypical teratoid/rhabdoid tumours. Although several constitutional chromosome conditions are known to have increased susceptibility to various forms of cancer, very little is known regarding the magnitude of risk for malignancy associated with distal 22q11.2 deletion syndrome. In view of this finding we suggest that patients diagnosed with distal 22q11.2 deletion syndrome undergo careful prolonged monitoring for this type of tumour. This case demonstrates the need to carefully assess regions found to be deleted in individuals, referred for dysmorphia and/or developments delay, by array-CGH for the presence of genes known to be implicated in malignancy. PMID:21187175

Beddow, R A; Smith, M; Kidd, A; Corbett, R; Hunter, A G

2010-12-25

116

Safety of Live Viral Vaccines in Patients With Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome\\/Velocardiofacial Syndrome)  

Microsoft Academic Search

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Never- theless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syn- drome and is associated with thymic hypoplasia and diminished T-cell

Elena E. Perez; Aleksandra Bokszczanin; Elaine H. Zackai; Kathleen E. Sullivan

117

16p Subtelomeric Duplication with Vascular Anomalies: an Albanian Case Report and Literature Review  

PubMed Central

A patient with karyotype 46,XY,der(4) was recognized by standard cytogenetic techniques, and presented with facial features, neurological impairment and pulmonary hypertension. Multiplex ligation-dependent probe amplification (MLPA) demonstrated duplication of the subtelomeric region of chromosome 16p and deletion of the subtelomeric region of chromosome 4q, suggesting a translocation between 4q and 16p. The karyotype of his parents was normal and their MLPA analysis also indicated a de novo imbalance. He had microcephaly, high frontal hairline, thin blond hair, bilateral blepharophimosis and palpebral ptosis, short nose, everted upper lip, cleft palate, micrognathia, cupped anteverted ears, hypoplastic distal phalanges and bilateral inguinal hernia. He also had pulmonary hypertension with tricuspidal regurgitation; cavernous liver hemangioma anomalies have been previously described in association with dup16p. We concluded that pulmonary and other vascular anomalies can be a feature of dup16p. We believe this is the first confirmed case of a 16p subtelomeric duplication with vascular anomalies identified in Albania.

Babameto-Laku, A; Mokini, V; Kuneshka, N; Sallabanda, S; Ylli, Z

2012-01-01

118

16p subtelomeric duplication with vascular anomalies: an Albanian case report and literature review.  

PubMed

A patient with karyotype 46,XY,der(4) was recognized by standard cytogenetic techniques, and presented with facial features, neurological impairment and pulmonary hypertension. Multiplex ligation-dependent probe amplification (MLPA) demonstrated duplication of the subtelomeric region of chromosome 16p and deletion of the subtelomeric region of chromosome 4q, suggesting a translocation between 4q and 16p. The karyotype of his parents was normal and their MLPA analysis also indicated a de novo imbalance. He had microcephaly, high frontal hairline, thin blond hair, bilateral blepharophimosis and palpebral ptosis, short nose, everted upper lip, cleft palate, micrognathia, cupped anteverted ears, hypoplastic distal phalanges and bilateral inguinal hernia. He also had pulmonary hypertension with tricuspidal regurgitation; cavernous liver hemangioma anomalies have been previously described in association with dup16p. We concluded that pulmonary and other vascular anomalies can be a feature of dup16p. We believe this is the first confirmed case of a 16p subtelomeric duplication with vascular anomalies identified in Albania. PMID:24052735

Babameto-Laku, A; Mokini, V; Kuneshka, N; Sallabanda, S; Ylli, Z

2012-12-01

119

Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome.  

PubMed

Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked whether smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed single-nucleotide polymorphism array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions involving RPS14 were identified in a 5-year-old patient with nonclassical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with nonclassical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by fluorescence in situ hybridization or cytogenetic testing, thus refining the spectrum of disorders with 5q- deletions. PMID:23943650

Vlachos, Adrianna; Farrar, Jason E; Atsidaftos, Eva; Muir, Ellen; Narla, Anupama; Markello, Thomas C; Singh, Sharon A; Landowski, Michael; Gazda, Hanna T; Blanc, Lionel; Liu, Johnson M; Ellis, Steven R; Arceci, Robert J; Ebert, Benjamin L; Bodine, David M; Lipton, Jeffrey M

2013-08-13

120

Deletion of locus D15S113 in a mother and son without features of Angelman syndrome  

SciTech Connect

Deletions of the proximal long arm of chromosome 15 result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The minimal critical deletion region for Angelman syndrome has been reported to include D15S74 (B1.5), D15S10 (TD3-21), and D15S113 (LS6-1). We report a mother and son who have deletions that include D15S113 but who do not have features of Angelman syndrome. D.H. is a 10-year-old white male referred for genetic evaluation due to mental retardation. He has mild to moderate mental retardation and minor dysmorphic features, including downslanting palpebral fissures, prominent nose, broad forehead, small chin, midface hypoplasia, and large ears. His mother (B.S.) has slightly downslanting palpebral fissures and a borderline intellectual deficit. Neither individual has the seizures, excessive laughter, hand clapping, ataxia or facial dysmorphism which are characteristic of Angelman syndrome. The linear order of probes mapping to 15q11-q13 is 15cen-D15S11-D15S13-D15S10-D15S113-GABRB3-D15S12-tel. The proximal border of the deletion in our patients lies between D15S10 and D15S113. The fact that these two individuals do not have Angelman syndrome, despite deletion of D15S113, suggests that the Angelman syndrome critical deletion region should be further refined to exclude the D15S113 locus. In addition, the findings of a more severe intellectual impairment in the son than in the mother suggests that the region immediately telomeric to the critical deletion region for Angelman syndrome may contain imprintable genes that influence intellectual function.

Michaelis, R.C.; Tarleton, J.C.; Donlon, T.A.; Simensen, R.J. [Greenwood Gneetic Center, SC (United States)] [and others

1994-09-01

121

Fifty microdeletions among 112 cases of sotos syndrome: Low copy repeats possibly mediate the common deletion  

SciTech Connect

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploin sufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45 percent) and 16 point mutations (14 percent) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52 percent) of the 95 Japanese patients and only one (6 percent) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion. This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

Kurotaki, Naohiro; Harada, Naoki; Shimokawa, Osamu; Miyake, Noriko; Kawame, Hiroshi; Uetake, Kimiaki; Makita, Yoshio; Kondoh, Tatsuro; Ogata, Tsutomu; Hasegawa, Tomoko; Nagai, Toshiro; Ozaki, Takao; Touyama, Mayumi; Shenhav, Ruthie; Ohashi, Hirofumi; Medne, Livija; Shiihara, Takashi; Ohtsu, Shigeyuki; Kato, Zen-ichiro; Okamoto, Nobuhiko; Nishimoto, Junji; Lev, Dorit; Miyoshi, Yoko; Ishikiriyama, Satoshi; Sonoda, Tohru; Sakazume, Satoru; Fukushima, Yoshimitsu; Kurosawa, Kenji; Cheng, Jan-Fang; Yoshiura, Koh-ichiro; Ohta, Tohru; Kishino, Tatsuya; Niikawa, Norio; Matsumoto, Naomichi

2003-04-15

122

22q11.2 Distal Deletion Syndrome: Description of a New Case with Truncus Arteriosus Type 2 and Review  

PubMed Central

22q11.2 deletion syndrome is mainly characterized by conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial appearance. The etiology in the majority of patients is a 3-Mb recurrent deletion in region 22q11.2. Nevertheless, recently some cases of infrequent deletions with various sizes have been reported with a different phenotype. We report on a patient with congenital heart disease (truncus arteriosus type 2) in whom a de novo 1.3-Mb 22q11.2 deletion was detected by array comparative genomic hybridization. The deletion described corresponds to an atypical and distal deletion which spans low copy repeat (LCR) 4 and is associated with breakpoint sites that do not correspond to known LCRs of 22q11.2. We examine the clinical phenotype of our case and compare our findings with those published in the literature. The most prevalent clinical features in this type of deletion are a history of prematurity, pre-natal and post-natal growth retardation, slight facial dysmorphic features, microcephaly and developmental delay, with a speech defect in particular. These are clearly different from those found in the classic 22q11.2 deletion syndrome, and we believe that the main differential diagnosis should be with Silver-Russel syndrome. In our case we observe the cardiac phenotype with truncus arteriosus communis usually seen in the classic 22q11.2 deletion syndrome, and so far associated with the TBX1 gene. Significantly, however, TBX1 is not included in our patient's deletion. The possible roles of a position effect or other genes are discussed.

Garavelli, L.; Rosato, S.; Wischmeijer, A.; Gelmini, C.; Esposito, A.; Mazzanti, L.; Franchi, F.; De Crescenzo, A.; Palumbo, O.; Carella, M.; Riccio, A.

2011-01-01

123

Comparison of facial features of DiGeorge syndrome (DGS) due to deletion 10p13-10pter with DGS due to 22q11 deletion  

SciTech Connect

DiGeorge syndrome (DGS) is a congenital anomaly consisting of cardiac defects, aplasia or hypoplasia of the thymus and parathroid glands, and dysmorphic facial features. The majority of DGS cases have a submicroscopic deletion within chromosome 22q11. However there have been a number of reports of DGS in association with other chromosomal abnormalities including four cases with chromosome 10p deletions. We describe a further 10p deletion case and suggest that the facial features in children with DGS due to deletions of 10p are different from those associated with chromosome 22 deletions. The propositus was born at 39 weeks gestation to unrelated caucasian parents, birth weight 2580g (10th centile) and was noted to be dysmorphic and cyanosed shortly after birth. The main dysmorphic facial features were a broad nasal bridge with very short palpebral fissures. Echocardiography revealed a large subsortic VSD and overriding aorta. She had a low ionised calcium and low parathroid hormone level. T cell subsets and PHA response were normal. Abdominal ultrasound showed duplex kidneys and on further investigation she was found to have reflux and raised plasma creatinine. She had an anteriorly placed anus. Her karyotype was 46,XX,-10,+der(10)t(3;10)(p23;p13)mat. The dysmorphic facial features in this baby are strikingly similar to those noted by Bridgeman and Butler in child with DGS as the result of a 10p deletion and distinct from the face seen in children with DiGeorge syndrome resulting from interstitial chromosome 22 deletions.

Goodship, J.; Lynch, S.; Brown, J. [Univ. of Newcastle, Tyne (United Kingdom)] [and others

1994-09-01

124

Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia  

ERIC Educational Resources Information Center

|The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

2010-01-01

125

Critical region in 2q31.2q32.3 deletion syndrome: Report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region  

PubMed Central

Background Standard cytogenetic analysis has revealed to date more than 30 reported cases presenting interstitial deletions involving region 2q31-q32, but with poorly defined breakpoints. After the postulation of 2q31.2q32.3 deletion as a clinically recognizable disorder, more patients were reported with a critical region proposed and candidate genes pointed out. Results We report two female patients with de novo chromosome 2 cytogenetically visible deletions, one of them with an additional de novo deletion in chromosome 20p12.2p12.3. Patient I presents a 16.8?Mb deletion in 2q31.2q32.3 while patient II presents a smaller deletion of 7?Mb in 2q32.1q32.3, entirely contained within patient I deleted region, and a second 4?Mb deletion in Alagille syndrome region. Patient I clearly manifests symptoms associated with the 2q31.2q32.3 deletion syndrome, like the muscular phenotype and behavioral problems, while patient II phenotype is compatible with the 20p12 deletion since she manifests problems at the cardiac level, without significant dysmorphisms and an apparently normal psychomotor development. Conclusions Whereas Alagille syndrome is a well characterized condition mainly caused by haploinsufficiency of JAG1 gene, with manifestations that can range from slight clinical findings to major symptoms in different domains, the 2q31.2q32.3 deletion syndrome is still being delineated. The occurrence of both imbalances in reported patient II would be expected to cause a more severe phenotype compared to the individual phenotype associated with each imbalance, which is not the case, since there are no manifestations due to the 2q32 deletion. This, together with the fact that patient I deleted region overlaps previously reported cases and patient II deletion is outside this common region, reinforces the existence of a critical region in 2q31.3q32.1, between 181 to 185?Mb, responsible for the clinical phenotype.

2012-01-01

126

A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Gouti?res syndrome associated with mtDNA deletions  

PubMed Central

Aicardi–Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLG?, POLG?, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9?kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components.

Leshinsky-Silver, Esther; Malinger, Gustavo; Ben-Sira, Liat; Kidron, Dvora; Cohen, Sarit; Inbar, Shani; Bezaleli, Tali; Levine, Arie; Vinkler, Chana; Lev, Dorit; Lerman-Sagie, Tally

2011-01-01

127

A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutiéres syndrome associated with mtDNA deletions.  

PubMed

Aicardi-Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLG?, POLG?, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components. PMID:21102625

Leshinsky-Silver, Esther; Malinger, Gustavo; Ben-Sira, Liat; Kidron, Dvora; Cohen, Sarit; Inbar, Shani; Bezaleli, Tali; Levine, Arie; Vinkler, Chana; Lev, Dorit; Lerman-Sagie, Tally

2010-11-24

128

MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus.  

PubMed

Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0MB to 43.8MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia, severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder. PMID:23414621

Saito, Mari; Yamagata, Takanori; Matsumoto, Ayumi; Shiba, Yusuke; Nagashima, Masako; Taniguchi, Shuhei; Jimbo, Eriko; Momoi, Mariko Y

2013-02-13

129

Intermediate interstitial deletion of chromosome 7q detected by first-trimester Down's syndrome screening.  

PubMed

We report a case of prenatally diagnosed chromosome 7q intermediate interstitial deletion with the aid of first-trimester Down's syndrome (DS) screening. After detection of a significantly diminished maternal serum pregnancy-associated plasma protein A and correspondingly high DS risk, the pregnant woman underwent amniocentesis for fetal chromosomal analysis. Amniocytes revealed a 46,XY,del(7) (q21.2q31.1) karyotype and 21 weeks' sonography revealed fetal growth restriction, elevated nuchal fold thickness and cardiomegaly. After therapeutic induction at 22 weeks of gestation, a 310-gram male fetus was born with multiple gross abnormalities including hypertelorism, wide nasal bridge, low-set ears, cleft palate, prominent cheeks, prominent nuchal skin, simian crease and postaxial polydactyly. We review the associated prenatal screening findings, the sonographic profile and phenotypical features associated with chromosome 7q intermediate interstitial deletion. PMID:18841024

Cheong, Mei-Leng Joy; Tsai, Ming-Song; Cortes, Raul A; Harrison, Michael R

2008-10-08

130

Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4.  

PubMed

Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders. PMID:22378281

Bondurand, Nadége; Fouquet, Virginie; Baral, Viviane; Lecerf, Laure; Loundon, Natalie; Goossens, Michel; Duriez, Benedicte; Labrune, Philippe; Pingault, Veronique

2012-02-29

131

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.  

PubMed Central

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Barrientos, A; Volpini, V; Casademont, J; Genis, D; Manzanares, J M; Ferrer, I; Corral, J; Cardellach, F; Urbano-Marquez, A; Estivill, X; Nunes, V

1996-01-01

132

Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case.  

PubMed

Contiguous ABCD1 DXS1357E deletion syndrome (CADDS) is a contiguous deletion syndrome involving the ABCD1 and DXS1357E/BAP31 genes on Xq28. Although ABCD1 is responsible for X-linked adrenoleukodystrophy (X-ALD), its phenotype differs from that of CADDS, which manifests with many features of Zellweger syndrome (ZS), including severe growth and developmental retardation, liver dysfunction, cholestasis and early infantile death. We report here the fourth case of CADDS, in which a boy had dysmorphic features, including a flat orbital edge, hypoplastic nose, micrognathia, inguinal hernia, micropenis, cryptorchidism and club feet, all of which are shared by ZS. The patient achieved no developmental milestones and died of pneumonia at 8 months. Biochemical studies demonstrated abnormal metabolism of very long chain fatty acids, which was higher than that seen in X-ALD. Immunocytochemistry and Western blot showed the absence of ALD protein (ALDP) despite the presence of other peroxisomal proteins. Pathological studies disclosed a small brain with hypomyelination and secondary hypoxic-ischemic changes. Neuronal heterotopia in the white matter and leptomeningeal glioneuronal heterotopia indicated a neuronal migration disorder. The liver showed fibrosis and cholestasis. The thymus and adrenal glands were hypoplastic. Array comparative genomic hybridization (CGH) analysis suggested that the deletion was a genomic rearrangement in the 90-kb span starting in DXS1357E/BACP31 exon 4 and included ABCD1, PLXNB3, SRPK3, IDH3G and SSR4, ending in PDZD4 exon 8. Thus, the absence of ALDP, when combined with defects in the B-cell antigen receptor associated protein 31 (BAP31) and other factors, severely affects VLCFA metabolism on peroxisomal functions and produces ZS-like pathology. PMID:22994209

Iwasa, Mitsuaki; Yamagata, Takanori; Mizuguchi, Masashi; Itoh, Masayuki; Matsumoto, Ayumi; Hironaka, Mitsugu; Honda, Ayako; Momoi, Mariko Y; Shimozawa, Nobuyuki

2012-09-21

133

Midline defects in deletion 18p syndrome: clinical and molecular characterization of three patients.  

PubMed

The phenotype of monosomy 18p varies widely, the main clinical manifestations being mental and growth retardation, and craniofacial dysmorphism. Clinical features also include growth hormone (GH) deficiency, or holoprosencephaly (HPE). Haploinsufficiency for TGIF, mapped to 18p11.3, is not generally sufficient to cause HPE. To perform a genotype-phenotype correlation, and delineate the region involved in GH deficiency, we carried out a molecular characterization of the 18p deletions, in three patients with midline defects. Two unrelated children, a 7-month-old girl and a 2-month-old boy had del(18p) syndrome and GH deficiency. In addition, the boy had HPE. HPE genes, SHH, ZIC2, SIX3, and TGIF, were tested by denaturing high-performance liquid chromatography and quantitative multiplex of PCR short fluorescent fragments analyses. A deletion of TGIF was confirmed, without any associated mutation for the tested HPE genes, suggesting the role of other genetic or environmental factors. The third patient was his moderately retarded mother. A set of chromosome 18p-specific BACs clones was used as fluorescence in-situ hybridization probes to define the breakpoints. Recently, it was found that there seem to be a breakpoint cluster in the centromeric region at 18p11.1, which was not observed in our patients. The girl was found to have a deletion of 10.3 Mb, with a breakpoint in 18p11.22. The boy and his mother had a smaller deletion (8 Mb), with a breakpoint in 18p11.23. These findings suggest that the distal region on 18p is involved in the main clinical features, and GH deficiency, in 18p deletions. PMID:17786116

Portnoï, Marie-France; Gruchy, Nicolas; Marlin, Sandrine; Finkel, Lina; Denoyelle, Françoise; Dubourg, Christèle; Odent, Sylvie; Siffroi, Jean-Pierre; Le Bouc, Yves; Houang, Muriel

2007-10-01

134

Hypocalcemia in a Patient With Osteosarcoma and 22q11.2 Deletion Syndrome  

PubMed Central

Summary Hypocalcemia is a rare complication of osteosarcoma, having been described in only 4 reports. We present the case of a 16-year-old male with metastatic osteosarcoma of the right humerus who was found to have severe asymptomatic hypocalcemia. Cytogenetic analysis of peripheral blood revealed a microdeletion in band 22q11.2. Following amputation of the tumor-bearing extremity, the patient’s calcium levels increased, but did not normalize. These findings suggested that the etiology of his hypocalcemia was osteoblastic utilization of calcium by the tumor, exacerbated by 22q11.2 deletion syndrome.

Mussai, Francis J.; Cunningham, Lea C.; Rezvani, Geoffrey; Stratakis, Constantine A.; Reynolds, James C.; Nesterova, Galina; Henshaw, Robert M.; Levine, Jason E.; Helman, Lee J.; Arthur, Diane C.; Kim, Su Young

2009-01-01

135

Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA)  

PubMed Central

Background COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown. Case presentations We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone. Conclusion Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.

2013-01-01

136

Exclusion of 22q11 deletion in Noonan syndrome with Tetralogy of Fallot  

SciTech Connect

We read with interest the report of Robin et al. [1995] published in recent issue of the Journal. The authors described 6 patients with Noonan syndrome (NS) who underwent molecular evaluation for submicroscopic deletion of chromosome band 22q11. None of those patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only one patient. This patient had NS-like manifestations without clinical manifestations of DiGeorge (DG) or velo-cardio-facial (VCF) syndromes. The molecular results obtained in the other 5 patients led the authors to conclude that classical NS is not due to del(22)(q11), even if some patients with del(22)(q11) may present NS-like manifestations. 12 refs., 1 tab.

Digilio, M.C.; Marino, B.; Giannotti, A. [Bambino Gesu Hospital, Rome (Italy); Dallapiccola, B. [Univ. of Tor Vergata, Rome (Italy)]|[Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo (Italy)

1996-04-24

137

mtDNA Deletion in an Iranian Infant with Pearson Marrow Syndrome  

PubMed Central

Background Pearson syndrome (PS) is a rare multisystem mitochondrial disorder of hematopoietic system, characterized by refractory sideroblastic anemia, pancytopenia, exocrine pancreatic insufficiency, and variable neurologic, hepatic, renal, and endocrine failure. Case Presentation We describe a six-month-old female infant with Pearson marrow syndrome who presented with neurological manifestations. She had several episodes of seizures. Hematopoietic abnormalities were macrocytic anemia and neutropenia. Bone marrow aspiration revealed a cellular marrow with marked vacuolization of erythroid and myeloid precursors. Analysis of mtDNA in peripheral blood showed 8.5 kb deletion that was compatible with the diagnosis of PS. Conclusion PS should be considered in infants with neurologic diseases, in patients with cytopenias, and also in patients with acidosis or refractory anemia.

Arzanian, Mohammad Taghi; Eghbali, Aziz; Karimzade, Parvaneh; Ahmadi, Mitra; Houshmand, Massoud; Rezaei, Nima

2010-01-01

138

Autosomal recessive Wolfram syndrome associated with an 8.5 kb mtDNA single deletion  

SciTech Connect

Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and {approximately}5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level. 39 refs., 6 figs., 3 tabs.

Barrientos, A.; Casademont, J.; Cardellach, F. [Universitat de Barcelona (Spain)] [and others

1996-05-01

139

A novel human gene FKBP6 is deleted in Williams syndrome.  

PubMed

Williams syndrome (WS) is a developmental disorder caused by haploinsufficiency of genes at 7q11.23. We have shown that hemizygosity of elastin is responsible for one feature of WS, supravalvular aortic stenosis. We have also implicated LIM-kinase 1 hemizygosity as a contributing factor to impaired visual-spatial constructive cognition in WS. Here we identify and characterize a novel gene, FKBP6, within the common WS deletion region. FKBP6 shows homology to the FK-506 binding protein (FKBP) class of immunophilins. FKBP6 has a putative N-terminal FK-506 binding and peptidylproyl isomerase (rotamase) domain and, like known high-molecular-weight FKBPs, an imperfect C-terminal tetratricopeptide repeat domain. FKBP6 is expressed in testis, heart, skeletal muscle, liver, and kidney. FKBP6 consists of nine exons and is completely contained within a 35-kb cosmid clone. Fluorescence in situ hybridization experiments show that FKBP6 gene is deleted in 40/40 WS individuals. Hemizygous deletion of FKBP6 may contribute to certain defects such as hypercalcemia and growth delay in WS. PMID:9782077

Meng, X; Lu, X; Morris, C A; Keating, M T

1998-09-01

140

Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes  

Microsoft Academic Search

Williams syndrome (WS) is a contiguous gene deletion disorder caused by haploinsufficiency of genes at 7q11.23 . We have shown\\u000a that hemizygosity of elastin is responsible for one feature of WS, supravalvular aortic stenosis (SVAS). We have also implicated LIM-kinase 1 hemizygosity as a contributing factor to impaired visual-spatial constructive cognition in WS. However, the common WS deletion\\u000a region has

Xun Meng; Xiaojun Lu; Zhizhong Li; Eric D. Green; Hillary Massa; Barbara J. Trask; Colleen A. Morris; Mark T. Keating

1998-01-01

141

Functional Gene-Expression Analysis Shows Involvement of Schizophrenia-Relevant Pathways in Patients with 22q11 Deletion Syndrome  

Microsoft Academic Search

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's)

Nico J. M. van Beveren; Lianne C. Krab; Sigrid Swagemakers; Gabriella Buitendijk; Erik Boot; Peter van der Spek; Ype Elgersma; Therese A. M. J. van Amelsvoort

2012-01-01

142

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3  

PubMed Central

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16pl3.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective confirmation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome. ImagesFigure 2

Breuning, Martijn H.; Dauwerse, Hans G.; Fugazza, Gluseppina; Saris, Jasper J.; Spruit, Lia; Wijnen, Herman; Tommerup, Niels; van der Hagen, C. B.; Imaizumi, Kiyoshi; Kuroki, Yoshikazu; van den Boogaard, Marie-Jose; de Pater, Joke M.; Mariman, Edwin C. M.; Hamel, Ben C. J.; Himmelbauer, Heinz; Frischauf, Anne-Marie; Stallings, Raymond L.; Beverstock, Geoffrey C.; van Ommen, Gert-Jan B.; Hennekam, Raoul C. M.

1993-01-01

143

Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome  

SciTech Connect

The 5q syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensemblgene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34 cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.

Boultwood, Jacqueline; Fidler, Carrie; Strickson, Amanda J.; Watkins, Fiona; Gama, Susana; Kearney, Lyndal; Tosi, Sabrina; Kasprzyk, Arek; Cheng, Jan-Fang; Jaju, Rina J.; Wainscoat, James S.

2002-01-15

144

Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family  

PubMed Central

We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed

Madhu, Sri Venkat; Kant, Saket; Holla, Vikram Venkappayya; Arora, Rakesh; Rathi, Sahaj

2012-01-01

145

Werner syndrome protein suppresses the formation of large deletions during the replication of human telomeric sequences  

PubMed Central

Werner syndrome (WS) is a disorder characterized by features of premature aging and increased cancer that is caused by loss of the RecQ helicase WRN. Telomeres consisting of duplex TTAGGG repeats in humans protect chromosome ends and sustain cellular proliferation. WRN prevents the loss of telomeres replicated from the G-rich strand, which can form secondary G-quadruplex (G4) structures. Here, we dissected WRN roles in the replication of telomeric sequences by examining factors inherent to telomeric repeats, such as G4 DNA, independently from other factors at chromosome ends that can also impede replication. For this we used the supF shuttle vector (SV) mutagenesis assay. We demonstrate that SVs with [TTAGGG]6 sequences are stably replicated in human cells, and that the repeats suppress the frequency of large deletions despite G4 folding potential. WRN depletion increased the supF mutant frequency for both the telomeric and non-telomeric SVs, compared with the control cells, but this increase was much greater (27-fold) for telomeric SVs. The higher SV mutant frequencies in WRN-deficient cells were primarily due to an increase in large sequence deletions and rearrangements. However, WRN depletion caused a more dramatic increase in deletions and rearrangements arising within the telomeric SV (70-fold), compared with non-telomeric SV (8-fold). Our results indicate that WRN prevents large deletions and rearrangements during replication, and that this role is particularly important in templates with telomeric sequence. This provides a possible explanation for increased telomere loss in WS cells.

Damerla, Rama Rao; Knickelbein, Kelly E.; Strutt, Steven; Liu, Fu-Jun; Wang, Hong; Opresko, Patricia L.

2012-01-01

146

Phylogenetic analysis of mitochondrial DNA in a patient with Kearns-Sayre syndrome containing a novel 7629-bp deletion.  

PubMed

Mitochondrial DNA mutations have been associated with different illnesses in humans, such as Kearns-Sayre syndrome (KSS), which is related to deletions of different sizes and positions among patients. Here, we report a Mexican patient with typical features of KSS containing a novel deletion of 7629 bp in size with 85% heteroplasmy, which has not been previously reported. Sequence analysis revealed 3-bp perfect short direct repeats flanking the deletion region, in addition to 7-bp imperfect direct repeats within 9-10 bp. Furthermore, sequencing, alignment and phylogenetic analysis of the hypervariable region revealed that the patient may belong to a founder Native American haplogroup C4c. PMID:23391298

Montiel-Sosa, Jose Francisco; Herrero, María Dolores; Munoz, Maria de Lourdes; Aguirre-Campa, Luis Enrique; Pérez-Ramírez, Gerardo; García-Ramírez, Rubén; Ruiz-Pesini, Eduardo; Montoya, Julio

2013-02-08

147

Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome.  

PubMed Central

Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4, 000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb-resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion.

Edelmann, L; Pandita, R K; Morrow, B E

1999-01-01

148

Macular lesion resembling adult-onset vitelliform macular dystrophy in Kearns-Sayre syndrome with multiple mtDNA deletions.  

PubMed

We present the case of a 48-year-old woman with a clinically and histopathologically confirmed Kearns-Sayre syndrome who developed a maculopathy resembling an adult-onset vitelliform macular dystrophy in her right eye. DNA analysis identified the presence of multiple deletions in the mtDNA of the muscle sample, with the common deletion of 4977 bp the most abundant. To the best of our knowledge, there have been no previous reports of such macular lesion occurring in association with Kearns-Sayre syndrome. PMID:20497429

Ascaso, Francisco J; Lopez-Gallardo, Ester; Del Prado, Eduardo; Ruiz-Pesini, Eduardo; Montoya, Julio

2010-11-01

149

A case of Kearns-Sayre syndrome with two novel deletions (9.768 and 7.253 kb) of the mtDNA associated with the common deletion in blood leukocytes, buccal mucosa and hair follicles.  

PubMed

Kearns-Sayre syndrome is a mitochondrial disorder characterized by the emergence before the age of 20 years of progressive external ophthalmoplegia, pigmentary retinopathy, with other heterogeneous clinical manifestations. Generally, mitochondrial DNA deletions were associated with KSS but the size and position of these deletions differ among patients. This study reported a Tunisian patient with typical features of KSS. Long-range PCR amplification of the mtDNA in different tissues from this patient showed multiple mitochondrial deletions: two novel 9.768 and 7.253 kb deletions spanning respectively nucleotides 6124-15,893 and 8572-15,826 associated with the common 4.977 kb deletion. PMID:20388556

Mkaouar-Rebai, Emna; Chamkha, Imen; Kammoun, Thouraya; Chabchoub, Imen; Aloulou, Hajer; Fendri, Nourhene; Hachicha, Mongia; Fakhfakh, Faiza

2010-04-11

150

AZF and DAZ gene copy-specific deletion analysis in maturation arrest and Sertoli cell-only syndrome.  

PubMed

Deletions of the AZFc region in Yq11.2, which include the DAZ gene family, are responsible for most cases of male infertility and were associated with severe oligozoospermia and also with a variable testicular pathology. To uncover the functional contribution of DAZ to human spermatogenesis, a DAZ gene copy-specific deletion analysis was previously established and showed that DAZ1/DAZ2 deletions associate with oligozoospermia. In this study we applied the same screening method to 50 control fertile males and 91 non-obstructive azoospermic males, 39 with Sertoli cell-only syndrome (SCOS) and 52 with meiotic arrest (MA). Samples were also screened with 24 sequence-tagged sites to the different AZF regions, including 114 control fertile males. After biopsy (testicular sperm extraction, TESE), residual spermiogenesis was found in 57.7% MA and 30.8% SCOS cases (incomplete syndromes). DAZ1/DAZ2 deletions were associated with the testicular phenotype of residual spermiogenesis as they were only found in two patients (8%) with incomplete MA. Differences between incomplete (23.3%) and complete (4.5%) MA cases regarding AZFc and DAZ1/DAZ2 deletion frequencies, and between incomplete (58.3%) and complete (11.1%) SCOS cases for AZFc deletions, suggest that incomplete syndromes might represent an aggravation of the oligozoospermic phenotype. As successful TESE was achieved in 87.5% of MA cases with AZFc and DAZ1/DAZ2 deletions and in 58.3% of SCOS cases with AZFc deletions, the present results also suggest that these molecular markers might be used for the establishment of a prognosis before TESE. PMID:15347736

Ferrás, C; Fernandes, S; Marques, C J; Carvalho, F; Alves, C; Silva, J; Sousa, M; Barros, A

2004-09-03

151

Prenatal diagnosis of a 7p15-p21 deletion encompassing the TWIST1 gene involved in Saethre-Chotzen syndrome.  

PubMed

Saethre-Chotzen syndrome is a craniosynostosis syndrome that is rarely diagnosed prenatally. It is caused by cytogenetic deletions or mutations of the TWIST1 gene. We report here a de novo prenatal case with clinically and molecularly well defined Saethre-Chotzen syndrome due to a TWIST1 deletion. This is the first reported case of a deletion encompassing the TWIST1 gene to be diagnosed prenatally. We recommend screening for a deletion of the TWIST1 gene if signs of coronal craniosynostosis with no clear etiology are observed on ultrasound examination. PMID:22569119

Spaggiari, Emmanuel; Aboura, Azzedine; Sinico, Martine; Mabboux, Philippe; Dupont, Céline; Delezoide, Anne-Lise; Guimiot, Fabien

2012-05-05

152

Brain and Behavior in Children with 22Q11.2 Deletion Syndrome: A Volumetric and Voxel-Based Morphometry MRI Study  

ERIC Educational Resources Information Center

|In people with velo-cardio-facial syndrome [or 22q11.2 deletion syndrome (22qDS)], a single interstitial deletion of chromosome 22q11.2 causes a wide spectrum of cognitive deficits ranging from global learning difficulties to specific cognitive deficits. People with 22qDS are also at high risk of developing attention-deficit hyperactivity…

Campbell, Linda E.; Daly, Eileen; Toal, Fiona; Stevens, Angela; Azuma, Rayna; Catani, Marco; Ng, Virginia; Van Amelsvoort, Therese; Chitnis, Xavier; Cutter, William; Murphy, Declan G. M.; Murphy, Kieran C.

2006-01-01

153

Ventricular tachycardia in a Brugada syndrome patient caused by a novel deletion in SCN5A  

PubMed Central

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain during agitation is described. An electrocardiogram revealed monomorphic ventricular tachycardia; after he was converted to nodal rhythm, he spontaneously went into sinus rhythm, and showed classic Brugada changes with coved ST elevation in leads V1 to V2. Mutation analysis of SCN5A revealed a novel mutation, 3480 deletion T frame shift mutation, resulting in premature truncation of the protein. Heterologous expression of this truncated protein in human embryonic kidney 293 cells showed a markedly reduced protein expression level. By performing whole-cell patch clamp experiments using human embryonic kidney 293 cells transfected with the mutated SCN5A, no current could be recorded. Hence, the results suggest that the patient suffered from haploinsufficiency of Nav1.5, and that this mutation was the cause of his Brugada syndrome.

Tfelt-Hansen, Jacob; Jespersen, Thomas; Hofman-Bang, Jacob; Rasmussen, Hanne Borger; Cedergreen, Pernille; Skovby, Flemming; Abriel, Hugues; Svendsen, Jesper Hastrup; Olesen, Soren-Peter; Christiansen, Michael; Haunso, Stig

2009-01-01

154

High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome.  

PubMed

Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent. PMID:22072402

Lundin, Catarina; Hjorth, Lars; Behrendtz, Mikael; Nordgren, Ann; Palmqvist, Lars; Andersen, Mette Klarskov; Biloglav, Andrea; Forestier, Erik; Paulsson, Kajsa; Johansson, Bertil

2011-11-10

155

Temporal Lobe Anatomy and Psychiatric Symptoms in Velocardiofacial Syndrome (22Q11.2 Deletion Syndrome)  

ERIC Educational Resources Information Center

|Objective: To investigate the association between mesial temporal lobe morphology, ratios of prefrontal cortex to amygdala and hippocampus volumes, and psychiatric symptomatology in children and adolescents with velocardiofacial syndrome (VCFS). Method: Scores on behavioral rating scales and volumetric measures of the amygdala, hippocampus, and…

Kates, Wendy R.; Miller, Adam M.; Abdulsabur, Nuria; Antshel, Kevin M.; Conchelos, Jena; Fremont, Wanda; Roizen, Nancy

2006-01-01

156

Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome.  

PubMed

Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin's deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk. PMID:14708107

Saitta, Sulagna C; Harris, Stacy E; McDonald-McGinn, Donna M; Emanuel, Beverly S; Tonnesen, Melissa K; Zackai, Elaine H; Seitz, Suzanne C; Driscoll, Deborah A

2004-01-30

157

Cri du chat syndrome determined by the 5p15.3?pter deletion—diagnostic problems  

Microsoft Academic Search

A cytogenetic analysis was performed on an 8-day-old girl, who was suspected of Cri du chat syndrome (CdCS) on the basis of a cat-like cry, despite her dysmorphic features not being characteristic of this syndrome. The cytogenetic analysis revealed a partial deletion of the short arm of chromosome 5, but did not allow precise specification of the break points. Fluorescence

Izabela Laczmanska; Agnieszka Stembalska; Justyna Gil; Halina Czemarmazowicz; Maria Sasiadek

2006-01-01

158

Memory and Learning in Children with 22q11.2 Deletion Syndrome: Evidence for Ventral and Dorsal Stream Disruption?  

Microsoft Academic Search

This study examined memory functioning in children and adolescents with 22q11.2 Deletion Syndrome (DS; velocardiofacial syndrome). An overall verbal better than nonverbal memory pattern was evident on the Test of Memory and Learning (TOMAL), with children with 22q11.2 DS performing significantly below their siblings and children with low average IQ but similar to children with autism on facial memory. Children

Renée R. Lajiness-O’Neill; Isabelle Beaulieu; Jeffrey B. Titus; Alexander Asamoah; Erin D. Bigler; Erawati V. Bawle; Rebecca Pollack

2005-01-01

159

Familial translocations involving 15q11-q13 can give rise to interstitial deletions causing Prader-Willi or Angelman syndrome  

Microsoft Academic Search

A de novo interstitial deletion of 15q11-q13 is the major cause of Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Here we describe two unrelated PWS patients with a typical deletion, whose fathers have a balanced translocation involving the PWS\\/AS region. Microsatellite data suggest that the deletion is the result of an unequal crossover between the derivative chromosome 15 and the

B Horsthemke; A Maat-Kievit; E Sleegers; A van den Ouweland; K Buiting; C Lich; P Mollevanger; G Beverstock; G Gillessen-Kaesbach; G Schwanitz

1996-01-01

160

Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review.  

PubMed

We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR) in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery. aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0-3,165,530)×1. The qPCR assays revealed a maternal origin of the deletion. Metaphase FISH analysis detected the absence of the LIS1 probe signal on the aberrant chromosome 17. The karyotype was 46,XX,del(17)(p13.3). We review the literature of chromosome 17p13.3 deletion syndrome with prenatal findings and diagnosis, and suggest that prenatal ultrasound detection of central nervous system anomalies such as lissencephaly, corpus callosum dysgenesis/agenesis, ventriculomegaly and microcephaly associated with IUGR, polyhydramnios, congenital heart defects, abdominal wall defects and renal abnormalities should include a differential diagnosis of chromosome 17p13.3 deletion syndrome. PMID:24055730

Chen, Chih-Ping; Chang, Tung-Yao; Guo, Wan-Yuo; Wu, Pei-Chen; Wang, Liang-Kai; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chen, Yu-Ting; Chen, Li-Feng; Wang, Wayseen

2013-09-19

161

Mosaicism for the fragile X syndrome full mutation and deletions within the CGG repeat of the FMR1 gene.  

PubMed Central

The main mutation responsible for the fragile X syndrome is the expansion of an untranslated CGG repeat in the first exon of the FMR1 gene, associated with the hypermethylation of the proximal CpG island and the CGG repeat region, and repression of transcription of FMR1. Fragile X syndrome mosaicism has been described as the coexistence of the full mutation and the permutation. We present here two cases of mosaicism for the full mutation in the FMR1 gene and deletions involving the CGG repeat region. In one case the deletion removed 113 bp proximal to the CGG repeat and part of the repeat itself, leaving 30 pure repeats, and representing 17% of lymphocytes of the patient. The 5' breakpoint of this deletion falls outside the putative hotspot for deletions in the CGG region of FMR1. In the second case the deleted region only involved the CGG sequence (leaving 15 pure repeats), with normal sequences flanking the repeat; this deleted ("normal") FMR1 was estimated to be in about 31% of blood lymphocytes. This second case can be considered a true regression of the CGG FMR1 expansion to a normal sized allele, although in mosaic form. Images

Mila, M; Castellvi-Bel, S; Sanchez, A; Lazaro, C; Villa, M; Estivill, X

1996-01-01

162

An interstitial deletion of 8q23.3-q24.22 associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and epilepsy.  

PubMed

We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q23.3-q24.22 deletion detected by array comparative genomic hybridization. The patient was previously misdiagnosed as having Ehlers-Danlos syndrome. However, his clinical findings are in fact correlated with trichorhinophalangeal syndrome type II/Langer-Giedion syndrome and Cornelia de Lange syndrome-4. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TRPS1, RAD21, EXT1 and KCNQ3 in this case. PMID:23933416

Chen, Chih-Ping; Lin, Shuan-Pei; Liu, Yu-Peng; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chen, Yu-Ting; Lee, Chen-Chi; Wang, Wayseen

2013-08-07

163

MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported  

Microsoft Academic Search

Sotos syndrome (MIM #117550) is an autosomal dominant condition characterized by pre and postnatal overgrowth, macrocephaly and typical facial gestalt with frontal bossing, hypertelorism, antimongoloid slant of the palpebral fissures, prominent jaw and high and narrow palate. This syndrome is also frequently associated with brain, cardiovascular, and urinary anomalies and is occasionally accompanied by malignant lesions such as Wilms tumour

Claudia Fagali; Fernando Kok; Pablo Nicola; Chong Kim; Débora Bertola; Lílian Albano; Célia P. Koiffmann

2009-01-01

164

Isolation of expressed sequences from the region commonly deleted in Velo-cardio-facial syndrome  

SciTech Connect

Velo-cardio-facial syndrome (VCFS) is a relatively common autosomal dominant genetic disorder characterized by cleft palate, cardiac abnormalities, learning disabilities and a characteristic facial dysmorphology. Most VCFS patients have interstitial deletions of 22q11 of 1-2 mb. In an effort to isolate the gene(s) responsible for VCFS we have utilized a hybrid selection protocol to recover expressed sequences from three non-overlapping YACs comprising almost 1 mb of the commonly deleted region. Total yeast genomic DNA or isolated YAC DNA was immobilized on Hybond-N filters, blocked with yeast and human ribosomal and human repetitive sequences and hybridized with a mixture of random primed short fragment cDNA libraries. Six human short fragment libraries derived from total fetus, fetal brain, adult brain, testes, thymus and spleen have been used for the selections. Short fragment cDNAs retained on the filter were passed through a second round of selection and cloned into lambda gt10. cDNAs shown to originate from the YACs and from chromosome 22 are being used to isolate full length cDNAs. Three genes known to be present on these YACs, catechol-O-methyltransferase, tuple 1 and clathrin heavy chain have been recovered. Additionally, a gene related to the murine p120 gene and a number of novel short cDNAs have been isolated. The role of these genes in VCFS is being investigated.

Sirotkin, H.; Morrow, B.; DasGupta, R. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others

1994-09-01

165

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome  

PubMed Central

Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage—the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)—specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement.

Meechan, Daniel W.; Tucker, Eric S.; Maynard, Thomas M.; LaMantia, Anthony-Samuel

2012-01-01

166

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome.  

PubMed

Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage-the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)-specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement. PMID:23091025

Meechan, Daniel W; Tucker, Eric S; Maynard, Thomas M; LaMantia, Anthony-Samuel

2012-10-22

167

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

PubMed

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

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

2010-05-12

168

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

PubMed Central

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.

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

169

Emotion Regulation and Development in Children with Autism and 22q13 Deletion Syndrome: Evidence for Group Differences  

ERIC Educational Resources Information Center

Emotion regulation (ER) abilities and developmental differences were investigated among 19 children with autism and 18 children with 22q13 Deletion Syndrome (a rare chromosomal disorder with certain autistic symptoms). The purpose of this study was to examine the phenotypic similarities between the two disorders. ER was measured by the Temperament…

Glaser, Sarah E.; Shaw, Steven R.

2011-01-01

170

Pathologic features of dilated cardiomyopathy with localized noncompaction in a child with deletion 1p36 syndrome.  

PubMed

Dilated cardiomyopathy and ventricular noncompaction have been reported in association with deletion 1p36 syndrome. Previous descriptions include echocardiographic and/or gross pathologic descriptions. There are no previous reports of microscopic findings. We report a case with descriptions of echocardiographic, gross pathologic, and microscopic findings. PMID:21492410

Pearce, F Bennett; Litovsky, Silvio H; Dabal, Robert J; Robin, Nathaniel; Dure, Leon J; George, James F; Kirklin, James K

2011-04-14

171

A Longitudinal Examination of the Psychoeducational, Neurocognitive, and Psychiatric Functioning in Children with 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

|The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnesses appearing in late adolescence/early adulthood. Little is known of the developmental…

Hooper, Stephen R.; Curtiss, Kathleen; Schoch, Kelly; Keshavan, Matcheri S.; Allen, Andrew; Shashi, Vandana

2013-01-01

172

Emotion regulation and development in children with autism and 22q13 Deletion Syndrome: Evidence for group differences  

Microsoft Academic Search

Emotion regulation (ER) abilities and developmental differences were investigated among 19 children with autism and 18 children with 22q13 Deletion Syndrome (a rare chromosomal disorder with certain autistic symptoms). The purpose of this study was to examine the phenotypic similarities between the two disorders. ER was measured by the Temperament and Atypical Behavior Scale (TABS) and development was measured by

Sarah E. Glaser; Steven R. Shaw

2011-01-01

173

Emotion Regulation and Development in Children with Autism and 22q13 Deletion Syndrome: Evidence for Group Differences  

ERIC Educational Resources Information Center

|Emotion regulation (ER) abilities and developmental differences were investigated among 19 children with autism and 18 children with 22q13 Deletion Syndrome (a rare chromosomal disorder with certain autistic symptoms). The purpose of this study was to examine the phenotypic similarities between the two disorders. ER was measured by the…

Glaser, Sarah E.; Shaw, Steven R.

2011-01-01

174

Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes.  

PubMed

Patients with X-linked agammaglobulinemia (XLA) can present with sensorineural deafness. This can result from a gross deletion that not only involved the Bruton's tyrosine kinase (BTK) gene, but also TIMM8A, mutations in which underlie the Mohr-Tranebjærg syndrome (MTS). We analyzed the genomic break points observed in three XLA-MTS patients and compared these with deletions break points from XLA patients. Patient 1 had a 63-kb deletion with break points in intron 15 of BTK and 4?kb upstream of TAF7L. Patients 2 and 3 had 149.7 and 196?kb deletions comprising BTK, TIMM8A, TAF7L and DRP2. The break points in patients 1 and 3 were located in Alu and endogenous retrovirus (ERV) repeats, whereas the break points in patient 2 did not show involvement of transposable elements. Comparison of gross deletion sizes and involvement of transposable elements in XLA and XLA-MTS patients from the literature showed preferential involvement of Alu elements in smaller deletions (<10?kb). These results show further insights into the molecular mechanisms underlying gross deletions in patients with primary immunodeficiency. PMID:21753765

Arai, Takashi; Zhao, Meina; Kanegane, Hirokazu; van Zelm, Menno C; Futatani, Takeshi; Yamada, Masafumi; Ariga, Tadashi; Ochs, Hans D; Miyawaki, Toshio; Oh-ishi, Tsutomu

2011-07-14

175

Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene.  

PubMed

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia. PMID:24056535

Conti, Valerio; Carabalona, Aurelie; Pallesi-Pocachard, Emilie; Parrini, Elena; Leventer, Richard J; Buhler, Emmanuelle; McGillivray, George; Michel, François J; Striano, Pasquale; Mei, Davide; Watrin, Françoise; Lise, Stefano; Pagnamenta, Alistair T; Taylor, Jenny C; Kini, Usha; Clayton-Smith, Jill; Novara, Francesca; Zuffardi, Orsetta; Dobyns, William B; Scheffer, Ingrid E; Robertson, Stephen P; Berkovic, Samuel F; Represa, Alfonso; Keays, David A; Cardoso, Carlos; Guerrini, Renzo

2013-09-20

176

Nonverbal and verbal learning: A comparative study of children and adolescents with 22q11 deletion syndrome, non-syndromal Nonverbal Learning Disorder and memory disorder  

Microsoft Academic Search

The 22q11 deletion syndrome (DS) is a common genetic disorder, and a Nonverbal Learning Disorder (NLD) is considered as a predominant part of the phenotype. The focus of our study was to investigate the role of learning in this NLD characteristic. We compared results of children and adolescents with 22q11 DS; with non-syndromal NLD and with memory disorders on multi-trial

A. C. Lepach; F. Petermann

2011-01-01

177

Neuroanatomic Predictors to Prodromal Psychosis in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome): A Longitudinal Study  

PubMed Central

Background Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest. Methods We acquired high-resolution anatomic MR images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings and 24 age-matched community controls at two timepoints, between late childhood (mean age, 11.9 years) and mid-adolescence (mean age, 15.1 years). Results With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community controls during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p < .002) and verbal IQ (p < .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2. Conclusions These findings are in line with studies of non-VCFS individuals at risk for schizophrenia, and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS.

Kates, Wendy R.; Antshel, Kevin M.; Faraone, Stephen V.; Fremont, Wanda P.; Higgins, Anne Marie; Shprintzen, Robert J.; Botti, Jo-Anna; Kelchner, Lauren; McCarthy, Christopher

2010-01-01

178

A novel homozygous 10 nucleotide deletion in BBS10 causes Bardet-Biedl syndrome in a Pakistani family.  

PubMed

Bardet-Biedl Syndrome is a multisystem autosomal recessive disorder characterized by central obesity, polydactyly, hypogonadism, learning difficulties, rod-cone dystrophy and renal dysplasia. Bardet-Biedl Syndrome has a prevalence rate ranging from 1 in 100,000 to 1 in 160,000 births although there are communities where Bardet-Biedl Syndrome is found at a higher frequency due to consanguinity. We report here a Pakistani consanguineous family with two affected sons with typical clinical features of Bardet-Biedl Syndrome, in addition to abnormal liver functioning and bilateral basal ganglia calcification, the latter feature being typical of Fahr's disease. Homozygous regions obtained from SNP array depicted three known genes BBS10, BBS14 and BBS2. Bidirectional sequencing of all coding exons by traditional sequencing of all these three genes showed a homozygous deletion of 10 nucleotides (c.1958_1967del), in BBS10 in both affected brothers. The segregation analysis revealed that the parents, paternal grandfather, maternal grandmother and an unaffected sister were heterozygous for the deletion. Such a large deletion in BBS10 has not been reported previously in any population and is likely to be contributing to the phenotype of Bardet-Biedl Syndrome in this family. PMID:23403234

Agha, Zehra; Iqbal, Zafar; Azam, Maleeha; Hoefsloot, Lies H; van Bokhoven, Hans; Qamar, Raheel

2013-02-09

179

Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)  

PubMed

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic, neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter. PMID:8882782

Greenberg, F; Lewis, R A; Potocki, L; Glaze, D; Parke, J; Killian, J; Murphy, M A; Williamson, D; Brown, F; Dutton, R; McCluggage, C; Friedman, E; Sulek, M; Lupski, J R

1996-03-29

180

Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms  

PubMed Central

Methods: The 22q13 deletion syndrome (MIM 606232) is characterised by moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features. We have determined the deletion size and parent of origin in 56 patients with this syndrome. Results: Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions vary widely in size, from 130 kb to over 9 Mb; however all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene. The molecular structure of SHANK3 was further characterised. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate to deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. Conclusion: Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome.

Wilson, H; Wong, A; Shaw, S; Tse, W; Stapleton, G; Phelan, M; Hu, S; Marshall, J; McDermid, H

2003-01-01

181

Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).  

PubMed

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syndrome and is associated with thymic hypoplasia and diminished T-cell numbers and has a wide spectrum of phenotypic features that include cardiac anomalies, dysmorphic facial features, and hypocalcemia. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. The aims of this study were to investigate the incidence of side effects after live viral vaccine administration in a population with chromosome 22q11.2 deletion syndrome. The high frequency of this syndrome in the population (1:3000 children) mandates a greater understanding of the risks and benefits related to live viral vaccine administration. A retrospective analysis of vaccine adverse events was performed. The data acquisition form evaluated the frequency of live vaccine administration and the consequences of both vaccination and withholding the vaccine. Flow cytometric enumeration of T cells was performed as part of an immunologic evaluation. Thirty-two of 59 responders were vaccinated with the varicella vaccine. Only 9% of patients reported adverse events. However, 63% of unvaccinated children developed chickenpox. Comparison of patients who tolerated the vaccine with those who reported adverse events showed no statistically significant differences in current age (7 vs 5.7 years), age at vaccination (3 vs 2.5 years), or T-cell subset counts: CD3 (1951 vs 2083 cells/ microL), CD4 (1283 vs 1463 cells/ microL), and CD8 (530 vs 502 cells/ microL). Fifty-two of 59 responders were vaccinated with measles-mumps-rubella (MMR). Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional symptoms. No severe adverse reactions were reported. No patient reported natural disease with measles, mumps, or rubella. There were no statistically significant differences between the T-cell counts in the vaccinated group reporting side effects versus the vaccinated group without side effects (mean CD3 counts: 1928 vs 1736 cells/ microL; CD4 counts: 1250 vs 1127 cells/ microL; and CD8 counts: 528 vs 483 cells/ microL). In our study, patients with chromosome 22q11.2 deletion syndrome had a similar incidence of adverse effects with varicella and MMR vaccines compared with that reported in the general population. All side effects were mild. However, in patients who did not receive the varicella vaccine, an overwhelming 63% contracted the disease. Patients who were not vaccinated against MMR did not develop natural disease. The data suggest that this is a cohort of patients with 22q11.2 deletion syndrome who have tolerated live viral vaccinations without evidence of significant side effects. A prospective study could address whether there are T-cell thresholds below which vaccination is unsafe; however, the information that we present suggests that vaccinating children with chromosome 22q11.2 deletion with live viral vaccines does not carry a significantly higher risk of adverse reactions compared with the general population, provided that they have no evidence of severe immunocompromise. PMID:14523220

Perez, Elena E; Bokszczanin, Aleksandra; McDonald-McGinn, Donna; Zackai, Elaine H; Sullivan, Kathleen E

2003-10-01

182

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion  

PubMed Central

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

Duraturo, Francesca; Cavallo, Angela; Liccardo, Raffaella; Cudia, Bianca; De Rosa, Marina; Diana, Giuseppe; Izzo, Paola

2013-01-01

183

1.4Mb recurrent 22q11.2 distal deletion syndrome, two new cases expand the phenotype.  

PubMed

We report two new patients with the 1.4Mb recurrent 22q11.2 distal deletion syndrome. Features common to both children, as well as to several of the previously reported cases, include normal palate, smooth philtrum, hypoplastic alae nasi and delayed development. Both children are small but not growth retarded, and are microcephalic. Their developmental delay is global and most pronounced for language acquisition. One child has unilateral sensorineural hearing loss and encopresis, and the other child has treatment-responsive nocturnal epileptogenic activity. These two new cases confirm the recurrent nature of the deletion and help to further delineate the phenotype. PMID:18725332

Rødningen, Olaug K; Prescott, Trine; Eriksson, Ann-Sofie; Røsby, Oddveig

2008-08-05

184

The 13q- syndrome: the molecular definition of a critical deletion region in band 13q32.  

PubMed Central

Patients with interstitial deletions of the long arm of chromosome 13 may have widely varying phenotypes. From cytogenetic analysis, we have postulated that there is a discrete region in 13q32 where deletion leads to a syndrome of severe malformations, including digital and brain anomalies. To test this hypothesis at the molecular level, we have studied the deletions in 17 patients; 5 had severe malformations, while the remaining 12 had only minor malformations. Our results indicate that the deletions in the severely affected patients all involve an overlapping region in q32, while the deletions in the mildly affected patients include some, but not all, of this overlapping region. Our findings are consistent with the hypothesis that the severely malformed 13q- phenotype results from the deletion of a critical region in 13q32. This region is presently defined as lying between D13S136 and D13S147 and is on the order of 1 Mb in size. Images Figure 3 Figure 4

Brown, S; Russo, J; Chitayat, D; Warburton, D

1995-01-01

185

Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family.  

PubMed

Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. PMID:14630904

Wang, Y; Zhao, H; Zhang, X; Feng, H

2003-12-01

186

HIGH COLORECTAL AND LOW ENDOMETRIAL CANCER RISK IN EPCAM DELETION-POSITIVE LYNCH SYNDROME: A COHORT STUDY  

PubMed Central

Summary BACKGROUND Lynch syndrome is caused by germline mutations in mismatch repair genes (MSH2, MLH1, MSH6 or PMS2), which lead to a high risk of predominantly colorectal and endometrial cancer. Recently, we found that also constitutional 3? end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM expressing tissues. This results in a tissue specific MSH2-deficiency, which may evoke a different cancer risk and spectrum. To optimize the care for EPCAM deletion carriers we studied their cancer risk and spectrum. METHODS Clinical data of 194 carriers from 41 EPCAM families were systematically collected and compared to those of 431 carriers from 91 families with mutations in MLH1, MSH2, or MSH6. FINDINGS EPCAM deletion carriers exhibited a 75% [95%CI 65–85%] cumulative risk of colorectal cancer before the age of 70 years, with a mean age at diagnosis of 43 years, which is comparable to that of carriers of a combined EPCAM-MSH2 deletion (69% [95%CI 47-91%], p=0·8609) or of a mutation in MSH2 (77% [95%CI 64-90%], p=0·5892) or MLH1 (79% [95%CI 68-90%], p=0·5492) and higher than that of MSH6 mutation carriers (50% [95%CI 38-62%], p<0·0001). In contrast, women with EPCAM deletions (n=87) exhibited a 12% [95%CI 0-27%] cumulative risk of endometrial cancer, which is significantly lower than in carriers of a combined EPCAM-MSH2 deletion (55% [95%CI 20-90%], p<0·0001) or of a mutation in MSH2 (51% [95%CI 33-69%], p=0·0006) or MSH6 (34% [95%CI 20-48%], p=0·0309) and lower than in MLH1 (33% [95%CI 15-51%] p=0·1193) mutation carriers. This risk seems to be restricted to large deletions that extend close to the MSH2 gene promoter. Overall, a relatively high incidence of duodenal (n=3) and pancreatic (n=4) cancers was observed. INTERPRETATION EPCAM deletion carriers do have a high risk of colorectal cancer. Only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the impact of mosaic MSH2-deficiency on cancer risk and are indicative for a protocol revision for surveillance and preventive surgery in EPCAM deletion carriers.

Kempers, Marlies JE; Kuiper, Roland P; Ockeloen, Charlotte W; Chappuis, Pierre O; Hutter, Pierre; Rahner, Nils; Schackert, Hans K; Steinke, Verena; Holinski-Feder, Elke; Morak, Monika; Kloor, Matthias; Buttner, Reinhard; Verwiel, Eugene TP; van Krieken, J. Han; Nagtegaal, Iris D; Goossens, Monique; van der Post, Rachel S.; Niessen, Renee C; Sijmons, Rolf H; Kluijt, Irma; Hogervorst, Frans BL; Leter, Edward M; Gille, Johan JP; Aalfs, Cora M; Redeker, Egbert JW; Hes, Frederik J; Tops, Carli MJ; van Nesselrooij, Bernadette PM; van Gijn, Marielle E; Garcia, Encarna B Gomez; Eccles, Diana M; Bunyan, David J; Syngal, Sapna; Stoffel, Elena M; Culver, Julie O; Palomares, Melanie R; Graham, Tracy; Velsher, Lea; Papp, Janos; Olah, Edith; Chan, Tsun L; Leung, Suet Y; van Kessel, Ad Geurts; Kiemeney, Lambertus ALM; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn JL

2013-01-01

187

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome  

PubMed Central

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.

Beri, Silvana; De Agostini, Cristina; Novara, Francesca; Fichera, Marco; Grillo, Lucia; Galesi, Ornella; Vetro, Annalisa; Ciccone, Roberto; Bonati, Maria Teresa; Giglio, Sabrina; Guerrini, Renzo; Osimani, Sara; Marelli, Susan; Zucca, Claudio; Grasso, Rita; Borgatti, Renato; Mani, Elisa; Motta, Cristina; Molteni, Massimo; Romano, Corrado; Greco, Donatella; Reitano, Santina; Baroncini, Anna; Lapi, Elisabetta; Cecconi, Antonella; Arrigo, Giulia; Patricelli, Maria Grazia; Pantaleoni, Chiara; D'Arrigo, Stefano; Riva, Daria; Sciacca, Francesca; Dalla Bernardina, Bernardo; Zoccante, Leonardo; Darra, Francesca; Termine, Cristiano; Maserati, Emanuela; Bigoni, Stefania; Priolo, Emanuela; Bottani, Armand; Gimelli, Stefania; Bena, Frederique; Brusco, Alfredo; di Gregorio, Eleonora; Bagnasco, Irene; Giussani, Ursula; Nitsch, Lucio; Politi, Pierluigi; Martinez-Frias, Maria Luisa; Martinez-Fernandez, Maria Luisa; Martinez Guardia, Nieves; Bremer, Anna; Anderlid, Britt-Marie; Zuffardi, Orsetta

2011-01-01

188

Deficits in mental state attributions in individuals with 22q11.2 deletion syndrome (velo-cardio-facial syndrome).  

PubMed

Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites University of California, Los Angeles (UCLA) and State University of New York (SUNY) Upstate Medical University. The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e. mentalizing) and Appropriateness. Using Repeated Measures analysis of variance (ANOVA), we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions. PMID:22962003

Ho, Jennifer S; Radoeva, Petya D; Jalbrzikowski, Maria; Chow, Carolyn; Hopkins, Jessica; Tran, Wen-Ching; Mehta, Ami; Enrique, Nicole; Gilbert, Chelsea; Antshel, Kevin M; Fremont, Wanda; Kates, Wendy R; Bearden, Carrie E

2012-09-07

189

Two cases of deletion 5p syndrome: one with paternal involvement and another with atypical presentation.  

PubMed

We report two cases of deletion 5p or cri du chat syndrome (CdCS) with different presentations and risks of transmission: one case with paternal chromosome 5 involvement and another, a de novo case with atypical clinical presentation. Cytogenetic analysis was performed on the two cases and their parents. GTG-banded karyotype analysis of Cases 1 and 2 revealed abnormal 46,XY,del(5)(p13-15) male karyotypes. For Case 1, the mother showed normal female karyotype while the father showed an abnormal karyotype involving a balanced translocation 46,XY,t(5;10)(p13;p15). For Case 2, however, both parents showed a normal karyotype pattern. In Case 1, the clinical features, particularly the distinct facial phenotype in combination with a characteristic cat-like cry and hypotonia, aided in the diagnosis at birth and the karyotype analysis was resolutive. The boy in Case 2 presented with atypical clinical features. Even though this patient had multiple syndromic features, the typical high pitched cat-like cry was not prominent. Instead, the patient manifested persistent stridor (from day three of life), which might have prevented the clinician from suspecting CdCS at birth. However, when this patient was presented at seven months of age for cytogenetic analysis, a confirmatory diagnosis of CdCS was established. For children with congenital abnormalities, an early clinical diagnosis confirmed through cytogenetic and molecular investigations, is important for providing personalised diagnostic and prognostic evaluation, and also for genetic counselling on the reproductive risk, particularly for patients with parental chromosome translocation involvement. PMID:18418516

Azman, B Z; Akhir, S M; Zilfalil, B A; Ankathil, R

2008-04-01

190

22q11.2 Deletion Syndrome: Attitudes towards Disclosing the Risk of Psychiatric Illness  

PubMed Central

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features. There is a strong association with psychiatric disorders. One in every four to five patients develop schizophrenia. Despite studies showing that early diagnosis and treatment are likely to lead to improved outcome, genetic counselors may be reluctant to discuss the risk of psychiatric illness. The aim of this research was to explore parental attitudes and genetic counselors’ perspectives and practice regarding disclosure of the clinical manifestations of 22q11.2DS, particularly the risk of psychiatric illness. We delivered a questionnaire to genetic counselors via established list-serves, 54 of which were completed. We also conducted interviews with four parents of adults with 22q11.2DS and schizophrenia. The majority of counselors and parents felt that the increased risk to develop a psychiatric illness is important to disclose. However, in the initial counseling session when the diagnosis was made in infancy genetic counselors were significantly less likely to discuss the risk of psychiatric disorders compared to other later onset features such as hypothyroidism (41 % vs. 83 %, p=0.001). When the diagnosis of 22q11.2DS was made in infancy, counselors’ responses in regard to timing of disclosure about psychiatric illnesses were fairly evenly divided between infancy, childhood and adolescence. In contrast, for other major features of 22q11.2DS, disclosure would predominantly be in infancy. The respondents reported that the discussion of psychiatric issues with parents was challenging due to the stigma associated with mental illness. Some also noted limited knowledge about psychiatric illness and treatment. These results suggest that genetic counselors could benefit from further education regarding psychiatric illness in 22q11.2DS and best strategies for discussing this important subject with parents and patients.

Martin, Nicole; Mikhaelian, Marina; Cytrynbaum, Cheryl; Shuman, Cheryl; Chitayat, David A.; Weksberg, Rosanna

2012-01-01

191

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

SciTech Connect

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.

Ravnan, J.B.; Golabi, M.; Lebo, R.V. [Univ. of California, San Francisco, CA (United States)

1994-09-01

192

Prodromal and autistic symptoms in schizotypal personality disorder and 22q11.2 deletion syndrome.  

PubMed

Despite clear diagnostic distinctions, schizophrenia and autism share symptoms on several dimensions. Recent research has suggested the two disorders overlap in etiology, particularly with respect to inherited and noninherited genetic factors. Studying the relationship between psychotic-like and autistic-like symptoms in risk groups such as 22q11 deletion syndrome (22q11DS) and schizotypal personality disorder (SPD) has the potential to shed light on such etiologic factors; thus, the current study examined prodromal symptoms and autistic features in samples of 22q11DS and SPD subjects using standardized diagnostic measures, including the Structured Interview for Prodromal Symptoms (SIPS) and the Autism Diagnostic Inventory-Revised (ADI-R). Results showed that SPD subjects manifested significantly more severe childhood and current social as well as stereotypic autistic features, as well as more severe positive prodromal symptoms. The two groups did not differ on negative, disorganized, or general prodromal symptoms, but were distinguishable based on correlations between prodromal and autistic features; the relationships between childhood autistic features and current prodromal symptoms were stronger for the SPD group. The results suggest that childhood autistic features are less continuous with subsequent prodromal signs in 22q11DS patients relative to those with SPD, and the findings highlight the importance of studying the overlap in diagnostic phenomenology in groups at risk for developing psychosis and/or autism. PMID:22686870

Esterberg, Michelle L; Ousley, Opal Y; Cubells, Joseph F; Walker, Elaine F

2012-06-11

193

Detailed molecular and clinical investigation of a child with a partial deletion of chromosome 11 (Jacobsen syndrome)  

PubMed Central

Background Jacobsen syndrome (JBS) is a rare chromosomal disorder leading to multiple physical and mental impairment. This syndrome is caused by a partial deletion of chromosome 11, especially subband 11q24.1 has been proven to be involved. Clinical cases may easily escape diagnosis, however pancytopenia or thrombocytopenia may be indicative for JBS. Results We report a 7.5 years old boy presenting with speech development delay, hearing impairment and abnormal platelet function. High resolution SNP oligonucleotide microarray analysis revealed a terminal deletion of 11.4 Mb in size, in the area 11q24.1-11qter. This specific deletion encompasses around 170 genes. Other molecular techniques such as fluorescence in situ hybridization and multiplex ligation-dependent probe amplification were used to confirm the array-result. Discussion Our results suggest that the identification and detailed analysis of similar patients with abnormal platelet function and otherwise mild clinical features will contribute to identification of more patients with 11q deletion and JBS.

2009-01-01

194

Similar interstitial deletions of the KAL-1 gene in two Brazilian families with X-linked Kallmann Syndrome  

Microsoft Academic Search

Mutations in the KAL-1 gene localized at Xp22.3 have been shown to be responsible for the X-linked Kallmann syndrome (KS), a disorder characterized by the association of hypogonadotropic hypogonadism and anosmia. In this paper, we describe the investigation of two families with X-linked KS, in which similar interstitial deletions spanning exons 5 to 10 of the KAL-1 gene were identified.

Ericka Barbosa Trarbach; Isabella Lopes Monlleo; Carlos Guilherme Gaelzer Porciuncula; Marshall Italo Barros Fontes; Maria Teresa Mathias Baptista; Christine Hackel

2004-01-01

195

Intelligence and Visual Motor Integration in 5-Year-Old Children with 22q11-Deletion Syndrome  

ERIC Educational Resources Information Center

|The purpose of this study was to explore the relationship between intelligence and visual motor integration skills in 5-year-old children with 22q11-deletion syndrome (22q11DS) (N = 65, 43 females, 22 males; mean age 5.6 years (SD 0.2), range 5.23-5.99 years). Sufficient VMI skills seem a prerequisite for IQ testing. Since problems related to…

Duijff, Sasja; Klaassen, Petra; Beemer, Frits; Swanenburg de Veye, Henriette; Vorstman, Jacob; Sinnema, Gerben

2012-01-01

196

Hippocampal volume reduction in children with chromosome 22q11.2 deletion syndrome is associated with cognitive impairment  

Microsoft Academic Search

BACKGROUND: Previous investigations of individuals with chromosome 22q11.2 deletion syndrome (DS22q11.2) have reported alterations in both brain anatomy and cognitive function. Neuroanatomical studies have reported multiple abnormalities including changes in both gray and white matter in the temporal lobe, including the amygdala and hippocampus. Separate investigations of cognitive abilities have established the prevalence of general intellectual impairment, although the actual

Tracy DeBoer; Zhongle Wu; Aaron Lee; Tony J Simon

2007-01-01

197

Gender-Moderated Dorsolateral Prefrontal Reductions in 22q11.2 Deletion Syndrome: Implications for Risk for Schizophrenia  

Microsoft Academic Search

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks

Wendy R. Kates; Kevin Antshel; Rachael Willhite; Brandy A. Bessette; Nuria AbdulSabur; Anne Marie Higgins

2005-01-01

198

Excess of deletions of maternal origin in the DiGeorge\\/Velo-cardio-facial syndromes. A study of 22 new patients and review of the literature  

Microsoft Academic Search

We have determined the parental origin of the deleted chromosome 22 in 29 cases of DiGeorge syndrome (DGS) using a CA-repeat mapping within the commonly deleted region, and in one other case by using a chromosome 22 short arm heteromorphism. The CA-repeat was informative in 21 out of 29 families studied and the deleted chromosome was of maternal origin in

Suzanne Demczuk; Annie Lévy; Muriel Aubry; Marie-Françoise Croquette; Nicole Philip; Marguerite Prieur; Ursula Sauer; Patrice Bouvagnet; Guy A. Rouleau; Gilles Thomas; Alain Aurias

1995-01-01

199

Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.  

PubMed

Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed. PMID:24035971

Passariello, Annalisa; De Brasi, Daniele; Defferrari, Raffaella; Genesio, Rita; Tufano, Maria; Mazzocco, Katia; Capasso, Maria; Migliorati, Roberta; Martinsson, Tommy; Siani, Paolo; Nitsch, Lucio; Tonini, Gian Paolo

2013-09-13

200

A novel deletion of the L-ferritin iron-responsive element responsible for severe hereditary hyperferritinaemia-cataract syndrome.  

PubMed

In the last few years, mutations that cause disease through increased efficiency of mRNA translation have been discovered. Hereditary hyperferritinaemia-cataract syndrome (HHCS) arises from various point mutations or deletions within the iron-responsive element (IRE) in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinaemia and severity of cataract in affected individuals. We report a novel six-nucleotide deletion identified in an Italian family presenting with elevated serum ferritin and early onset bilateral cataract. This deletion involves a sequence with a TCT repetition and may have occurred through a mechanism of slippage mispairing. Because of the above repetition, the observed mutation can be interpreted as deletion 22-27, 23-28, 24-29 or 25-30. Structural modelling predicted an IRE stem modification that is expected to markedly reduce the binding to iron-regulatory proteins. A double-gradient denaturing gradient gel electrophoresis (DG-DGGE) method easily detected the above deletion. PMID:11849230

Cazzola, Mario; Foglieni, Barbara; Bergamaschi, Gaetano; Levi, Sonia; Lazzarino, Mario; Arosio, Paolo

2002-03-01

201

Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome  

Microsoft Academic Search

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly\\/mental retardation syndrome associated with del(17)(p11.2p11.2). The phenotype is variable even in patients with deletions of the same size. RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spec- trum of the phenotype remains unclear. Df(11)17\\/1 mice contain a heterozygous deletion

Jiong Yan; Victoria W. Keener; Weimin Bi; Katherina Walz; Allan Bradley; Monica J. Justice; James R. Lupski

2004-01-01

202

A case of Kearns-Sayre syndrome showing a constant proportion of deleted mitochondrial DNA in blood cells during 6 years of follow-up  

Microsoft Academic Search

Kearns-Sayre syndrome (KSS) and Pearson syndrome (PS) show quite different phenotypes despite the same underlying genetic defect, i.e. a large deletion of one population of mitochondrial (mt) DNA. The main feature of KSS is progressive encephalomyopathy; on the other hand, PS shows fatal hematological problems in early infancy. Through Southern blot analysis of mtDNA of blood cells, deletion has been

Ikuko Mohri; Masako Taniike; Harutoshi Fujimura; Taro Matsuoka; Koji Inui; Toshisaburo Nagai; Shintaro Okada

1998-01-01

203

[Partial deletion of the short arm of chromosome 4 (the Wolf-Hirschhorn syndrome) with reference to the neurological and electroencephalographic aspects].  

PubMed

We describe a case of Wolf-Hirschhorn syndrome (partial deletion of the short arm of chromosome 4). The syndrome is characterized by mental and growth retardation and characteristic facial dysmorphism. The fetus was karyotyped for severe intrauterine growth retardation diagnosed on routine ultrasound. High resolution chromosomal analysis of infant and parents showed "de novo" deletion. Very interesting in our case are ictal phenomena and neurological development. PMID:7816704

Bonaventura, F; Adamoli, P; Bernardini, E; Branchi, M; Siani, A; Bonora, G

204

The Subtelomere of Short Telomeres is Hypermethylated in Alzheimer's Disease.  

PubMed

Telomere shortening has been reported to be related to oxidative stress (OS) associated with the aging process and aging-associated diseases, including Alzheimer's disease (AD). We measured the methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells of 34 AD patients and 49 healthy controls by a Southern blotting analysis, using methylation-sensitive and - insensitive restriction enzyme isoschizomers, MspI and HpaII. AD patients bore normal mean telomere lengths and had an unchanged distribution of the telomere length in peripheral leukocytes. However, the subtelomeres in the shortest telomeres were relatively more methylated in AD patients of both genders, compared with age-matched controls. We observed that the pathogenesis of AD was associated with the epigenetic condition of the subtelomere, but not on the overall telomere length and distribution. The relative elevation of subtelomeric methylation of short telomeres in peripheral blood leukocytes may be a characteristic of AD. This implies that leukocytes containing short telomeres with less methylated subtelomeres tend to be removed faster from the peripheral blood in AD patients. PMID:22724077

Guan, Jing-Zhi; Guan, Wei-Ping; Maeda, Toyoki; Makino, Naoki

2011-12-10

205

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes  

PubMed Central

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

Delio, Maria; Guo, Tingwei; McDonald-McGinn, Donna M.; Zackai, Elaine; Herman, Sean; Kaminetzky, Mark; Higgins, Anne Marie; Coleman, Karlene; Chow, Carolyn; Jarlbrzkowski, Maria; Bearden, Carrie E.; Bailey, Alice; Vangkilde, Anders; Olsen, Line; Olesen, Charlotte; Skovby, Flemming; Werge, Thomas M.; Templin, Ludivine; Busa, Tiffany; Philip, Nicole; Swillen, Ann; Vermeesch, Joris R.; Devriendt, Koen; Schneider, Maude; Dahoun, Sophie; Eliez, Stephan; Schoch, Kelly; Hooper, Stephen R.; Shashi, Vandana; Samanich, Joy; Marion, Robert; van Amelsvoort, Therese; Boot, Erik; Klaassen, Petra; Duijff, Sasja N.; Vorstman, Jacob; Yuen, Tracy; Silversides, Candice; Chow, Eva; Bassett, Anne; Frisch, Amos; Weizman, Abraham; Gothelf, Doron; Niarchou, Maria; van den Bree, Marianne; Owen, Michael J.; Suner, Damian Heine; Andreo, Jordi Rosell; Armando, Marco; Vicari, Stefano; Digilio, Maria Cristina; Auton, Adam; Kates, Wendy R.; Wang, Tao; Shprintzen, Robert J.; Emanuel, Beverly S.; Morrow, Bernice E.

2013-01-01

206

The Structure and Evolution of Subtelomeric Y' Repeats in Saccharomyces Cerevisiae  

PubMed Central

The subtelomeric Y' family of repeated DNA sequences in the yeast Saccharomyces cerevisiae is of unknown origin and function. Y's vary in copy number and location among strains. Eight Y's, from two strains, were cloned and sequenced over the same 3.2-kb interval in order to assess the withinand between-strain variation as well as address their origin and function. One entire Y' sequence was reconstructed from two clones presented here and a previously sequenced 833-bp region. It contains two large overlapping open reading frames (ORFs). The putative protein sequences have no strong homologies to any known proteins except for one region that has 27% identity with RNA helicases. RNA homologous to each ORF was detected. Comparison of the sequences revealed that the known long (Y'-L) and short (Y'-S) size classes, which coexist within cells, differ by several insertions and/or deletions within this region. The Y'-Ls from strain Y55 also differ from those of strain YP1 by several short deletions in the same region. Most of these deletions appear to have occurred between short (2-10 bp) direct repeats. The single base pair polymorphisms and the deletions are clustered in the first half of the interval compared. There is 0.30-1.13% divergence among Y'-Ls within a strain and 1.15-1.75% divergence between strains in the interval. This is similar to known unique sequence variation but contrasts with the 8-18% divergence among the adjacent subtelomeric repeats, X. Subsets of Y's exhibit concerted evolution; however, more than one variant appears to be maintained within strains. The observed sequence variation disrupts the first ORF in many Y's while most of the second ORF including the putative helicase region is unaffected. The structure and distribution of the Y' elements are consistent with having originated as a mobile element. However, they now appear to move via recombination. Recombination can account for the homogenization within subsets of Y's but does not account for the maintenance of different variants.

Louis, E. J.; Haber, J. E.

1992-01-01

207

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.  

PubMed

Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR. PMID:23486540

Higashimoto, Ken; Maeda, Toshiyuki; Okada, Junichiro; Ohtsuka, Yasufumi; Sasaki, Kensaku; Hirose, Akiko; Nomiyama, Makoto; Takayanagi, Toshimitsu; Fukuzawa, Ryuji; Yatsuki, Hitomi; Koide, Kayoko; Nishioka, Kenichi; Joh, Keiichiro; Watanabe, Yoriko; Yoshiura, Koh-Ichiro; Soejima, Hidenobu

2013-03-13

208

Cri du chat syndrome determined by the 5p15.3-->pter deletion--diagnostic problems.  

PubMed

A cytogenetic analysis was performed on an 8-day-old girl, who was suspected of Cri du chat syndrome (CdCS) on the basis of a cat-like cry, despite her dysmorphic features not being characteristic of this syndrome. The cytogenetic analysis revealed a partial deletion of the short arm of chromosome 5, but did not allow precise specification of the break points. Fluorescence in situ hybridization (FISH) analysis, using the specific probe for CdCS, revealed two signals in all the cells analyzed. However, one of two signals was less intense than the other. Thus, telomere probes were applied for all chromosomes. Two signals from 5q and one signal from 5p were observed. The results allowed us to establish the location of the deleted fragment as 5p15.3-->5pter [46,XX,del(5)(p15.3)]. The analysis of a genotype-phenotype correlation confirmed that the cat-like cry, but not the characteristic dysmorphic features of CdCS are correlated with the deletion of 5p15.3. PMID:16473315

Laczmanska, Izabela; Stembalska, Agnieszka; Gil, Justyna; Czemarmazowicz, Halina; Sasiadek, Maria

2005-07-06

209

A Case of 9.7 Mb Terminal Xp Deletion Including OA1 Locus Associated with Contiguous Gene Syndrome  

PubMed Central

Terminal or interstitial deletions of Xp (Xp22.2?Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea.

Cho, Eun-Hae; Kim, Sook-Young

2012-01-01

210

A case of 9.7 Mb terminal Xp deletion including OA1 locus associated with contiguous gene syndrome.  

PubMed

Terminal or interstitial deletions of Xp (Xp22.2?Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea. PMID:23091330

Cho, Eun-Hae; Kim, Sook-Young; Kim, Jin-Kyung

2012-10-02

211

Patient with terminal 9 Mb deletion of chromosome 9p: refining the critical region for 9p monosomy syndrome with trigonocephaly.  

PubMed

We describe a patient with typical manifestations of 9p monosomy syndrome, including trigonocephaly and sex reversal. Array comparative genomic hybridization (CGH) revealed a 9p terminal deletion of approximately 9 Mb with the breakpoint at 9p23. We compared the deleted segments of 9p associated with reported cases of 9p monosomy syndrome with trigonocephaly. We did not identify a region that was shared by all patients; however, when only pure terminal or interstitial deletions that did not involve material from any other chromosome were compared, we identified a segment from D9S912 to RP11-439I6 of approximately 1 Mb that was deleted in every patient. We propose that this 1-Mb segment might be the critical region for 9p monosomy syndrome with trigonocephaly. PMID:23480358

Mitsui, Norimasa; Shimizu, Kenji; Nishimoto, Hiroshi; Mochizuki, Hiroshi; Iida, Masao; Ohashi, Hirofumi

2013-03-01

212

Identification of multiple complex rearrangements associated with deletions in the 6q23-27 region in sézary syndrome.  

PubMed

The 6q23-27 region, recurrently deleted in Sézary syndrome (SS), was characterized at the molecular level in 13 SS patients and SS cell line SeAx. Using fine-tiling comparative genomic hybridization, deletions within the 6q23-27 region were detected in half of the samples (six patients and SeAx). All samples with deletions were further analyzed by ligation-mediated PCR. In addition, in one patient sample and in SeAx, paired-end next-generation sequencing was performed on the HiSeq2000 Illumina platform. Using those techniques, 23 rearrangements associated with the deletions were identified. The majority of rearrangements showed enormous complexity and diversity, including eight inversions, three transpositions, and four translocations (with chromosomes 3, 17, 10, and 12). Fifteen genes were disrupted by those rearrangements, the MYB proto-oncogene three times and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2) twice. All three patients with MYB alterations showed low MYB expression, whereas seven of the remaining patients showed overexpression. Most patients overexpressing MYB also presented increased expression of MYC, HSPA8, and BCL2. Five gene fusions were identified, of which two, CCDC28A-IL22RA2 and AIG1-GOSR1, both in SeAx, were in the same orientation and were expressed at the messenger RNA level. PMID:23698072

I?ykowska, Katarzyna; Zawada, Mariola; Nowicka, Karina; Grabarczyk, Piotr; Braun, Floriane C M; Delin, Martin; Möbs, Markus; Beyer, Marc; Sterry, Wolfram; Schmidt, Christian A; Przybylski, Grzegorz K

2013-04-18

213

Smith-Magenis syndrome deletion: a case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization.  

PubMed

The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith-Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400-550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism. PMID:8533833

Juyal, R C; Greenberg, F; Mengden, G A; Lupski, J R; Trask, B J; van den Engh, G; Lindsay, E A; Christy, H; Chen, K S; Baldini, A

1995-09-11

214

Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities  

Microsoft Academic Search

Background: Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2–29% because of different inclusion criteria.Methods: This study presents data compiled from 11 688 cases referred for subtelomere FISH testing in

J B Ravnan; J H Tepperberg; P Papenhausen; A N Lamb; J Hedrick; D Eash; D H Ledbetter; C L Martin

2006-01-01

215

Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2  

SciTech Connect

The so-called {open_quotes}conotruncal anomaly face syndrome{close_quotes} (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet ring ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients, 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other know malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. 20 refs., 3 figs., 2 tabs.

Matsuoka, Rumiko; Takao, Atsuyoshi; Kimura, Misa; Kondo, Chisato; Ando, Masahiko; Momma, Kazuo; Imamura, Shin-ichiro [Heart Institute, Tokyo (Japan); Joh-o, Kunitaka [Welfare Pension Hospital, Kyushu (Japan); Ikeda, Kazuo [Sapporo Medical Univ. (Japan); Nishibatake, Makoto [Kagoshima Seikyo Hospital (Japan)

1994-11-15

216

Human homologue sequences to the Drosophila dishevelled segment-polarity gene are deleted in the DiGeorge syndrome  

SciTech Connect

DiGeorge syndrome (DGS) is a developmental defect of some of the neural crest derivatives. Most DGS patients show haploinsufficiency due to interstitial deletions of the proximal long arm of chromosome 22. Deletions of 22q11 have also been reported in patients with the velo-cardio-facial syndrome and familial conotruncal heart defects. It has been suggested that the wide phenotype spectrum associated with 22q11 monosomy is a consequence of contiguous-gene deletions. We report the isolation of human cDNAs homologous to the Drosophila dishevelled (dsh) segment-polarity gene. Sequences homologous to the 3{prime} UTR of these transcripts (DVL-22) were positioned within the DGS critical region and were found to be deleted in DGS patients. Human DVL mRNAs are expressed in several fetal and adult tissues, including the thymus and, at high levels, the heart. Two transcripts, 3.2 and 5 kb, were detected, in Northern blot analysis, with different expression patterns in the surveyed tissues when different cDNAs were used. The isolated cDNAs exhibit high amino acid homology with the mouse and Xenopus Dvl-1 gene, the only other vertebrate dsh homologues so far isolated. The pivotal role of dsh in fly development suggests an analogous key function in vertebrate embryogenesis of its homologue genes. Since DGS may be due to perturbation of differentiation mechanisms at decisive embryological stages, a Dsh-like gene in the small-region overlap (SRO) might be a candidate for the pathogenesis of this disorder. 52 refs., 3 figs.

Pizzuti, A.; Ratti, A.; Penso, D.; Silani, V.; Scarlato, G. [Universita di Milano, Milan (Italy)] [and others

1996-04-01

217

The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1.  

PubMed

Hemizygous deletion of 22q11 affects approximately 1:4000 live births and may give rise to many different malformations but classically results in a constellation of phenotypes that receive a diagnosis of DiGeorge syndrome or velocardiofacial syndrome. Particularly affected are the heart and great vessels, the endocrine glands of the neck, the face, the soft palate, and cognitive development. Although up to 50 genes may be deleted, it is haploinsufficiency of the transcription factor TBX1 that is thought to make the greatest contribution to the disorder. Mouse embryos are exquisitely sensitive to varying levels of Tbx1 mRNA, and Tbx1 is required in all three germ layers of the embryonic pharyngeal region for normal development. TBX1 controls cell proliferation and affects cellular differentiation in a cell autonomous fashion, but it also directs non-cell autonomous effects, most notably in the signaling between pharyngeal surface ectoderm and the rostral neural crest. TBX1 interacts with several signaling pathways, including fibroblast growth factor, retinoic acid, CTNNB1 (formerly known as ?-catenin), and bone morphogenetic protein (BMP), and may regulate pathways by both DNA-binding and non-binding activity. In addition to the structural abnormalities seen in 22q11 deletion syndrome (DS) and Tbx1 mutant mouse models, patients reaching adolescence and adulthood have a predisposition to psychiatric illness. Whether this has a developmental basis and, if so, which genes are involved is an ongoing strand of research. Thus, knowledge of the genetic and developmental mechanisms underlying 22q11DS has the potential to inform about common disease as well as developmental defect. PMID:23799583

Papangeli, Irinna; Scambler, Peter

2012-06-19

218

Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions  

PubMed Central

Background: Sotos syndrome (SoS) is a disorder characterised by excessive growth, typical craniofacial features, and developmental retardation. It is caused by haploinsuffiency of NSD1 at 5q35. There is a 3.0 kb recombination hotspot in which the breakpoints of around 80% of SoS patients with a common deletion can be mapped. Objective: To identify deletion breakpoints located outside the SoS recombination hotspot. Methods: A screening system for the directly orientated segments of the SoS LCRs was developed for 10 SoS patients with a common deletion who were negative for the SoS hotspot. Deletion-junction fragments were analysed for DNA duplex stability and their relation to scaffold/matrix attachment regions (S/MARs). These features were compared with the SoS hotspot and recombination hotspots of other genomic disorders. Results: The breakpoint was mapped in four SoS patients, two with a deletion in the maternally derived chromosome. These breakpoint regions were located ?2.5 kb, ?9.6 kb, ?27.2, and ?27.7 kb telomeric to the SoS hotspot and were confined to 164 bp, 46 bp, 256 bp, and 124 bp, respectively. Two of the regions were mapped within Alu elements. All crossover events were found to have occurred within or adjacent to a highly destabilised DNA duplex with a high S/MAR probability. In contrast, the SoS hotspot and other genomic disorders' recombination hotspots were mapped to stabilised DNA helix regions, flanked by destabilised regions with high probability of containing S/MAR elements. Conclusions: The data suggest that a specific chromatin structure may increase susceptibility for recurrent crossover events and thus predispose to recombination hotspots in genomic disorders.

Visser, R; Shimokawa, O; Harada, N; Niikawa, N; Matsumoto, N

2005-01-01

219

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.  

PubMed

Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ?1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL. PMID:22441210

Buitenkamp, T D; Pieters, R; Gallimore, N E; van der Veer, A; Meijerink, J P P; Beverloo, H B; Zimmermann, M; de Haas, V; Richards, S M; Vora, A J; Mitchell, C D; Russell, L J; Schwab, C; Harrison, C J; Moorman, A V; van den Heuvel-Eibrink, M M; den Boer, M L; Zwaan, C M

2012-03-22

220

Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions  

PubMed Central

Background The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM. Methods and results Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q. Conclusions Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS.

2013-01-01

221

Identification of Novel Imprinted Transcripts in the Prader-Willi Syndrome and Angelman Syndrome Deletion Region: Further Evidence for Regional Imprinting Control  

PubMed Central

Deletions and other abnormalities of human chromosome 15q11-q13 are associated with two developmental disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Loss of expression of imprinted, paternally expressed genes has been implicated in PWS. However, the number of imprinted genes that contribute to PWS, and the range over which the imprinting signal acts to silence one copy of the gene in a parent-of-origin–specific manner, are unknown. To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, we have constructed an imprinted transcript map of the PWS-AS deletion interval. The imprinting status of 22 expressed sequence tags derived from the radiation-hybrid human transcript maps or physical maps was determined in a reverse transcriptase–PCR assay and correlated with the position of the transcripts on the physical map. Seven new paternally expressed transcripts localize to an ?1.5-Mb domain surrounding the SNRPN-associated imprinting center, which already includes four imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggests strong regional control of the imprinting process. This study provides the means for further investigation of additional genes that cause or modify the phenotypes associated with rearrangements of 15q11-q13.

Lee, Syann; Wevrick, Rachel

2000-01-01

222

Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study  

Microsoft Academic Search

22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition\\u000a to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with\\u000a 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the\\u000a neurobiological substrate underlying these deficits is poorly understood. We investigated brain

Rayna Azuma; Eileen M. Daly; Linda E. Campbell; Angela F. Stevens; Quinton Deeley; Vincent Giampietro; Michael J. Brammer; Beate Glaser; Fiona Z. Ambery; Robin G. Morris; Steven C. R. Williams; Michael J. Owen; Declan G. M. Murphy; Kieran C. Murphy

2009-01-01

223

Deletion 4q21/4q22 syndrome: Two patients with de novo 4q21.3q23 and 4q13.2q23 deletions  

SciTech Connect

We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosome 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/ 4q22 region reported previously detected a characteristic phenotype in 8 patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region. 39 refs., 6 figs., 1 tab.

Nowaczyk, M.J.M.; Seigel-Bartelt, J.; Clarke, J.T.R. [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)] [and others

1997-04-14

224

Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype.  

PubMed

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype. PMID:15521982

Shrimpton, A E; Braddock, B R; Thomson, L L; Stein, C K; Hoo, J J

2004-12-01

225

Problem Behaviors Associated with Deletion Prader-Willi, Smith-Magenis, and Cri Du Chat Syndromes.  

ERIC Educational Resources Information Center

Problem behaviors of 38 individuals with Cri-du-Chat syndrome, 55 individuals with Prader Willi syndrome, and 21 individuals with Smith-Magenis syndrome were investigated. All three disorders were Associated with greater ratings of problem behaviors (besides eating abnormalities and sleep abnormalities) than comparison groups. (Author/CR)

Clarke, David J.; Boer, Harm

1998-01-01

226

A Saudi Patient with an Interstitial Deletion of Short Arm of Chromosome 3 (p13 to p21) and its Association with Joubert's Syndrome Features.  

PubMed

We report a case of 4 weeks old girl with a de novo interstitial deletion of the short arm of chromosome 3 (p13-p21) and clinical findings typical of proximal 3p deletion together with heart defects, choanal atresia, ear anomalies, central nervous system anomalies, renal anomalies and associated Joubert's syndrome (JS). Family history is unremarkable and parenteral chromosomes were normal. The clinical manifestations of the patient are compared with those of 11 patients previously described with a proximal 3p deletion. The additional JS features associated with this syndrome were described. This is the first case report in English literature describing 3p deletion associated with additional JS features. PMID:24027747

Mersal, Ali Y; Basha, Mahaboob K; Brinji, Zaina S; Avand, Ghazal

2013-01-01

227

Congenital adrenal hypoplasia, Duchenne muscular dystrophy, and glycerol kinase deficiency: importance of laboratory investigations in delineating a contiguous gene deletion syndrome.  

PubMed

We describe an infant with adrenal insufficiency who was subsequently diagnosed with Duchenne muscular dystrophy (DMD) and hyperglycerolemia due to glycerol kinase deficiency. Karyotyping showed a deletion on the short arm of the X chromosome (p21.1 to p22.1). Molecular mapping revealed that the deletion extended from the 3' end of the DMD gene to a site telomeric to the loci for X-linked congenital adrenal hypoplasia and glycerol kinase deficiency. These results are diagnostic for an Xp21 contiguous gene deletion syndrome--so named because the deletion manifests as a distinctive cluster of otherwise unrelated single-gene disorders in the same individual. The Xp21 syndrome should be considered in any infant with adrenal insufficiency. Measurement of serum triglycerides (without glycerol blanking) and creatine kinase activity are simple screening tests that may facilitate early diagnosis and appropriate genetic counseling about risks of recurrence in subsequent offspring. PMID:7955386

Cole, D E; Clarke, L A; Riddell, D C; Samson, K A; Seltzer, W K; Salisbury, S

1994-11-01

228

A novel deletion in the FTL gene causes hereditary hyperferritinemia cataract syndrome (HHCS) by alteration of the transcription start site.  

PubMed

Hereditary hyperferritinemia cataract syndrome (HHCS) is characterized by distinctive cataracts and high serum ferritin in the absence of iron overload. It is caused by mutations in the iron response element (IRE) of the Ferritin Light Chain (FTL) gene. Here we investigate the genetics of HHCS in a three generation Australian kindred with typical HHCS ocular lens morphology and high ferritin levels. Initial sequencing of the IRE failed to detect any mutations. Sequencing of the entire gene including the promoter region revealed a novel 25 bp deletion upstream of the IRE abolishing the transcription start site. In lymphoblastoid cells, the deletion allele was transcribed from an alternate start site within the lower stem of the IRE and mutation carriers had high cellular L-ferritin levels. This novel deletion in the promoter encompassing the transcription start site of the FTL gene is responsible for HHCS in this kindred. The initial primers for amplifying the IRE similar to those used by other researchers failed to detect this mutation. Therefore the genomic region assessed in HHCS cases for diagnosis should be expanded to include mutations of this type. PMID:17579362

Burdon, Kathryn P; Sharma, Shiwani; Chen, Celia S; Dimasi, David P; Mackey, David A; Craig, Jamie E

2007-07-01

229

Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen syndrome: evidence for a common mechanism of chromosome breakage  

Microsoft Academic Search

Folate-sensitive fragile sites are associated with the expansion and hypermethylation of CCG-repeats. The fragile site in 11q23.3, FRA11B, has been shown to cause chromosome deletions in vivo, its expression being associated with Jacobsen (11q-) syndrome. However, the majority of Jacobsen deletions are distal to FRA11B and are not related to its expression. To test the hypothesis that other unidentified fragile

Christopher Jones; Roman Müllenbach; Paul Grossfeld; Rebecca Auer; Remi Favier; Ken Chien; Michael James; Alan Tunnacliffe; Finbarr Cotter

2000-01-01

230

Lenalidomide Promotes p53 Degradation by Inhibiting MDM2 Auto-ubiquitination in Myelodysplastic Syndrome with Chromosome 5q Deletion  

PubMed Central

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion [del(5q)]. Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of MDM2, with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that lenalidomide inhibits the haplodeficient PP2Ac? phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS-14 to suppress MDM2 auto-ubiquitination; whereas PP2Ac? over expression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to lenalidomide over-expressed PP2Ac? accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that lenalidomide restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.

Wei, Sheng; Chen, Xianghong; McGraw, Kathy; Zhang, Ling; Komrokji, Rami; Clark, Justine; Caceres, Gisela; Billingsley, Debbie; Sokol, Lubomir; Lancet, Jeffrey; Fortenbery, Nicole; Zhou, Junmin; Eksioglu, Erika A.; Sallman, David; Wang, Huaquan; Epling-Burnette, Pearlie K.; Djeu, Julie; Maciejewski, Jaroslaw P.; Sekeres, Mikkael; List, Alan

2013-01-01

231

Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion.  

PubMed

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Ac?) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Ac? overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Ac? accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis. PMID:22525275

Wei, S; Chen, X; McGraw, K; Zhang, L; Komrokji, R; Clark, J; Caceres, G; Billingsley, D; Sokol, L; Lancet, J; Fortenbery, N; Zhou, J; Eksioglu, E A; Sallman, D; Wang, H; Epling-Burnette, P K; Djeu, J; Sekeres, M; Maciejewski, J P; List, A

2012-04-23

232

Chromosome Deletion of 14q32.33 Detected by Array Comparative Genomic Hybridization in a Patient with Features of Dubowitz Syndrome  

PubMed Central

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

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

2011-01-01

233

Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome  

PubMed Central

Background Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established. Design We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells. Results Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500?000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions. Conclusions The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS.

Bondy, Carolyn; Bakalov, Vladimir K; Cheng, Clara; Olivieri, Laura; Rosing, Douglas R; Arai, Andrew E

2013-01-01

234

RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome.  

PubMed

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother. PMID:17041942

Bi, Weimin; Saifi, G Mustafa; Girirajan, Santhosh; Shi, Xin; Szomju, Barbara; Firth, Helen; Magenis, R Ellen; Potocki, Lorraine; Elsea, Sarah H; Lupski, James R

2006-11-15

235

Structural chromosomal abnormalities detected during CVS analysis and their role in the prenatal ascertainment of cryptic subtelomeric rearrangements.  

PubMed

Mosaic structural chromosomal abnormalities observed along the trophoblast-mesenchyme-fetal axis, although rare, pose a difficult problem for their prognostic interpretation in prenatal diagnosis. Additional issues are raised by the presence of mosaic imbalances of the same chromosome showing different sizes in the different tissues, that is, deletions and duplications in the cytotrophoblast and mesenchyme of chorionic villi (CV). Some of these cytogenetic rearrangements originate from the post-zygotic breakage of a dicentric chromosome or of the product of its first anaphasic breakage. Selection of the most viable cell line may result in confined placental mosaicism of the most severe imbalance, favoring the presence of the cell lines with the mildest duplications or deletions in the fetal tissues. We document three cases of ambiguous results in CV analysis due to the presence of different cell lines involving structural rearrangements of the same chromosome which were represented differently in the trophoblast and the mesenchyme. Observation by conventional karyotype of a grossly rearranged chromosome in one of the CV preparations (direct or culture) was crucial to call attention to the involved chromosomal region in other tissues (villi or amniotic fluid), allowing the prenatal diagnosis through molecular cytogenetic methods of subtelomeric rearrangements [del(7)(q36qter); del(11)(q25qter); del(20)(p13pter)]. This would have surely been undiagnosed with the routine banding technique. In conclusion, the possibility to diagnose complex abnormalities leading to cryptic subtelomeric rearrangements, together with a better knowledge of the initial/intermediate products leading to the final abnormal cryptic deletion should be added to the advantages of the CV sampling technique. © 2013 Wiley Periodicals, Inc. PMID:23922197

Pittalis, Maria Carla; Mattarozzi, Angela; Menozzi, Cristina; Malacarne, Michela; Baccolini, Ilaria; Farina, Antonio; Pompilii, Eva; Magini, Pamela; Percesepe, Antonio

2013-08-06

236

CHILD Syndrome Caused by a Deletion of Exons 6–8 of the NSDHL Gene  

Microsoft Academic Search

The X-linked dominant CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is a rare developmental defect characterized by a strictly lateralized inflammatory nevus. In the majority of cases, the right side of the body is affected. Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys. We describe a case of CHILD syndrome involving the

C. A. Kim; A. König; D. R. Bertola; L. M. J. Albano; G. J. F. Gattás; D. Bornholdt; L. Leveleki; R. Happle; K.-H. Grzeschik

2005-01-01

237

The underlying structure of the subtelomeric region detected by microphotometrical scanning and chromosome graphic image analysis  

Microsoft Academic Search

Previous research showed that the microphotometrical scanning of T-banded subtelomeric regions reveals the presence of specific patterns of the Giemsa stain density distributions as detected in chromosomes of normal human lymphocytes and CHO cells. Analyses with this method of the T-banded subtelomeric segments of CHO endoreduplicated chromosomes confirmed that these density patterns replicate in a similar way in sister chromosomes.

Máximo E. Drets; Marcos Mendizábal

1998-01-01

238

Cutaneous features in 17q21.31 deletion syndrome: a differential diagnosis for cardio-facio-cutaneous syndrome  

PubMed Central

Microdeletion of 17q21.31 causes a recurrent recognisable dysmorphic syndrome. Four further patients with 17q21.31 microdeletions are reported here where previously the diagnosis of cardio-facio-cutaneous (CFC) syndrome was suggested. These patients have significant similarities of facial gestalt to previously reported 17q21.31 microdeletion patients, but a striking feature that has not been emphasised previously is the large number of naevi and other pigmentary skin abnormalities that may be present. These features, together with a coarse facial appearance, relative macrocephaly and significant learning disabilities, had led to the previous diagnostic suggestion of CFC syndrome in each of these four cases.

Burkitt Wright, Emma; Donnai, Dian; Johnson, Diana; Clayton-Smith, Jill

2010-01-01

239

Evaluation of MLPA for the detection of cryptic subtelomeric rearrangements.  

PubMed

Chromosomal rearrangements involving the telomeres are implied as a significant cause of idiopathic mental retardation. The most frequently used technique to detect these rearrangements was fluorescent in situ hybridization (FISH), an expensive and labor-intensive technique. One of the most promising alternative techniques is multiplex ligation-dependent probe amplification (MLPA). Here, the authors present the evaluation of a double set of probes (the SALSA P036, P019, and P020 human telomere test kits) on a series of 95 patients and 22 normal controls. Overall, 34 patients had been studied by telomeric FISH and MLPA, which was demonstrated to be a reliable method to detect essentially all subtelomeric rearrangements characterized by FISH. In addition, in these 34 patients, 13 dose imbalances were detected by MLPA, but not by FISH analysis. Overall, 12 alterations were observed only with one of the two sets, and they corresponded to polymorphic variants, as they were inherited from healthy parents or also appear in normal controls. The remaining 61 patients were initially studied with SALSA P036, and any putative dose alteration was confirmed with the two other kits and FISH. In the whole series, the authors found 9 dose imbalances evidenced with 2 MLPA kits and confirmed by FISH, representing 10% of patients with subtelomeric rearrangements. On the other hand, one small duplication at 14q11 may be clinically relevant as it appears de novo in one patient. In conclusion, MLPA can be considered a quick, sensitive, cost-effective, and easy method to screen for subtelomeric rearrangements, but any finding based in the testing of one probe should be confirmed by other sources. PMID:16750667

Monfort, Sandra; Orellana, Carmen; Oltra, Silvestre; Roselló, Mónica; Guitart, Miriam; Martínez, Francisco

2006-06-01

240

A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.  

PubMed

The immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disease characterized by targeted chromosome breakage, directly related to a genomic methylation defect. It manifests with phenotypic and clinical variability, with the most consistent features being developmental delay, facial anomalies, cytogenetic defects and immunodeficiency with a reduction in serum immunoglobulin levels. From the molecular point of view, ICF syndrome was always divided into ICF type I (ICF1) and ICF type 2 (ICF2). Mutations in DNMT3B gene are responsible for ICF1, while mutations in ZBTB24 have been reported to be responsible for ICF2. In this study, we describe a Lebanese family with three ICF2 affected brothers. Sanger sequencing of the coding sequence of ZBTB24 gene was conducted and revealed a novel deletion: c.396_397delTA (p.His132Glnfs*19), resulting in a loss-of-function of the corresponding protein. ZBTB24 belongs to a large family of transcriptional factors and may be involved in DNA methylation of juxtacentromeric DNA. Detailed molecular and functional studies of the ZBTB24 and DNMT3B genes are needed to understand the pathophysiology of ICF syndrome. PMID:21906047

Chouery, E; Abou-Ghoch, J; Corbani, S; El Ali, N; Korban, R; Salem, N; Castro, C; Klayme, S; Azoury-Abou Rjeily, M; Khoury-Matar, R; Debo, G; Germanos-Haddad, M; Delague, V; Lefranc, G; Mégarbané, A

2011-10-05

241

Pleiotropy in microdeletion syndromes: Neurologic and spermatogenic abnormalities in mice homozygous for the p{sup 6H} deletion are likely due to dysfunction of a single gene  

SciTech Connect

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p{sup 6H} deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p{sup 6H} deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p{sup 6H} deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p{sup 6H} deletion homozygotes. Because etNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p{sup 6H} deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans. 29 refs., 3 figs., 1 tab.

Rinchik, E.M.; Carpenter, D.A. [Oak Ridge National Lab., TN (United States); Handel, M.A. [Univ. of Tennessee, Knoxville, TN (United States)

1995-07-03

242

Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior  

Microsoft Academic Search

Coffin–Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It\\u000a is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have\\u000a shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2\\u000a deficiency and skeletal abnormalities

R. Poirier; S. Jacquot; C. Vaillend; A. A. Soutthiphong; M. Libbey; S. Davis; S. Laroche; A. Hanauer; H. Welzl; H.-P. Lipp; D. P. Wolfer

2007-01-01

243

Atypical Neuropsychological Profile in a Boy with 22q11.2 Deletion Syndrome Keywords  

Microsoft Academic Search

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast,

Peter Stiers; Ann Swillen; Bert De Smedt; Lieven Lagae; Koen Devriendt; Emiliano D’Agostino; Stefan Sunaert; andJean-Pierre Fryns

2005-01-01

244

Homozygous deletion in TUSC3 causing syndromic intellectual disability: a new patient.  

PubMed

Defects in the TUSC3 gene have been identified in individuals with nonsyndromic autosomal recessive intellectual disability (ARID), due to either point mutations or intragenic deletions. We report on a boy with a homozygous microdeletion 8p22, sizing 203?kb, encompassing the first exon of the TUSC3 gene, detected by SNP-array analysis (Human Gene Chip 6.0; Affymetrix). Both nonconsanguineous parents come from a small Sicilian village and were heterozygous carriers of the microdeletion. The propositus had a few dysmorphic features and a moderate cognitive impairment. Verbal communication was impaired, with an inappropriate phonetic inventory, important phono-articolatory distortions, and bucco-phonatory dyspraxia. Comprehension was possible for simple sentences. Behavior was characterized by motor instability, high tendency to irritability and distraibility, anxiety traits, and an oppositional-defiant disorder. His parents were of normal intelligence. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltranferase complex that catalyzes a pivotal step in the protein N-glycosylation process. TUSC3 has been recently reported as a member of the plasma membrane Mg(2+) transport system, with a possible involvement in learning abilities, working memory and short- and long-term memory. This is the third family in which a deletion has been described. Although the pathogenic mechanism has not been clarified yet, our report argues for a more prominent role of TUSC3 in the etiology of intellectual disability and that deletions encompassing this gene could be more common than expected. PMID:23825019

Loddo, Sara; Parisi, Valentina; Doccini, Viola; Filippi, Tiziana; Bernardini, Laura; Brovedani, Paola; Ricci, Federica; Novelli, Antonio; Battaglia, Agatino

2013-07-04

245

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p.  

PubMed

We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198?kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests. PMID:23511928

Gurrieri, Fiorella; Zollino, Marcella; Oliva, Antonio; Pascali, Vincenzo; Orteschi, Daniela; Pietrobono, Roberta; Camporeale, Antonella; Coll Vidal, Monica; Partemi, Sara; Brugada, Ramon; Bellocci, Fulvio; Neri, Giovanni

2013-03-20

246

Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence  

PubMed Central

Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence.

Thijssen, Peter E.; Tobi, Elmar W.; Balog, Judit; Schouten, Suzanne G.; Kremer, Dennis; El Bouazzaoui, Fatiha; Henneman, Peter; Putter, Hein; Eline Slagboom, P.; Heijmans, Bastiaan T.; Van der Maarel, Silvere M.

2013-01-01

247

Expanded Prader-Willi syndrome due to chromosome 15q11.2-14 deletion: report and a review of literature.  

PubMed

We report on a male infant with de novo unbalanced t(5;15) translocation resulting in a 17.23?Mb deletion within 15q11.2-q14 and a 25.12?kb deletion in 5pter. The 15q11.2-q14 deletion encompassed the 15q11.2-q13 Prader-Willi syndrome (PWS) critical region and the recently described 15q13.3 microdeletion syndrome region while the 5pter deletion contained no RefSeq genes. From our literature review, patients with similar deletions in chromosome 15q exhibit expanded phenotype of severe developmental delay, protracted feeding problem, absent speech, central visual impairment, congenital malformations and epilepsy in addition to those typical of PWS. The patient reported herein had previously unreported anomalies of mega cisterna magna, horseshoe kidney and the rare neonatal interstitial lung disease known as pulmonary interstitial glycogenosis. Precise breakpoint delineation by microarray is useful in patients with atypical PWS deletions to guide investigation and prognostication. PMID:23633107

Liu, Anthony P Y; Tang, Wing Fai; Lau, Elizabeth T; Chan, Kelvin Y K; Kan, Anita S Y; Wong, Kar Yin; Tso, Winnie W Y; Jalal, Khair; Lee, So Lun; Chau, Christy S K; Chung, Brian H Y

2013-04-30

248

Velocardiofacial syndrome in father and daughter: What is the mechanism for the deletion 22(q11.2q11.2) in only the daughter?  

SciTech Connect

E.G. had marked feeding difficulty noted at birth; the cause was determined to be a paralyzed palate. In 1992 chromosome studies were performed because of the provisional diagnosis of velocardiofacial syndrome, and a small interstitial deletion of chromosome 22 was found. Recently the family was seen in our Genetics Clinic. The father had unusual facial features shared by his daughter, a paralyzed upper lip and a history of repaired Tetralogy of Fallot. His chromosomes appeared normal. FISH studies were performed on the child`s peripheral blood using the ONCOR DiGeorge region probe (D22S75) and the deletion verified. However, the father`s chromosomes were not deleted for the ONCOR probe (D22S75) and probe DO832 sent to us by Peter Scambler. Skin cells were then obtained and no deletion was detected in a total of 66 cells examined using both probes. Several questions arise from these data: does the father have velocardiofacial syndrome? Does he have occult mosaicism? Does he have a molecular deletion not detected by the probes used? And was this deletion somehow {open_quotes}amplified{close_quotes} in his daughter?

Magenis, R.E.; Gunter, K.; Toth-Fejel, S. [Oregon Health Sciences Univ., Portland, OR (United States)] [and others

1994-09-01

249

Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.  

PubMed

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion. PMID:22775350

Hoppman-Chaney, N; Wain, K; Seger, P R; Superneau, D W; Hodge, J C

2012-08-07

250

Mesomelia-Synostoses Syndrome Results from Deletion of SULF1 and SLCO5A1 Genes at 8q13  

PubMed Central

Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1—which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families—was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

Isidor, Bertrand; Pichon, Olivier; Redon, Richard; Day-Salvatore, Debra; Hamel, Antoine; Siwicka, Karolina A.; Bitner-Glindzicz, Maria; Heymann, Dominique; Kjellen, Lena; Kraus, Cornelia; Leroy, Jules G.; Mortier, Geert R.; Rauch, Anita; Verloes, Alain; David, Albert; Le Caignec, Cedric

2010-01-01

251

Reduced Fractional Anisotropy and Axial Diffusivity in White Matter in 22q11.2 Deletion Syndrome: A Pilot Study  

PubMed Central

Individuals with 22q11.2 deletion syndrome (22q11.2DS) evince a 30% incidence of schizophrenia. We compared the white matter (WM) of 22q11.2DS patients without schizophrenia to a group matched healthy controls using Tract-Based-Spatial-Statistics (TBSS). We found localized reduction of Fractional Anisotropy (FA) and Axial Diffusivity (AD; measure of axonal integrity) in WM underlying the left parietal lobe. No changes in Radial Diffusivity (RD; measure of myelin integrity) were observed. Of note, studies in chronic schizophrenia patients report reduced FA, no changes in AD, and increases in RD in WM. Our findings suggest different WM microstructure in 22q11.2DS than in patients with schizophrenia.

Kikinis, Z.; Asami, T.; Bouix, S.; Finn, C. T.; Ballinger, T.; Tworog-Dube, E.; Kucherlapati, R.; Kikinis, R.; Shenton, M. E.; Kubicki, M.

2012-01-01

252

Craniofacial malformations: intrinsic vs extrinsic neural crest cell defects in Treacher Collins and 22q11 deletion syndromes.  

PubMed

The craniofacial complex is anatomically the most sophisticated part of the body. It houses all the major sensory organ systems and its origins are synonymous with vertebrate evolution. Of fundamental importance to craniofacial development is a specialized population of stem and progenitor cells, known as the neural crest, which generate the majority of the bone, cartilage, connective and peripheral nerve tissue in the head. Approximately one third of all congenital abnormalities exhibit craniofacial malformations and consequently, most craniofacial anomalies are considered to arise through primary defects in neural crest cell development. Recent advances however, have challenged this classical dogma, underscoring the influence of tissues with which the neural crest cells interact as the primary origin of patterning defects in craniofacial morphogenesis. In this review we discuss these neural crest cell interactions with mesoderm, endoderm and ectoderm in the head in the context of a better understanding of craniofacial malformations such as in Treacher Collins and 22q11 deletion syndromes. PMID:16712696

Walker, M B; Trainor, P A

2006-06-01

253

Differential gene expression reveals mitochondrial dysfunction in an imprinting center deletion mouse model of prader-willi syndrome.  

PubMed

Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity, and diabetes. Previous clinical studies suggest that a defect in energy metabolism may be involved in the pathogenesis of PWS. We focused our attention on the genes associated with energy metabolism and found that there were 95 and 66 mitochondrial genes differentially expressed in PWS muscle and brain, respectively. Assessment of enzyme activities of mitochondrial oxidative phosphorylation complexes in the brain, heart, liver, and muscle were assessed. We found the enzyme activities of the cardiac mitochondrial complexes II?III were up-regulated in the PWS imprinting center deletion mice compared to the wild-type littermates. These studies suggest that differential gene expression, especially of the mitochondrial genes may contribute to the pathophysiology of PWS. PMID:24127921

Yazdi, Puya G; Su, Hailing; Ghimbovschi, Svetlana; Fan, Weiwei; Coskun, Pinar E; Nalbandian, Angèle; Knoblach, Susan; Resnick, James L; Hoffman, Eric; Wallace, Douglas C; Kimonis, Virginia E

2013-07-29

254

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

SciTech Connect

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.

Brown, A. [Greenwood Genetic Center, SC (United States)]|[Clemson Univ., SC (United States); Phelan, M.C.; Rogers, R.C. [Greenwood Genetic Center, SC (United States)] [and others

1996-05-17

255

Deletion of Complement Factor H-Related Genes CFHR1 and CFHR3 Is Associated with Atypical Hemolytic Uremic Syndrome  

PubMed Central

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H–related 1 (CFHR1) and complement factor H–related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of ?84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.

Zipfel, Peter F; Edey, Matthew; Heinen, Stefan; Jozsi, Mihaly; Richter, Heiko; Misselwitz, Joachim; Hoppe, Bernd; Routledge, Danny; Strain, Lisa; Hughes, Anne E; Goodship, Judith A; Licht, Christoph; Goodship, Timothy H. J; Skerka, Christine

2007-01-01

256

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

PubMed

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-Magnesis 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). PMID:8725788

Brown, A; Phelan, M C; Patil, S; Crawford, E; Rogers, R C; Schwartz, C

1996-05-17

257

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

PubMed Central

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

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

2013-01-01

258

The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion  

Microsoft Academic Search

Williams syndrome (WS) is a developmental disorder with multiple system manifestations, including supraval var aortic stenosis (SVAS), peripheral pulmonic stenosis, connective tissue abnormalities, short stature, characteristic personality profile and cognitive deficits, and variable hypercalcemia in infancy. It is caused by heterozygosity for a chromosomal deletion of part of band 7q11.23 including the elastin locus (ELN). Since disruption of the ELN

R. Peoples; L. Perez-Jurado; U. Francke; Yu-Ker Wang; P. Kaplan

1996-01-01

259

A New Account of the Neurocognitive Foundations of Impairments in Space, Time, and Number Processing in Children with Chromosome 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

|In this article, I present an updated account that attempts to explain, in cognitive processing and neural terms, the nonverbal intellectual impairments experienced by most children with deletions of chromosome 22q11.2. Specifically, I propose that this genetic syndrome leads to early developmental changes in the structure and function of clearly…

Simon, Tony J.

2008-01-01

260

Relationship between Reaction Time, Fine Motor Control, and Visual-Spatial Perception on Vigilance and Visual-Motor Tasks in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and…

Howley, Sarah A.; Prasad, Sarah E.; Pender, Niall P.; Murphy, Kieran C.

2012-01-01

261

The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome.  

PubMed

Tests for allelism among mice with four different mutant alleles at the shaker-with-syndactylism locus on mouse Chromosome (Chr) 18 provide evidence that the original radiation-induced mutation, sy, is a deletion including at least two genes associated with distinct phenotypes. Mice homozygous for sy have syndactylous feet and other skeletal malformations, are deaf, and exhibit abnormal behavior characteristic of vestibular dysfunction. Two less severe spontaneous mutations, shown to be allelic with sy, cause syndactylism when homozygous (hence named fused phalanges, sy(fp) and sy(fp-2J)), but do not affect hearing and behavior. Here we describe a third spontaneous mutation allelic with sy that does not affect foot morphology (hence named no syndactylism, sy(ns)), but that does cause deafness and balance defects when homozygous. Complementation test results indicate that sy(fp) and sy(fp-2J) are alleles of the same gene, but that sy(ns) is an allele of a different gene. The original sy mutation, therefore, includes both of the genes defined by these three spontaneous mutations. Typing of DNA markers in sy/sy mice revealed a deletion of approximately 1 cM in the sy region of Chr 18, including D18Mit52, D18Mit124, D18Mit181, and D18Mit205. The genetic relationships described here will aid in positional cloning efforts to identify the genes responsible for the disparate phenotypes associated with the sy locus. PMID:9799839

Johnson, K R; Cook, S A; Zheng, Q Y

1998-11-01

262

The putative imprinted locus D15S9 within the common deletion region for the Prader-Willi and Angelman syndromes encodes two overlapping mRNAs transcribed from opposite strands  

Microsoft Academic Search

Prader-Willi syndrome is typically caused by a deletion of paternal 15q11-q13, or maternal uniparental disomy (UPD) of chromosome 15, while Angelman syndrome is caused by a maternal deletion or paternal UPD of the same region. Therefore, these two clinically distinct neurobehavioral syndromes result from differential expression of imprinted genes within 15q11-q13. A 3.1 kb cDNA, DN34, from the D15S9 locus

C. C. Glenn; D. J. Driscoll; S. Saitoh

1994-01-01

263

Autistic Spectrum Disorders in Velo-Cardio Facial Syndrome (22q11.2 Deletion)  

ERIC Educational Resources Information Center

|The extent to which the phenotype of children comorbid for velocardiofacial syndrome (VCFS) and autism spectrum disorders (ASD) differs from that of VCFS-only has not been studied. The sample consisted of 41 children (20 females) with VCFS, ranging in age from 6.5 years to 15.8 years. Eight children with VCFS met formal DSM-IV diagnostic criteria…

Antshel, Kevin M.; Aneja, Alka; Strunge, Leslie; Peebles, Jena; Fremont, Wanda P.; Stallone, Kimberly; AbdulSabur, Nuria; Higgins, Anne Marie; Shprintzen, Robert J.; Kates, Wendy R.

2007-01-01

264

Parental Origin of the Deletion 22q11.2 and Brain Development in Velocardiofacial Syndrome  

Microsoft Academic Search

Background: As children with velocardiofacial syn- drome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizo- phrenia. Because VCFS and the concomitant symptom- atology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The pur-

Stephan Eliez; Stylianos E. Antonarakis; Michael A. Morris; Sophie P. Dahoun; Allan L. Reiss

2001-01-01

265

Psychiatric Disorders and Intellectual Functioning throughout Development in Velocardiofacial (22q11.2 Deletion) Syndrome  

ERIC Educational Resources Information Center

|Objective: Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample.…

Green, Tamar; Gothelf, Doron; Glaser, Bronwyn; Debbane, Martin; Frisch, Amos; Kotler, Moshe; Weizman, Abraham; Eliez, Stephan

2009-01-01

266

Molecular and cytogenetic analysis of familial Xp deletions  

SciTech Connect

Deletions involving the short arm of the X chromosome (del(Xp)) manifest phenotypes ranging from Turner syndrome to isolated short stature to normal. We have studied five familial cases of del(Xp), four with transmission over two generations and one over four generations, utilizing both high resolution chromosome banding and FISH with cosmid and YAC probes spanning the short arm of the X chromosome. Four of the families were ascertained because of short stature while the remaining family demonstrates normal stature and was ascertained through prenatal diagnosis. Consistent with existing data for a growth gene located within Xp22.33, the more terminal breakpoints in the female with normal stature is distal to CSF2RA. A correlation between genotype and phenotype amongst the families may reveal that this case is representative of an interstitial deletion and the other four cases have breakpoints distal to the growth gene locus possibly within the subtelomeric region of the chromosome. The proximal breakpoints are heterogenous; however, three of the families with short stature share a common proximal breakpoint which is located between two YAC probes 2-3 Mb apart in Xp22.12. The proximal break in the phenotypically normal female is in Xp11.4. Late replication studies in addition to methylation assays of the FMR1 locus reveal non-random X inactivation in these cases. This study shows the presence of a breakpoint distal to the CSF2RA locus in the family demonstrating normal stature confirming the location of a growth gene distal to this locus and within Xp22.33. The shared proximal breakpoint between the three families suggests a {open_quotes}hot spot{close_quotes} for chromatin breakage. The proximal breakpoint, Xp11.4, in the normal female patient excludes this region as an etiologic factor in Turner syndrome. Work is in progress using additional probes to further elucidate both the proximal and distal breakpoints.

Wandstrat, A.E.; Conroy, J.M.; Zurcher, V.L. [Case Western Reserve, Cleveland, OH (United States)] [and others

1994-09-01

267

DDX11L: a novel transcript family emerging from human subtelomeric regions  

PubMed Central

Background The subtelomeric regions of human chromosomes exhibit an extraordinary plasticity. To date, due to the high GC content and to the presence of telomeric repeats, the subtelomeric sequences are underrepresented in the genomic libraries and consequently their sequences are incomplete in the finished human genome sequence, and still much remains to be learned about subtelomere organization, evolution and function. Indeed, only in recent years, several studies have disclosed, within human subtelomeres, novel gene family members. Results During a project aimed to analyze genes located in the telomeric region of the long arm of the human X chromosome, we have identified a novel transcript family, DDX11L, members of which map to 1pter, 2q13/14.1, 2qter, 3qter, 6pter, 9pter/9qter, 11pter, 12pter, 15qter, 16pter, 17pter, 19pter, 20pter/20qter, Xpter/Xqter and Yqter. Furthermore, we partially sequenced the underrepresented subtelomeres of human chromosomes showing a common evolutionary origin. Conclusion Our data indicate that an ancestral gene, originated as a rearranged portion of the primate DDX11 gene, and propagated along many subtelomeric locations, is emerging within subtelomeres of human chromosomes, defining a novel gene family. These findings support the possibility that the high plasticity of these regions, sites of DNA exchange among different chromosomes, could trigger the emergence of new genes.

Costa, Valerio; Casamassimi, Amelia; Roberto, Roberta; Gianfrancesco, Fernando; Matarazzo, Maria R; D'Urso, Michele; D'Esposito, Maurizio; Rocchi, Mariano; Ciccodicola, Alfredo

2009-01-01

268

Kearns-Sayre's syndrome developing in a boy who survived Pearson's syndrome caused by mitochondrial DNA deletion  

Microsoft Academic Search

A 7-year-old boy presented with bilateral ptosis and atypical retinitis pigmentosa. Before age two, he had had an Fe-refractory anemia, with neutropenia and thrombopenia. Just prior to the ophthalmic examination, the patient developed lactate acidosis, muscular hypotonia, ataxia and increased protein in the spinal fluid. Pancytopenia, pancreas dysfunction and growth retardation are the main features of Pearson's syndrome, most children

H. J. Simonsz; K. Bärlocher; A. Rötig

1992-01-01

269

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome.  

PubMed

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive-compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty-three subjects with VCFS of mean age 18.3 +/- 10.6 years were comprehensively assessed using semi-structured psychiatric interview and the Yale-Brown obsessive compulsive scale (Y-BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM-IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive-compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention-deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early-onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD. PMID:15048657

Gothelf, Doron; Presburger, Gadi; Zohar, Ada H; Burg, Merav; Nahmani, Ariela; Frydman, Moshe; Shohat, Mordechai; Inbar, Dov; Aviram-Goldring, Ayala; Yeshaya, Josepha; Steinberg, Tamar; Finkelstein, Yehuda; Frisch, Amos; Weizman, Abraham; Apter, Alan

2004-04-01

270

Fine mapping of chromosome 10q deletions in mycosis fungoides and sezary syndrome: identification of two discrete regions of deletion at 10q23.33-24.1 and 10q24.33-25.1.  

PubMed

Previous cytogenetic studies in mycosis fungoides (MF) and Sezary syndrome (SS) have identified a large and poorly defined area of chromosomal deletion on chromosome 10q. We report an extensive fine-mapping allelotyping study using 19 microsatellite markers in the region 10q22.3-10q26.13. Allelic loss was identified by loss of heterozygosity analysis in 26 of 60 (43%) cases: 15 of 45 (33%) with MF and 11 of 15 (73%) with SS. MF and SS samples showed similar patterns of allelic loss with the identification of two discrete regions of deletion which were mutually exclusive in all but two cases. Within the first region of deletion at 10q23.33-10q24.1, around microsatellite marker D10S185 (2.77 Mb), 23 genes were identified, including three (KIF11, HHEX, and HELLS) with functions that, if dysregulated, could be critical in MF and SS. The second region of deletion, 10q24.33-10q25.1, around microsatellite marker D10S530 (3.92 Mb), encodes 11 genes, the majority of which have poorly identified functions. This extensive allelotyping study provides the basis for future highly selective candidate gene analyses. PMID:15540164

Wain, E Mary; Mitchell, Tracey J; Russell-Jones, Robin; Whittaker, Sean J

2005-02-01

271

Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia  

PubMed Central

The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5–3Mb region of chromosome 22. 22q11DS constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2), which is responsible for loading Ca2+ into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca2+ load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8+/? mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.

Earls, Laurie R.; Fricke, R. Gaines; Yu, Jing; Berry, Raymond B.; Baldwin, Lisa T.; Zakharenko, Stanislav S.

2012-01-01

272

TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome.  

PubMed

The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK(1)-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state. PMID:22547700

Fernandes, Elizabeth S; Liang, Lihuan; Smillie, Sarah-Jane; Kaiser, Frank; Purcell, Robert; Rivett, Damian W; Alam, Saydul; Howat, Sarah; Collins, Helen; Thompson, Stephen J; Keeble, Julie E; Riffo-Vasquez, Yanira; Bruce, Kenneth D; Brain, Susan D

2012-04-30

273

Comprehensive analysis of human subtelomeres with combined binary ratio labelling fluorescence in situ hybridisation  

Microsoft Academic Search

Cryptic subtelomeric chromosome rearrangements play an important role in the aetiology of mental retardation, congenital anomalies, miscarriages and neoplasia. To facilitate a comprehensive molecular–cytogenetic analysis of these extremely gene-rich and mutation-prone chromosome regions, novel multicolour fluorescence in situ hybridisation (FISH) techniques are being developed. As yet, subtelomeric FISH methods have either had limited multiplicities, making it necessary to perform many

Hartmut Engels; Antje Ehrbrecht; Susanne Zahn; Kristin Bosse; Hans Vrolijk; Stefan White; Vera Kalscheuer; Jan M N Hoovers; Gesa Schwanitz; Peter Propping; Hans J Tanke; Joop Wiegant; Anton K Raap

2003-01-01

274

Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q.  

PubMed Central

Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both. Images

Van Camp, G; Van Thienen, M N; Handig, I; Van Roy, B; Rao, V S; Milunsky, A; Read, A P; Baldwin, C T; Farrer, L A; Bonduelle, M

1995-01-01

275

Visual scanpath abnormalities in 22q11.2 deletion syndrome: is this a face specific deficit?  

PubMed

People with 22q11.2 deletion syndrome (22q11DS) have deficits in face emotion recognition. However, it is not known whether this is a deficit specific to faces, or represents maladaptive information processing strategies to complex stimuli in general. This study examined the specificity of face emotion processing deficits in 22q11DS by exploring recognition accuracy and visual scanpath performance to a Faces task compared to a Weather Scene task. Seventeen adolescents with 22q11DS (11=females, age=17.4) and 18 healthy controls (11=females, age=17.7) participated in the study. People with 22q11DS displayed an overall impoverished scanning strategy to face and weather stimuli alike, resulting in poorer accuracy across all stimuli for the 22q11DS participants compared to controls. While the control subjects altered their information processing in response to faces, a similar change was not present in the 22q11DS group indicating different visual scanpath strategies to identify category within each of the tasks, of which faces appear to represent a particularly difficult subcategory. To conclude, while this study indicates that people with 22q11DS have a general visual processing deficit, the lack of strategic change between tasks suggest that the 22q11DS group did not adapt to the change in stimuli content as well as the controls, indicative of cognitive inflexibility rather than a face specific deficit. PMID:21831452

McCabe, Kathryn; Rich, Dominique; Loughland, Carmel Maree; Schall, Ulrich; Campbell, Linda Elisabet

2011-08-09

276

Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion).  

PubMed

Contiguous gene syndromes are disorders caused by deletions of genes that are adjacent to one another. One of them is complex glycerol kinase deficiency. It is caused by partial deletion of Xp21, which includes the genes responsible for glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy and intellectual disability. There are no definite dysmorphic features for this syndrome. The diagnosis is based on clinical and laboratory findings. Symptoms depend on the size of deletion and appear almost exclusively in the male gender. Usually the first and most severe are the signs of adrenal hypoplasia, which, if not cured, may lead to death in a short time. The symptoms of glycerol kinase deficiency occur also early in life, but they may be masked by the deficiency of mineralocorticoids. Duchenne muscular dystrophy appears in childhood and is always accompanied by certain symptoms. Developmental retardation and intellectual disability occur often with complex glycerol kinase deficiency. The reasons for it are heterogeneous, but usually, there is a connection with the deletion of DMD or I L1R A P L genes. Due to the fact that loci of all genes responsible for complex glycerol kinase deficiency were determined, it is possible to carry out molecular examination, confirm clinical diagnosis and determine female carriers of the disorder. PMID:23739620

Wikiera, Beata; Jakubiak, Aleksandra; Zimowski, Janusz; Noczy?ska, Anna; Smigiel, Robert

2012-01-01

277

Advanced imaging of the cervical spine and spinal cord in 22q11.2 deletion syndrome: age-matched, double-cohort, controlled study  

PubMed Central

Purpose The 22q11.2 deletion syndrome is a common genetic syndrome with a wide spectrum of abnormalities. We have previously described multiple anomalies of the upper cervical spine in this disorder. The objective of this study was to use advanced imaging to further define the morphology of the cervical spine and spinal cord in the 22q11.2 deletion syndrome, with a comparison to age-matched controls. Methods A total of 32 patients with a 22q11.2 deletion underwent advanced imaging (computed tomography/magnetic resonance imaging; CT/MRI) of the cervical spine. In 27 patients, space available for the cord (SAC); the sagittal diameter of the vertebral body, spinal canal, cerebrospinal fluid (CSF), and spinal cord; and the cross sectional area of the spinal canal, CSF, and spinal cord were measured at each cervical level and compared to 29 age-matched controls. Statistical analysis was performed and potential implications were hypothesized. Results In 22q11.2 patients, advanced imaging identified 40 pathologies not evident on plain radiographs with potential mechanical and/or neurological implications. These patients also had significantly smaller values (P ? 0.05) of the following parameters at one or more cervical levels, relative to age-matched controls: width of the vertebral body, spinal canal, CSF, and spinal cord; area of the spinal canal, CSF, and spinal cord. Neurologic symptoms were observed in 4/32 patients, with one patient requiring surgical intervention. Conclusions Advanced imaging of the cervical spine can detect findings not evident on plain radiographs in the 22q11.2 deletion syndrome. CT and/or MRI may be indicated when there is a high index of suspicion for clinical instability or neurologic compromise in order to rule out dynamic encroachment or impending neurologic sequelae. Spinal canal and spinal cord dimensions are reduced in these patients relative to controls with currently unknown clinical significance.

Ricchetti, Eric T.; Hosalkar, Harish S.; Gholve, Purushottam A.; Cameron, Danielle B.

2008-01-01

278

WBSCR14, a gene mapping to the Williams-Beuren syndrome deleted region, is a new member of the Mlx transcription factor network  

Microsoft Academic Search

Williams-Beuren syndrome (WBS) is a develop- mental disorder associated with haploinsufficiency of multiple genes at 7q11.23. Here, we report the functional characterization of WBS critical region gene 14 (WBSCR14), a gene contained in the WBS commonly deleted region. It encodes a basic-helix- loop-helix leucine zipper (bHLHZip) transcription factor of the Myc\\/Max\\/Mad superfamily. WBSCR14 is expressed in multiple tissues, including regions

Stefano Cairo; Giuseppe Merla; Fabrizia Urbinati; Andrea Ballabio; Alexandre Reymond

2001-01-01

279

Age-dependent clinical problems in a Norwegian national survey of patients with the 22q11.2 deletion syndrome  

Microsoft Academic Search

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up.\\u000a In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were\\u000a collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys\\u000a was also performed. In addition, multiplex ligation

Kari Lima; Ivar Følling; Kristin L. Eiklid; Solveig Natvig; Tore G. Abrahamsen

2010-01-01

280

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array comparative genomic hybridization characterization using uncultured amniocytes and literature review.  

PubMed

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot. PMID:23791650

Chen, Chih-Ping; Huang, Jian-Pei; Chen, Yi-Yung; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chen, Yu-Ting; Chen, Wen-Lin; Wang, Wayseen

2013-06-17

281

Recovery of viable porcine reproductive and respiratory syndrome virus from an infectious clone containing a partial deletion within the Nsp2-encoding region  

Microsoft Academic Search

Non-structural protein 2 (Nsp2) of porcine reproductive and respiratory syndrome virus (PRRSV) is the most variable region\\u000a and postulated to play an important role in cell and tissue tropism of PRRSV. To investigate the role of Nsp2 in the viability\\u000a and growth of PRRSV in cells in vitro, two cDNA clones were constructed containing a deletion of 63 consecutive nucleotides

Z. G. Ran; X. Y. Chen; X. Guo; X. N. Ge; K. J. Yoon; H. C. Yang

2008-01-01

282

Familial Williams-Beuren syndrome ascertained by screening rather than targeted diagnosis.  

PubMed

Williams-Beuren syndrome (WBS), a contiguous gene deletion syndrome, mostly occurs sporadically. Although a few cases of familial WBS have been reported in the literature, molecular confirmation of the deletion has not been carried out in all of them. Here, we report on the eighth clinically and molecularly confirmed inherited WBS detected in a family with 'familial mental retardation.' A comprehensive screening approach to mental retardation that included stepwise karyotyping, assessment for fragile-X syndrome, subtelomeric rearrangements and known microdeletion/microduplication syndromes, and a genome-wide array-CGH study was applied. The father, the mother, and their daughter were all mentally handicapped with nonspecific clinical manifestations and dysmorphic features. The first child of the family died from multiple congenital anomalies. The father and his daughter, who had never been suspected to have WBS, were diagnosed as having a deletion of the WBS critical region. No other abnormalities were detected in the family. Unlike other previously reported cases, in which the disease was ascertained on the basis of clinical manifestations, the present report represents an example of the detection of cryptic chromosomal abnormalities in mental retardation patients by the stepwise application of high-throughput screening methods. PMID:22473150

Rafati, Maryam; Seyyedaboutorabi, Elaheh; Brujerdi, Razieh; Moossavi, Shirin; Ghaffari, Saeed Reza

2012-07-01

283

Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics.  

PubMed

Liebenberg syndrome (MIM 186550) is a very rare autosomal dominant condition characterized by three main features: dysplasia of all of the bony components of the elbow joint, abnormalities in the shape of carpal bones, and brachydactyly. In this paper, we report a Saudi Arabian family with Liebenberg syndrome. Comparative genomic hybridization (CGH) revealed a 275-kb deletion within the cytogenetic band 5q31.1 which contains the H2AFY gene and 190,428bp of its downstream region. The deleted region is upstream to the PITX1 gene. The radiological features in the upper limbs of all affected members of the family were almost identical to the phenotype in the mouse model with ectopic expression of Pitx1 in the forelimbs. We therefore re-define the phenotype of Liebenberg syndrome as a transformation of the upper limbs to reflect lower limb characteristics and speculate that the area of deletion contains a regulatory sequence that suppresses the expression of PITX1 in the upper limb buds. PMID:23587911

Al-Qattan, Mohammad M; Al-Thunayan, Abdullah; Alabdulkareem, Ibrahim; Al Balwi, Mohammed

2013-04-12

284

Chromosome 2p15p16.1 microdeletion syndrome: 2.5 Mb deletion in a patient with renal anomalies, intractable seizures and a choledochal cyst.  

PubMed

Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.0 array we identified a de novo interstitial deletion on the short arm of chromosome 2, spanning approximately 2.5 Mb in the cytogenetic band position 2p15p16.1, in a female infant with characteristic features of 2p15p16.1 deletion syndrome including severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect. We further redefined the previously reported critical region, supporting the presence of a newly recognized microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 1.1 Mb segment of the 2p15p16.1 region. PMID:22579565

Hucthagowder, Vishwanathan; Liu, Ta-Chiang; Paciorkowski, Alex R; Thio, Liu Lin; Keller, Martin S; Anderson, Christopher D; Herman, Thomas; Dehner, Louis P; Grange, Dorothy K; Kulkarni, Shashikant

2012-04-22

285

The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion  

SciTech Connect

Williams syndrome (WS) is a developmental disorder with multiple system manifestations, including supraval var aortic stenosis (SVAS), peripheral pulmonic stenosis, connective tissue abnormalities, short stature, characteristic personality profile and cognitive deficits, and variable hypercalcemia in infancy. It is caused by heterozygosity for a chromosomal deletion of part of band 7q11.23 including the elastin locus (ELN). Since disruption of the ELN gene causes autosomal dominant SVAS, it is assumed that ELN haploinsufficiency is responsible for the cardiovascular features of WS. The deletion that extends from the ELN locus in both directions is {ge}200 kb in size, although estimates of {ge}2 Mb are suggested by high-resolution chromosome banding and physical mapping studies. We have searched for additional dosage-sensitive genes within the deletion that may be responsible for the noncardiovascular features. We report here that the gene for replication factor C subunit 2 (RFC2) maps within the WS deletion region and was found to be deleted in all of 18 WS patients studied. The protein product of RFC2 is part of a multimeric complex involved in DNA elongation during replication. 14 refs., 3 figs.

Peoples, R.; Perez-Jurado, L.; Francke, U.; Yu-Ker Wang [Stanford Univ. Medical Center, CA (United States); Kaplan, P. [Children`s Hospital of Philadelphia, PA (United States)

1996-06-01

286

Two families with isolated cat cry without the cri-du-chat syndrome phenotype have an inherited 5p15.3 deletion: Delineation of the larynx malformation region  

Microsoft Academic Search

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 that 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 two families

M. Gersh; J. Overhauser; L. M. Pasztor

1994-01-01

287

Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness.  

PubMed

We report the ophthalmological findings of a 6-year-old boy who has features of both Aland Island eye disease (also called Forsius-Eriksson ocular albinism) and incomplete congenital stationary night blindness, as defined by Miyake, leading us to suspect that they are the same entity. This child has a deletion of part of band 21 of the short arm of the X chromosome (Xp21) and three other X-linked disorders: congenital adrenal hypoplasia, glycerol kinase deficiency, and Duchenne type muscular dystrophy. The electroretinogram showed negative scotopic and abnormal photopic waveforms that were similar, if not identical, to the electroretinographic findings in both Aland Island eye disease and X-linked incomplete congenital stationary night blindness. Because of this similarity and the defective dark adaptometry that has been reported in patients with this disorder, we believe that Aland Island eye disease is more appropriately classified as a form of congenital night blindness than as a form of ocular albinism. From our case and review of the literature, Aland Island eye disease and incomplete congenital stationary night blindness appear indistinguishable. If further studies confirm that the disorders are the same, we recommend use of the term Aland Island eye disease or Forsius-Eriksson-Miyake syndrome. We also recommend that the gene symbols CSNB1 and CSNB2 be used for complete congenital stationary night blindness and Aland disease, respectively. PMID:2667510

Weleber, R G; Pillers, D A; Powell, B R; Hanna, C E; Magenis, R E; Buist, N R

1989-08-01

288

Deletions Involving Long-Range Conserved Nongenic Sequences Upstream and Downstream of FOXL2 as a Novel Disease-Causing Mechanism in Blepharophimosis Syndrome  

PubMed Central

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

Beysen, D.; Raes, J.; Leroy, B. P.; Lucassen, A.; Yates, J. R. W.; Clayton-Smith, J.; Ilyina, H.; Brooks, S. Sklower; Christin-Maitre, S.; Fellous, M.; Fryns, J. P.; Kim, J. R.; Lapunzina, P.; Lemyre, E.; Meire, F.; Messiaen, L. M.; Oley, C.; Splitt, M.; Thomson, J.; Peer, Y. Van de; Veitia, R. A.; De Paepe, A.; De Baere, E.

2005-01-01

289

AZF and DAZ gene copy-specific deletion analysis in maturation arrest and Sertoli cell-only syndrome  

Microsoft Academic Search

Deletions of the AZFc region in Yq11.2, which include the DAZ gene family, are responsible for most cases of male infertility and were associated with severe oligozoospermia and also with a variable testicular pathology. To uncover the functional con- tribution of DAZ to human spermatogenesis, a DAZ gene copy-specific deletion analysis was previously established and showed that DAZ1\\/DAZ2 deletions associate

C. Ferras; S. Fernandes; C. J. Marques; F. Carvalho; C. Alves; J. Silva; M. Sousa; A. Barros

2004-01-01

290

Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome  

PubMed Central

The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMTMet compared to COMTVal, and greater reduction in those with greater decline in verbal IQ over time. Leave- one-out multivariate pattern analysis (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders.

Gothelf, Doron; Hoeft, Fumiko; Ueno, Takefumi; Sugiura, Lisa; Lee, Agatha D.; Thompson, Paul; Reiss, Allan L.

2010-01-01

291

Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.  

PubMed

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. PMID:22495892

Burkitt-Wright, Emma M M; Bradley, Lisa; Shorto, Jennifer; McConnell, Vivienne P M; Gannon, Caroline; Firth, Helen V; Park, Soo-Mi; D'Amore, Angela; Munyard, Paul F; Turnpenny, Peter D; Charlton, Amanda; Wilson, Meredith; Kerr, Bronwyn

2012-04-11

292

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.  

PubMed

Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5?Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ?3.5?Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ?1.2?Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.European Journal of Human Genetics advance online publication, 12 June 2013; doi:10.1038/ejhg.2013.101. PMID:23756441

Fusco, Carmela; Micale, Lucia; Augello, Bartolomeo; Teresa Pellico, Maria; Menghini, Deny; Alfieri, Paolo; Cristina Digilio, Maria; Mandriani, Barbara; Carella, Massimo; Palumbo, Orazio; Vicari, Stefano; Merla, Giuseppe

2013-06-12

293

Deletions of Yq11 associated with short stature and the Turner syndrome. Tentative mapping of a region associated with specific Turner stigmata to proximal interval 5.  

SciTech Connect

Turner syndrome is a complex human phenotype, commonly associated with a 45,X karyotype. Mapping the Turner phenotype is difficult since hidden mosaicisms, partial monosomy and complex rearrangements are present in many affected individuals. In addition, attempts to map the genes involved to the X chromosome have failed to yield a consistent localisation. An alternative approach to map and identify Turner genes is to study XY individuals, with sex chromosome abnormalities, who present with or without characteristic Turner stigmata. We report the analysis of 4 individuals with terminal deletions of Yq. The individuals were azoospermic males without phenotypic abnormalities (2 cases) and azoospermic males presenting with a specific subset of Turner stigmata (2 cases). Breakpoints in each of the cytogenetically detectable Yq deletions were mapped by Southern analysis and Y chromosome-specific sequence tagged sites (STS). Correlation between the patients phenotypes and the extent of their deletion indicate a critical region associated with specific Turner stigmata (cubitus valgus, shield chest, short fourth metacarpals) and growth retardation at Yq at proximal interval 5. These data provide evidence that the somatic features of the Turner syndrome are most likely caused by haploinsufficiency of genes at several loci.

McElreavey, K.; Barbaux, S.; Vilain, E. [Immunogenetique Humaine 25 rue du Dr. Roux, Paris (France)] [and others

1994-09-01

294

Isolation of a transcription factor expressed in neural crest from the region of 22q11 deleted in DiGeorge syndrome  

SciTech Connect

Deletions within chromosome 22q11 cause a wide variety of birth defects including DiGeorge syndrome and Shprintzen syndrome. We have defined a commonly deleted region of over 2 Mb, and a critical region of 300 kb. A gene, TUPLE1, has been isolated from this critical region encoding a transcriptional regulator similar to the yeast HIR1 histone regulator gene. Since it has been suggested that DGS results from a defective neural crest, the expression of Tuple1 was examined in whole mouse and chick embryos, tissue sections and neural tube explants: Tuple1 is expressed in a dynamic pattern with high levels in regions containing migrating crest. Prior to crest migration Tuple1 is expressed in a rhombomere-specific expression pattern. Later Tuple1 is expressed in discrete domains within the developing neural tube. A remarkable feature of the experiments was the detection of a similar dynamic pattern with sense probe; i.e., there is an antisense Tuple1 transcript. This was confirmed using RPA. Tuple1 is being screened for mutations in non-deletion patients and constructs assembled for homologous recombination in ES cells. Tuple1 maps to MMU16 extending the homology of linkage with human chromosome 22. From these data we predict that the human homologue of the murine scid mutation maps to 22q11.

Wadey, R.; Roberts, C.; Daw, S. [and others

1994-09-01

295

Age-dependent clinical problems in a Norwegian national survey of patients with the 22q11.2 deletion syndrome.  

PubMed

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age. PMID:20186429

Lima, Kari; Følling, Ivar; Eiklid, Kristin L; Natvig, Solveig; Abrahamsen, Tore G

2010-02-26

296

Patient with dup(5)(q35.2-q35.3) reciprocal to the common Sotos syndrome deletion and review of the literature.  

PubMed

The recent implementation of array techniques in research and clinical practice has revealed the existence of recurrent reciprocal deletions and duplications in several genome loci. The most intriguing feature is that some reciprocal genomic events can result in opposite phenotypic outcome. One of such examples is 5q35.2-q35.3. Deletions in this locus lead to Sotos syndrome characterized by childhood overgrowth with advanced bone age, craniofacial dysmorphic features including macrocephaly, and learning difficulties; while duplications have been proposed to manifest in opposite phenotype related to growth. Here, we report a patient with 5q35.2-q35.3 duplication and compare her clinical phenotype with five previously described cases. Short stature since the birth, microcephaly, brachydactyly, delayed bone age, mild to moderate intellectual disability and mild facial dysmorphism seem to be characteristic features of 5q35.2-q35.3 duplication. PMID:23369838

Žilina, Olga; Reimand, Tiia; Tammur, Pille; Tillmann, Vallo; Kurg, Ants; Õunap, Katrin

2013-01-28

297

Temporal lobe pleomorphic xanthoastrocytoma and acquired BRAF mutation in an adolescent with the constitutional 22q11.2 deletion syndrome.  

PubMed

DiGeorge syndrome, or velocardiofacial syndrome (DGS/VCFS), is a rare and usually sporadic congenital genetic disorder resulting from a constitutional microdeletion at chromosome 22q11.2. While rare cases of malignancy have been described, likely due to underlying immunodeficiency, central nervous system tumors have not yet been reported. We describe an adolescent boy with DGS/VCFS who developed a temporal lobe pleomorphic xanthoastrocytoma. High-resolution single nucleotide polymorphism array studies of the tumor confirmed a constitutional 22q11.21 deletion, and revealed acquired gains, losses and copy number neutral loss of heterozygosity of several chromosomal regions, including a homozygous deletion of the CDKN2A/B locus. The tumor also demonstrated a common V600E mutation in the BRAF oncogene. This is the first reported case of a patient with DiGeorge syndrome developing a CNS tumor of any histology and expands our knowledge about low-grade CNS tumor molecular genetics. PMID:20730472

Murray, Jeffrey C; Donahue, David J; Malik, Saleem I; Dzurik, Yvette B; Braly, Emily Z; Dougherty, Margaret J; Eaton, Katherine W; Biegel, Jaclyn A

2010-08-21

298

Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse  

PubMed Central

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same ?4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three ?200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an ?1.1-Mb genomic interval that is syntenic to an ?1.0-Mb region in the mouse. Genes within the SMCR and its mouse syntenic region were identified by homology searches and by gene prediction programs, and their gene structures and expression profiles were characterized. In addition to 12 genes previously mapped, we identified 8 new genes and 10 predicted genes in the SMCR. In the mouse syntenic region of the human SMCR, 16 genes and 6 predicted genes were identified. The SMCR is highly conserved between humans and mice, including 19 genes with the same gene order and orientation. Our findings will facilitate both the identification of gene(s) responsible for the SMS phenotype and the engineering of an SMS mouse model.

Bi, Weimin; Yan, Jiong; Stankiewicz, Pawel; Park, Sung-Sup; Walz, Katherina; Boerkoel, Cornelius F.; Potocki, Lorraine; Shaffer, Lisa G.; Devriendt, Koen; Nowaczyk, Malgorzata J.M.; Inoue, Ken; Lupski, James R.

2002-01-01

299

A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD)  

PubMed Central

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reduction of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chromosomal rearrangement and is generally used for diagnosis. However, diagnosis of FSHD is complicated by three factors. First, the probe cross hybridises to a highly homologous repeat array locus on chromosome 10q26. Second, although a BlnI polymorphism allows discrimination between the repeat units on chromosomes 4 and 10 and greatly facilitates FSHD diagnosis, the occurrence of translocations between chromosomes 4 and 10 further complicates accurate FSHD diagnosis. Third, the recent identification of deletions of p13E-11 in both control and FSHD populations is an additional complicating factor. Although pulsed field gel electrophoresis is very useful and sometimes necessary to detect these rearrangements, this technique is not operational in most FSHD diagnostic laboratories. Moreover, repeat arrays >200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Therefore, we have developed an easy and reliable Southern blotting method to identify exchanges between 4 type and 10 type repeat arrays and deletions of p13E-11. This BglII-BlnI dosage test addresses all the above mentioned complicating factors and can be carried out in addition to the standard Southern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosis to the values obtained by PFGE based diagnosis of FSHD. Moreover, this study delimits the FSHD candidate gene region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit.???Keywords: FSHD; diagnosis; dosage; subtelomere

van der Maarel, S. M; Deidda, G.; Lemmers, R.; Bakker, E.; van der Wielen, M. J R; Sandkuijl, L.; Hewitt, J.; Padberg, G.; Frants, R.

1999-01-01

300

Chromosome 20p inverted duplication deletion identified in a Thai female adult with mental retardation, obesity, chronic kidney disease and characteristic facial features.  

PubMed

We report on a 21-year-old Thai woman presenting with mental retardation, developmental delays, selective mutism, distinctive facial features, sensorineural hearing loss, single right kidney, uterine didelphys and obesity. A longitudinal clinical course beginning in childhood revealed excessive weight gain, poor language skills and poor school performance. Chronic kidney disease stage 4, with elevated blood pressure, was first noted in adulthood. Array comparative genomic hybridization detected a copy loss at 20p13 co-existing with a copy gain at 20p13-20p11.22. A conventional cytogenetic study revealed the complex structural rearrangement of chromosome 20 [der (20) dup (20) (p11.2p13) del (20) (p13.pter)]. A FISH analysis, using probes against duplication and deletion regions, confirmed that there was an inverted duplication of p11.2-p13 and a deletion in the subtelomere region. Previous reports have identified this cytogenetic characterization in a Caucasian boy. Therefore, this is the first reported case of chromosome 20p inverted duplication deletion syndrome in an adult from the Southeast Asian population group. PMID:23542666

Trachoo, Objoon; Assanatham, Montira; Jinawath, Natini; Nongnuch, Arkom

2013-03-29

301

Chromosome 18p deletion syndrome presenting holoprosencephaly and premaxillary agenesis: prenatal diagnosis and aCGH characterization using uncultured amniocytes.  

PubMed

We present prenatal diagnosis of a de novo distal 18p deletion involving 14.06Mb at 18p11.32-p11.21 by aCGH using uncultured amniocytes in a pregnancy with fetal holoprosencephaly and premaxillary agenesis. QF-PCR analysis showed that distal 18p deletion was from maternal origin. Metaphase FISH analysis confirmed haploinsufficiency of TGIF. We discuss the functions of the genes that are deleted within this region. The present case shows the usefulness of applying aCGH on uncultured amniocytes for rapid aneuploidy diagnosis in cases with prenatally detected fetal structural abnormalities. PMID:23850725

Chen, Chih-Ping; Huang, Jian-Pei; Chen, Yi-Yung; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Pan, Chen-Wen; Wang, Wayseen

2013-07-11

302

A deletion 13q34/duplication 14q32.2-14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia.  

PubMed

During infancy, this 50-year-old man with a previously undiagnosed multiple congenital anomalies/intellectual disability (MCA/MR) syndrome had grossly symptomatic hypercalcemia and was (briefly) thought to have Williams syndrome. Results of studies with the cytogenetic methods of the 1960s and 1970s were apparently normal. He matured late, but is high-functioning and healthy. Over 50 years he remained a diagnostic enigma. Thus, it came as a surprise when recent high-resolution banding methods showed an abnormality of the terminal portion of 13q, determined on array-comparative genomic hybridization to constitute an unbalanced chromosome rearrangement with a 0.35?Mb loss of 13q34-ter and 7.67?Mb gain of 14q32.2q32.33 translocated to 13q34. This apparently de novo genomic abnormality must be presumed as the cause of this previously undescribed MCA/MR syndrome which, however, may remain a private syndrome in this family. Williams syndrome was ruled out, and presently it is not possible to ascribe this patient's severely symptomatic infantile hypercalcemia to any gene on the deleted or duplicated chromosome segments. This "case" does underscore the importance of re-studying previously obscure but evidently genetic conditions, of long-term follow-up and documentation of natural history, and of providing, at last, a causal explanation to the family. PMID:21595000

Pallister, Philip D; Pallister, Adam B; South, Sarah; Toydemir, Reha; Johnson, John P; Beischel, Linda; Opitz, John M

2011-03-15

303

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

PubMed

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

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

2012-03-09

304

A Novel Deletion Mutation of SLC16A2 Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome.  

PubMed

Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2. PMID:24170966

Yamamoto, Sayaka; Okuhara, Koji; Tonoki, Hidefumi; Iizuka, Susumu; Nihei, Noriko; Tajima, Toshihiro

2013-10-26

305

A Novel Deletion Mutation of SLC16A2 Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome  

PubMed Central

Abstract. Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2.

Yamamoto, Sayaka; Okuhara, Koji; Tonoki, Hidefumi; Iizuka, Susumu; Nihei, Noriko; Tajima, Toshihiro

2013-01-01

306

Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1)  

PubMed Central

Background Arachnomelia syndrome is an autosomal recessive inherited disease in cattle. Affected calves die around birth and show malformations of the skeleton mainly affecting the legs, the spinal column and the skull. A number of arachnomelia syndrome affected Simmental calves were recently detected by a surveillance system of anomalies with a peak of more than 120 recorded cases in the year 2006. The causative mutation was previously mapped to a 9 cM-region on bovine chromosome 23. We herein report the fine-mapping and identification of the gene causing arachnomelia syndrome in Simmental cattle. Results By using a dense set of markers, the arachnomelia syndrome linked region could be refined to 1.5 cM harbouring three protein coding genes. Comparative sequencing of these genes revealed a two-bp-deletion in the bovine MOCS1 gene resulting in a frame-shift and a premature termination codon. We genotyped affected calves and their ancestors and found that all affected were homozygous for the deletion whereas all carriers were heterozygous. Furthermore, cattle from the same population, but not directly related to known carriers mostly showed the wild type genotype. Conclusions MOCS1 encodes two proteins that are involved in the first synthesis step of molybdenum cofactor. A non functional sulfite-oxydase, one of the enzymes requiring molybdenum cofactor, leads to a similar pathology in Brown Swiss cattle. In combination the perfect association of the mutation with the phenotype and the obvious disruption of protein translation provide strong evidence for the causality of the MOCS1 mutation. Our results are the first example for an oligogenic lethal inherited disease in cattle. Furthermore, they show the potential involvement of sulfite metabolism in aberrant bone development.

2011-01-01

307

Contiguous gene syndrome due to an interstitial deletion in Xp22.3 in a boy with ichthyosis, chondrodysplasia punctata, mental retardation and ADHD.  

PubMed

Microdeletions of Xp22.3 can result in contiguous gene syndromes, showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism, anosmia, ocular albinism, short stature and mental retardation. We report on a boy with ichthyosis, dysmorphic features and mental retardation with ADHD. The patient was born at term after a pregnancy complicated by threatened abortion; decreased fetal movements and low estriol serum levels were reported during the last trimester. The boy was referred to us at the age of 13 years. He presented with aggressive and hyperactive behavior. He had dry hair, a flat face, bilateral lens opacities, a small nose with hypoplastic tip, alae nasi and nares, a high-arched palate with a very small cleft, mixed dentition with 7 unerupted permanent teeth, left sensorineural and right mixed hearing loss with a calcified plaque of the tympanic membrane, marked shortness of terminal phalanges of hands and feet, ichthyosis of trunk and limbs. The genomic interval between AFM248th5 and KAL1 was investigated. PCR analysis showed a deletion in Xp22.3, with the distal breakpoint between the marker AFM248th5 and PABX and the proximal one between DXS278 and KAL1. Array-CGH and FISH analysis confirmed the interstitial deletion (of about 5.5 Mb) and refined the breakpoints. We discuss the phenotype of our patient in relationship to the deleted segment and the possibility of mental retardation and ADHD genes in the region. PMID:17591464

Lonardo, Fortunato; Parenti, Giancarlo; Luquetti, Daniela Varela; Annunziata, Ida; Della Monica, Matteo; Perone, Lucia; De Gregori, Manuela; Zuffardi, Orsetta; Brunetti-Pierri, Nicola; Andria, Generoso; Scarano, Gioacchino

2007-05-21

308

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

PubMed

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, 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 subunit 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. PMID:8812460

Osborne, L R; Martindale, D; Scherer, S W; Shi, X M; Huizenga, J; Heng, H H; Costa, T; Pober, B; Lew, L; Brinkman, J; Rommens, J; Koop, B; Tsui, L C

1996-09-01

309

Three Phases of DiGeorge/22q11 Deletion Syndrome Pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes  

PubMed Central

Summary DiGeorge, or 22q11 Deletion Syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes—particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites—the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes—especially those that influence the cell cycle or mitochondrial function—remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/ hyperactivity disorder seen in most 22q11DS patients.

Meechan, D.W.; Maynard, T.M.; Tucker, E.S.; LaMantia, A-S.

2013-01-01

310

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis  

PubMed Central

Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ?26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family.

Zhang, Ya-nan; Dong, Xing-sheng; Huang, Yang-yu; Son, Xin-ming; Lu, Xinyan; Chen, Zheng

2013-01-01

311

Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome  

PubMed Central

A de novo 0.3?Mb deletion on 6p21.3 was detected by array-comparative genomic hybridization in a girl with mental retardation, drug-resistant seizures, facial dysmorphisms, gut malrotation and abnormal pancreas segmentation. Consistent with phenotypic manifestations is haploinsufficiency of SYNGAP1, which was recently demonstrated to cause non-syndromic mental retardation, and of the flanking genes CuTA, a likely modulator of the processing and trafficking of secretory proteins in the human brain, and hPHF1, involved in HOX gene silencing. Mutations of both CuTA and hPHF1 were never reported as causative of human diseases. Similarly, the present syndromic condition was not previously described and it can be regarded as a human model confirming the suggested biological properties of the genes included in the deletion interval. In addition, experimental evidence that SYNGAP1 and CuTA are involved in the secretory pathway in neurons, through glutamate and acetylcholinesterase signalling, prompted us to consider modulation of the glutamate pathway as target of a therapeutic strategy for seizure control.

Zollino, Marcella; Gurrieri, Fiorella; Orteschi, Daniela; Marangi, Giuseppe; Leuzzi, Vincenzo; Neri, Giovanni

2011-01-01

312

Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome.  

PubMed

A de novo 0.3?Mb deletion on 6p21.3 was detected by array-comparative genomic hybridization in a girl with mental retardation, drug-resistant seizures, facial dysmorphisms, gut malrotation and abnormal pancreas segmentation. Consistent with phenotypic manifestations is haploinsufficiency of SYNGAP1, which was recently demonstrated to cause non-syndromic mental retardation, and of the flanking genes CuTA, a likely modulator of the processing and trafficking of secretory proteins in the human brain, and hPHF1, involved in HOX gene silencing. Mutations of both CuTA and hPHF1 were never reported as causative of human diseases. Similarly, the present syndromic condition was not previously described and it can be regarded as a human model confirming the suggested biological properties of the genes included in the deletion interval. In addition, experimental evidence that SYNGAP1 and CuTA are involved in the secretory pathway in neurons, through glutamate and acetylcholinesterase signalling, prompted us to consider modulation of the glutamate pathway as target of a therapeutic strategy for seizure control. PMID:21119708

Zollino, Marcella; Gurrieri, Fiorella; Orteschi, Daniela; Marangi, Giuseppe; Leuzzi, Vincenzo; Neri, Giovanni

2010-12-01

313

Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice  

PubMed Central

Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an ?7 Mb ‘cardiac critical region’ in distal 11q that contains a putative causative gene(s) for congenital heart disease. In this study, we utilized chromosomal microarray mapping to characterize three patients with 11q- and congenital heart defects that carry interstitial deletions overlapping the 7 Mb cardiac critical region. We propose that this 1.2 Mb region of overlap harbors a gene(s) that causes at least a subset of the congenital heart defects that occur in 11q-. We demonstrate that one gene in this region, ETS-1 (a member of the ETS family of transcription factors), is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of ETS-1 in mice in a C57/B6 background causes, with high penetrance, large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle (one of the hallmarks of HLHS). Our results implicate an important role for the ETS-1 transcription factor in mammalian heart development and should provide important insights into some of the most common forms of congenital heart disease.

Ye, Maoqing; Coldren, Chris; Liang, Xingqun; Mattina, Teresa; Goldmuntz, Elizabeth; Benson, D. Woodrow; Ivy, Dunbar; Perryman, M.B.; Garrett-Sinha, Lee Ann; Grossfeld, Paul

2010-01-01

314

Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.  

PubMed

Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an approximately 7 Mb 'cardiac critical region' in distal 11q that contains a putative causative gene(s) for congenital heart disease. In this study, we utilized chromosomal microarray mapping to characterize three patients with 11q- and congenital heart defects that carry interstitial deletions overlapping the 7 Mb cardiac critical region. We propose that this 1.2 Mb region of overlap harbors a gene(s) that causes at least a subset of the congenital heart defects that occur in 11q-. We demonstrate that one gene in this region, ETS-1 (a member of the ETS family of transcription factors), is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of ETS-1 in mice in a C57/B6 background causes, with high penetrance, large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle (one of the hallmarks of HLHS). Our results implicate an important role for the ETS-1 transcription factor in mammalian heart development and should provide important insights into some of the most common forms of congenital heart disease. PMID:19942620

Ye, Maoqing; Coldren, Chris; Liang, Xingqun; Mattina, Teresa; Goldmuntz, Elizabeth; Benson, D Woodrow; Ivy, Dunbar; Perryman, M B; Garrett-Sinha, Lee Ann; Grossfeld, Paul

2009-11-26

315

Anatomy and evolution of telomeric and subtelomeric regions in the human protozoan parasite Trypanosoma cruzi  

PubMed Central

Background The subtelomeres of many protozoa are highly enriched in genes with roles in niche adaptation. T. cruzi trypomastigotes express surface proteins from Trans-Sialidase (TS) and Dispersed Gene Family-1 (DGF-1) superfamilies which are implicated in host cell invasion. Single populations of T. cruzi may express different antigenic forms of TSs. Analysis of TS genes located at the telomeres suggests that chromosome ends could have been the sites where new TS variants were generated. The aim of this study is to characterize telomeric and subtelomeric regions of T. cruzi available in TriTrypDB and connect the sequences of telomeres to T. cruzi working draft sequence. Results We first identified contigs carrying the telomeric repeat (TTAGGG). Of 49 contigs identified, 45 have telomeric repeats at one end, whereas in four contigs the repeats are located internally. All contigs display a conserved telomeric junction sequence adjacent to the hexamer repeats which represents a signature of T. cruzi chromosome ends. We found that 40 telomeric contigs are located on T. cruzi chromosome-sized scaffolds. In addition, we were able to map several telomeric ends to the chromosomal bands separated by pulsed-field gel electrophoresis. The subtelomeric sequence structure varies widely, mainly as a result of large differences in the relative abundance and organization of genes encoding surface proteins (TS and DGF-1), retrotransposon hot spot genes (RHS), retrotransposon elements, RNA-helicase and N-acetyltransferase genes. While the subtelomeric regions are enriched in pseudogenes, they also contain complete gene sequences matching both known and unknown expressed genes, indicating that these regions do not consist of nonfunctional DNA but are instead functional parts of the expressed genome. The size of the subtelomeric regions varies from 5 to 182?kb; the smaller of these regions could have been generated by a recent chromosome breakage and telomere healing event. Conclusions The lack of synteny in the subtelomeric regions suggests that genes located in these regions are subject to recombination, which increases their variability, even among homologous chromosomes. The presence of typical subtelomeric genes can increase the chance of homologous recombination mechanisms or microhomology-mediated end joining, which may use these regions for the pairing and recombination of free ends.

2012-01-01

316

The Subtelomeric khipu Satellite Repeat from Phaseolus vulgaris: Lessons Learned from the Genome Analysis of the Andean Genotype G19833  

PubMed Central

Subtelomeric regions in eukaryotic organisms are known for harboring species-specific tandemly repeated satellite sequences. However, studies on the molecular organization and evolution of subtelomeric repeats are scarce, especially in plants. Khipu is a satellite DNA of 528-bp repeat unit, specific of the Phaseolus genus, with a subtelomeric distribution in common bean, P. vulgaris. To investigate the genomic organization and the evolution of khipu, we performed genome-wide analysis on the complete genome sequence of the common bean genotype G19833. We identified 2,460 khipu units located at most distal ends of the sequenced regions. Khipu units are arranged in discrete blocks of 2–55 copies and are heterogeneously distributed among the different chromosome ends of G19833 (from 0 to 555 khipus units per chromosome arm). Phylogenetically related khipu units are spread between numerous chromosome ends, suggesting frequent exchanges between non-homologous subtelomeres. However, most subclades contain numerous khipu units from only one or few chromosome ends indicating that local duplication is also driving khipu expansion. Unexpectedly, we also identified 81 khipu units located at centromeres. All the centromeric khipu units belong to a single divergent clade also comprised of a few units from several subtelomeres, suggesting that a few sequence exchanges between centromeres and subtelomeres took place in the common bean genome. The divergence and low copy number of these centromeric units from the subtelomeric units could explain why they were not detected by FISH (Fluorescence in situ Hybridization) although it can not be excluded that these centromeric units may have resulted from errors in the pseudomolecule assembly. Altogether our data highlight extensive sequence exchanges in subtelomeres between non-homologous chromosomes in common bean and confirm that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes.

Richard, Manon M. S.; Chen, Nicolas W. G.; Thareau, Vincent; Pflieger, Stephanie; Blanchet, Sophie; Pedrosa-Harand, Andrea; Iwata, Aiko; Chavarro, Carolina; Jackson, Scott A.; Geffroy, Valerie

2013-01-01

317

The Subtelomeric khipu Satellite Repeat from Phaseolus vulgaris: Lessons Learned from the Genome Analysis of the Andean Genotype G19833.  

PubMed

Subtelomeric regions in eukaryotic organisms are known for harboring species-specific tandemly repeated satellite sequences. However, studies on the molecular organization and evolution of subtelomeric repeats are scarce, especially in plants. Khipu is a satellite DNA of 528-bp repeat unit, specific of the Phaseolus genus, with a subtelomeric distribution in common bean, P. vulgaris. To investigate the genomic organization and the evolution of khipu, we performed genome-wide analysis on the complete genome sequence of the common bean genotype G19833. We identified 2,460 khipu units located at most distal ends of the sequenced regions. Khipu units are arranged in discrete blocks of 2-55 copies and are heterogeneously distributed among the different chromosome ends of G19833 (from 0 to 555 khipus units per chromosome arm). Phylogenetically related khipu units are spread between numerous chromosome ends, suggesting frequent exchanges between non-homologous subtelomeres. However, most subclades contain numerous khipu units from only one or few chromosome ends indicating that local duplication is also driving khipu expansion. Unexpectedly, we also identified 81 khipu units located at centromeres. All the centromeric khipu units belong to a single divergent clade also comprised of a few units from several subtelomeres, suggesting that a few sequence exchanges between centromeres and subtelomeres took place in the common bean genome. The divergence and low copy number of these centromeric units from the subtelomeric units could explain why they were not detected by FISH (Fluorescence in situ Hybridization) although it can not be excluded that these centromeric units may have resulted from errors in the pseudomolecule assembly. Altogether our data highlight extensive sequence exchanges in subtelomeres between non-homologous chromosomes in common bean and confirm that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes. PMID:24137164

Richard, Manon M S; Chen, Nicolas W G; Thareau, Vincent; Pflieger, Stéphanie; Blanchet, Sophie; Pedrosa-Harand, Andrea; Iwata, Aiko; Chavarro, Carolina; Jackson, Scott A; Geffroy, Valérie

2013-10-16

318

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

ERIC Educational Resources Information Center

|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…

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

2012-01-01

319

Autism Spectrum Disorders and Symptoms in Children with Molecularly Confirmed 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

|In this study, we assessed the presence of autism spectrum disorders (ASD) among children with a confirmed 22q11.2 deletion (n = 98). The children's caregivers completed screening measures of ASD behaviors, and for those whose scores indicated significant levels of these behaviors, a standardized diagnostic interview (Autism Diagnostic…

Fine, Sarah E.; Weissman, Alison; Gerdes, Marsha; Pinto-Martin, Jennifer; Zackai, Elaine H.; McDonald-McGinn, Donna M.; Emanuel, Beverly S.

2005-01-01

320

Longitudinal Follow-up of Autism Spectrum Features and Sensory Behaviors in Angelman Syndrome by Deletion Class  

ERIC Educational Resources Information Center

|Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a "syndromic" form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (approximately 6 Mb) Class…

Peters, Sarika U.; Horowitz, Lucia; Barbieri-Welge, Rene; Taylor, Julie Lounds; Hundley, Rachel J.

2012-01-01

321

A patient with de novo 0.45 Mb deletion of 2p16.1: the role of BCL11A, PAPOLG, REL, and FLJ16341 in the 2p15-p16.1 microdeletion syndrome.  

PubMed

The 2p15-p16.1 microdeletion syndrome is a novel, rare disorder characterized by developmental delay, intellectual disability, microcephaly, growth retardation, facial abnormalities, and other medical problems. We report here on an 11-year-old female showing clinical features consistent with the syndrome and carrying a de novo 0.45 Mb long deletion of the paternally derived 2p16.1 allele. The deleted region contains only three protein-coding RefSeq genes, BCL11A, PAPOLG, and REL, and one long non-coding RNA gene FLJ16341. Based on close phenotypic similarities with six reported patients showing typical clinical features of the syndrome, we propose that the critical region can be narrowed down further, and that these brain expressed genes can be considered candidates for the features seen in this microdeletion syndrome. PMID:23495096

Hancarova, Miroslava; Simandlova, Martina; Drabova, Jana; Mannik, Katrin; Kurg, Ants; Sedlacek, Zdenek

2013-03-12

322

Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus  

PubMed Central

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3? AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

Beunders, Gea; Voorhoeve, Els; Golzio, Christelle; Pardo, Luba M.; Rosenfeld, Jill A.; Talkowski, Michael E.; Simonic, Ingrid; Lionel, Anath C.; Vergult, Sarah; Pyatt, Robert E.; van de Kamp, Jiddeke; Nieuwint, Aggie; Weiss, Marjan M.; Rizzu, Patrizia; Verwer, Lucilla E.N.I.; van Spaendonk, Rosalina M.L.; Shen, Yiping; Wu, Bai-lin; Yu, Tingting; Yu, Yongguo; Chiang, Colby; Gusella, James F.; Lindgren, Amelia M.; Morton, Cynthia C.; van Binsbergen, Ellen; Bulk, Saskia; van Rossem, Els; Vanakker, Olivier; Armstrong, Ruth; Park, Soo-Mi; Greenhalgh, Lynn; Maye, Una; Neill, Nicholas J.; Abbott, Kristin M.; Sell, Susan; Ladda, Roger; Farber, Darren M.; Bader, Patricia I.; Cushing, Tom; Drautz, Joanne M.; Konczal, Laura; Nash, Patricia; de Los Reyes, Emily; Carter, Melissa T.; Hopkins, Elizabeth; Marshall, Christian R.; Osborne, Lucy R.; Gripp, Karen W.; Thrush, Devon Lamb; Hashimoto, Sayaka; Gastier-Foster, Julie M.; Astbury, Caroline; Ylstra, Bauke; Meijers-Heijboer, Hanne; Posthuma, Danielle; Menten, Bjorn; Mortier, Geert; Scherer, Stephen W.; Eichler, Evan E.; Girirajan, Santhosh; Katsanis, Nicholas; Groffen, Alexander J.; Sistermans, Erik A.

2013-01-01

323

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.  

PubMed

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future. PMID:23332918

Beunders, Gea; Voorhoeve, Els; Golzio, Christelle; Pardo, Luba M; Rosenfeld, Jill A; Talkowski, Michael E; Simonic, Ingrid; Lionel, Anath C; Vergult, Sarah; Pyatt, Robert E; van de Kamp, Jiddeke; Nieuwint, Aggie; Weiss, Marjan M; Rizzu, Patrizia; Verwer, Lucilla E N I; van Spaendonk, Rosalina M L; Shen, Yiping; Wu, Bai-lin; Yu, Tingting; Yu, Yongguo; Chiang, Colby; Gusella, James F; Lindgren, Amelia M; Morton, Cynthia C; van Binsbergen, Ellen; Bulk, Saskia; van Rossem, Els; Vanakker, Olivier; Armstrong, Ruth; Park, Soo-Mi; Greenhalgh, Lynn; Maye, Una; Neill, Nicholas J; Abbott, Kristin M; Sell, Susan; Ladda, Roger; Farber, Darren M; Bader, Patricia I; Cushing, Tom; Drautz, Joanne M; Konczal, Laura; Nash, Patricia; de Los Reyes, Emily; Carter, Melissa T; Hopkins, Elizabeth; Marshall, Christian R; Osborne, Lucy R; Gripp, Karen W; Thrush, Devon Lamb; Hashimoto, Sayaka; Gastier-Foster, Julie M; Astbury, Caroline; Ylstra, Bauke; Meijers-Heijboer, Hanne; Posthuma, Danielle; Menten, Björn; Mortier, Geert; Scherer, Stephen W; Eichler, Evan E; Girirajan, Santhosh; Katsanis, Nicholas; Groffen, Alexander J; Sistermans, Erik A

2013-01-17

324

Deletion of Xpter encompassing the SHOX gene and PAR1 region in familial patients with Leri-Weill Dyschondrosteosis syndrome.  

PubMed

Heterozygote deletions or mutations of pseudoautosomal 1 region (PAR1) encompassing the short stature homeobox-containing (SHOX) gene cause Leri-Weill Dyschondrosteosis (LWD), which is a dominantly inherited osteochondroplasia characterized by short stature with mesomelic shortening of the upper and lower limbs and Madelung deformity of the wrists. SHOX is expressed by both sex chromosomes in males and females and plays an important role in bone growth and development. Clinically, the LWD expression is variable and more severe in females than males due to sex differences in oestrogen levels. Here, we report two familial cases of LWD with a large Xp terminal deletion (approximately 943 kb) of distal PAR1 encompassing the SHOX gene. In addition, the proband had mental retardation which appeared to be from recessive inheritance in the family. PMID:19400538

Mutesa, L; Vanbellinghen, J F; Hellin, A C; Segers, K; Jamar, M; Pierquin, G; Bours, V

2009-01-01

325

Characterization and rescue of telomeric abnormalities in ICF syndrome type I fibroblasts.  

PubMed

Mutations in the human DNA methyltransferase 3B (DNMT3B) gene lead to ICF (immunodeficiency, centromeric region instability, and facial anomalies) syndrome type I. We have previously described a telomere-related phenotype in cells from these patients, involving severe hypomethylation of subtelomeric regions, abnormally short telomeres and high levels of telomeric-repeat-containing RNA (TERRA). Here we demonstrate that ICF-patient fibroblasts carry abnormally short telomeres at a low population doubling (PD) and enter senescence prematurely. Accordingly, we attempted to rescue the senescence phenotype by ectopic expression of human telomerase, which led to elongated telomeres with hypomethylated subtelomeres. The senescence phenotype was overcome under these conditions, thus dissociating subtelomeric-DNA hypomethylation per se from the senescence phenotype. In addition, we examined whether the subtelomeric methylation could be restored by expression of a normal copy of full length DNMT3B1 in ICF fibroblasts. Ectopic expression of DNMT3B1 failed to rescue the abnormal hypomethylation at subtelomeres. However, partial rescue of subtelomeric-hypomethylation was achieved by co-expression of DNMT3B1 together with DNA methyltransferase 3-like (DNMT3L), encoding a protein that functions as a stimulator of DNMT3A and DNMT3B. DNMT3B1 and DNMT3L are predominantly expressed during early embryonic development, suggesting that de novo subtelomeric DNA methylation during crucial stages of human embryonic development may be necessary for setting and maintaining normal telomere length. PMID:23450006

Yehezkel, Shiran; Shaked, Rony; Sagie, Shira; Berkovitz, Ron; Shachar-Bener, Hofit; Segev, Yardena; Selig, Sara

2013-02-28

326

Autism Spectrum Disorders and Symptoms in Children with Molecularly Confirmed 22q11.2 Deletion Syndrome  

Microsoft Academic Search

In this study, we assessed the presence of autism spectrum disorders (ASD) among children with a confirmed 22q11.2 deletion (n = 98). The children’s caregivers completed screening measures of ASD behaviors, and for those whose scores indicated significant levels of these behaviors, a standardized diagnostic interview (Autism Diagnostic Interview-Revised; ADI-R) was administered. Results demonstrated that over 20% of children (n = 22) were exhibiting

Sarah E. Fine; Alison Weissman; Marsha Gerdes; Jennifer Pinto-Martin; Elaine H. Zackai; Donna M. McDonald-McGinn; Beverly S. Emanuel

2005-01-01

327

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

SciTech Connect

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

Masuno, Mitsuo; Imaizumi, Kiyoshi; Kurosawa, Kenji; Makita, Yoshio; Kuroki, Yoshikazu [Kanagawa Children`s Medical Center, Yokohama (Japan); Petrij, F.; Dauwerse, H.G.; Breuning, M.H. [Leiden Univ. (Netherlands)

1994-12-01

328

A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules  

Microsoft Academic Search

Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome,

Brunella Franco; Silvana Guioli; Antonella Pragliola; Barbara Incerti; Barbara Bardoni; Rossana Tonlorenzi; Romeo Carrozzo; Elena Maestrini; Maura Pieretti; Patricia Taillon-Miller; Carolyn J. Brown; Huntington F. Willard; Charles Lawrence; M. Graziella Persico; Giovanna Camerino; Andrea Ballabio

1991-01-01

329

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

SciTech Connect

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.

Osborne, L.R.; Rommens, J.; Tsui, Lap-Chee [Hospital for Sick Children, Ontario (Canada)]|[Univ. of Toronto, Ontario (Canada)] [and others

1996-09-01

330

Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion.  

PubMed

Large copy number variants (CNVs) have been recently found as structural polymorphisms of the human genome of still unknown biological significance. CNVs are significantly enriched in regions with segmental duplications or low-copy repeats (LCRs). Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of contiguous genes at 7q11.23 mediated by nonallelic homologous recombination (NAHR) between large flanking LCRs and facilitated by a structural variant of the region, a approximately 2-Mb paracentric inversion present in 20%-25% of WBS-transmitting progenitors. We now report that eight out of 180 (4.44%) WBS-transmitting progenitors are carriers of a CNV, displaying a chromosome with large deletion of LCRs. The prevalence of this CNV among control individuals and non-transmitting progenitors is much lower (1%, n=600), thus indicating that it is a predisposing factor for the WBS deletion (odds ratio 4.6-fold, P= 0.002). LCR duplications were found in 2.22% of WBS-transmitting progenitors but also in 1.16% of controls, which implies a non-statistically significant increase in WBS-transmitting progenitors. We have characterized the organization and breakpoints of these CNVs, encompassing approximately 100-300 kb of genomic DNA and containing several pseudogenes but no functional genes. Additional structural variants of the region have also been defined, all generated by NAHR between different blocks of segmental duplications. Our data further illustrate the highly dynamic structure of regions rich in segmental duplications, such as the WBS locus, and indicate that large CNVs can act as susceptibility alleles for disease-associated genomic rearrangements in the progeny. PMID:18292220

Cuscó, Ivon; Corominas, Roser; Bayés, Mònica; Flores, Raquel; Rivera-Brugués, Núria; Campuzano, Victoria; Pérez-Jurado, Luis A

2008-02-21

331

Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome  

PubMed Central

The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn, substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as ?-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.

Barrott, Jared J.; Cash, Gabriela M.; Smith, Aaron P.; Barrow, Jeffery R.; Murtaugh, L. Charles

2011-01-01

332

Association of the PIK4CA Schizophrenia-Susceptibility Gene in Adults With the 22q11.2 Deletion Syndrome  

PubMed Central

The 22q11.2 deletion syndrome (22q11DS) is associated with an increased prevalence (20–30%) of schizophrenia. Therefore, it is likely that one or more genes within the 22q11.2 region are causally related to schizophrenia. Recently, a significant association with schizophrenia in the general population was reported for three SNPs in phosphatidyl-inositol-4-kinase-catalytic-? (PIK4CA), a gene located in the 22q11.2 region. In the current study, we tested the hypothesis that the same PIK4CA risk-alleles would be associated with schizophrenia in individuals with 22q11DS. Our analysis of the PIK4CA genotypes in a sample of 79 adults with typical 22q11.2 deletions, comparing those with schizophrenia to those without, revealed a significant association. Our findings represent an independent replication of the previously reported PIK4CA association with schizophrenia in the general population. Second, the results of this study indicate that variation at PIK4CA may be a relevant factor influencing the risk of schizophrenia in individuals with 22q11DS.

Vorstman, Jacob A.S.; Chow, Eva W.; Ophoff, Roel A.; van Engeland, Herman; Beemer, Frits A.; Kahn, Rene S.; Sinke, Richard J.; Bassett, Anne S.

2011-01-01

333

Altered auditory processing in frontal and left temporal cortex in 22q11.2 deletion syndrome: a group at high genetic risk for schizophrenia.  

PubMed

In order to investigate electroencephalographic (EEG) biomarkers of auditory processing for schizophrenia, we studied a group with a well known high-risk profile: patients with 22q11.2 deletion syndrome (22q11 DS) have a 30% risk of developing schizophrenia during adulthood. We performed high-density EEG source imaging to measure auditory gating of the P50 component of the evoked potential and middle to late latency auditory processing in 21 participants with the 22q11.2 deletion and 17 age-matched healthy controls. While we found no indication of altered P50 suppression in 22q11 DS, we observed marked differences for the first N1 component with increased amplitudes on central electrodes, corresponding to increased activations in dorsal anterior cingulate and medial frontal cortex. We also found a left lateralized reduction of activation of primary and secondary auditory cortex during the second N1 (120ms) and the P2 component in 22q11 DS. Our results show that sensory gating and activations until 50ms were preserved in 22q11 DS, while impairments appear at latencies that correspond to higher order auditory processing. While the increased activation of cingulate and medial frontal cortex could reflect developmental changes in 22q11 DS, the reduced activity seen in left auditory cortex might serve as a biomarker for the development of schizophrenia, if confirmed by longitudinal research protocols. PMID:23137800

Rihs, Tonia A; Tomescu, Miralena I; Britz, Juliane; Rochas, Vincent; Custo, Anna; Schneider, Maude; Debbané, Martin; Eliez, Stephan; Michel, Christoph M

2012-11-06

334

Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model.  

PubMed

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions. PMID:24101523

Toritsuka, Michihiro; Kimoto, Sohei; Muraki, Kazue; Landek-Salgado, Melissa A; Yoshida, Atsuhiro; Yamamoto, Norio; Horiuchi, Yasue; Hiyama, Hideki; Tajinda, Katsunori; Keni, Ni; Illingworth, Elizabeth; Iwamoto, Takashi; Kishimoto, Toshifumi; Sawa, Akira; Tanigaki, Kenji

2013-10-07

335

Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene.  

PubMed

Iron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5' untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin > or = 1,000 microg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5' sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia. PMID:9292547

Girelli, D; Corrocher, R; Bisceglia, L; Olivieri, O; Zelante, L; Panozzo, G; Gasparini, P

1997-09-01

336

De novo 7p partial trisomy characterized by subtelomeric FISH and whole-genome array in a girl with mental retardation  

PubMed Central

Chromosome rearrangements involving telomeres have been established as one of the major causes of idiopathic mental retardation/developmental delay. This case of 7p partial trisomy syndrome in a 3-year-old female child presenting with developmental delay emphasizes the clinical relevance of cytogenetic diagnosis in the better management of genetic disorders. Application of subtelomeric FISH technique revealed the presence of interstitial telomeres and led to the ascertainment of partial trisomy for the distal 7p segment localized on the telomeric end of the short arm of chromosome 19. Whole-genome cytogenetic microarray-based analysis showed a mosaic 3.5 Mb gain at Xq21.1 besides the approximately 24.5 Mb gain corresponding to 7p15.3- > pter. The possible mechanisms of origin of the chromosomal rearrangement and the clinical relevance of trisomy for the genes lying in the critical regions are discussed.

2011-01-01

337

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

PubMed

Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n = 360) and genotyping data (n = 737) with respect to presence (n = 54) or absence (n = 683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant. PMID:23034814

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

2012-10-03

338

Toward closing rice telomere gaps: mapping and sequence characterization of rice subtelomere regions  

Microsoft Academic Search

Despite the collective efforts of the international community to sequence the complete rice genome, telomeric regions of most chromosome arms remain uncharacterized. In this report we present sequence data from subtelomere regions obtained by analyzing telomeric clones from two 8.8 × genome equivalent 10-kb libraries derived from partial restriction digestion with HaeIII or Sau3AI (OSJNPb HaeIII and OSJNPc Sau3AI). Seven telomere clones

Tae-Jin Yang; Yeisoo Yu; Song-Bin Chang; Hans de Jong; Chang-Sik Oh; Sang-Nag Ahn; Eric Fang; Rod A. Wing

2005-01-01

339

Atypical Ch?diak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease  

PubMed Central

Background Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction. Methods In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST. Results We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family. Conclusions We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.

2013-01-01

340

Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.  

PubMed

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability. PMID:23033313

Bisschoff, Izak J; Zeschnigk, Christine; Horn, Denise; Wellek, Brigitte; Rieß, Angelika; Wessels, Maja; Willems, Patrick; Jensen, Peter; Busche, Andreas; Bekkebraten, Jens; Chopra, Maya; Hove, Hanne Dahlgaard; Evers, Christina; Heimdal, Ketil; Kaiser, Ann-Sophie; Kunstmann, Erdmut; Robinson, Kristina Lagerstedt; Linné, Maja; Martin, Patricia; McGrath, James; Pradel, Winnie; Prescott, Katrina E; Roesler, Bernd; Rudolf, Gorazd; Siebers-Renelt, Ulrike; Tyshchenko, Nataliya; Wieczorek, Dagmar; Wolff, Gerhard; Dobyns, William B; Morris-Rosendahl, Deborah J

2012-10-17

341

Deletion (2)(q37)  

SciTech Connect

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.

Stratton, R.F.; Tolworthy, J.A.; Young, R.S. [South Texas Genetics Center, San Antonio, TX (United States)

1994-06-01

342

Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3Al) allele produces ehlers-danlos syndrome type IV in the heterozygous offspring  

SciTech Connect

Ehlers-Danlos syndrome (EDS) type IV is a dominantly inherited disorder that results from mutation in the type III collagen gene (COL3A1). The authors studied the structure of the COL3A1 gene of an individual with EDS type IV and that of her phenotypically normal parents. The proband was heterozygous for a 2-kb deletion in COL3A1, while her father was mosaic for the same deletion in somatic and germ cells. In fibroblasts from the father, approximately two-fifths of the COL3A1 alleles carried the deletion, but only 10% of the COL3A1 alleles in white blood cells were of the mutant species. The deletion in the mutant allele extended from intron 7 into intron 11. There was a 12-bp direct repeat in intron 7 and intron 11, the latter about 60 bp 5' to the junction. At the breakpoint there was a duplication of 10 bp from intron 11 separated by an insertion of 4 bp contained within the duplicated sequence. The father was mosaic for the deletion so that the gene rearrangement occurred during his early embryonic development prior to lineage allocation. These findings suggest that at least some of the deletions seen in human genes may occur during replication, rather than as a consequence of meiotic crossing-over, and that they thus have a risk for recurrence when observed de novo. 71 refs., 4 figs., 2 tabs.

McGookey Milewicz, D.; Witz, A.M.; Byers, P.H. (Univ of Washington, Seattle (United States)); Smith, A.C.M.; Manchester, D.K.; Waldstein, G. (Children's Hospital, Denver, CO (United States))

1993-07-01

343

Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome  

PubMed Central

Introduction Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS. Methods Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH. Results FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study. Conclusions Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.

2012-01-01

344

Ullrich-Turner syndrome associated with interstitial deletion of Xp11.4 leads to p22.31.  

PubMed

The full phenotype of the Ullrich-Turner syndrome (UTS) is thought to be due to loss of the short arm of X. We report a 16-year-old girl with lack of secondary sexual development, amenorrhea, and short stature. She had thyroiditis and numerous other UTS manifestations and was found to have a non-mosaic 46,X,del(Xp) chromosome abnormality. Breakpoints occurred at p11.4 and p22.31, with a loss of the intervening segment. PMID:6859107

Wilson, M G; Modebe, O; Towner, J W; Frasier, S D; Lin, M S

1983-03-01

345

Submicroscopic Deletion in Patients with Williams-Beuren Syndrome Influences Expression Levels of the Nonhemizygous Flanking Genes  

PubMed Central

Genomic imbalance is a common cause of phenotypic abnormalities. We measured the relative expression level of genes that map within the microdeletion that causes Williams-Beuren syndrome and within its flanking regions. We found, unexpectedly, that not only hemizygous genes but also normal-copy neighboring genes show decreased relative levels of expression. Our results suggest that not only the aneuploid genes but also the flanking genes that map several megabases away from a genomic rearrangement should be considered possible contributors to the phenotypic variation in genomic disorders.

Merla, Giuseppe; Howald, Cedric; Henrichsen, Charlotte N.; Lyle, Robert; Wyss, Carine; Zabot, Marie-Therese; Antonarakis, Stylianos E.; Reymond, Alexandre

2006-01-01

346

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report.  

PubMed

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1?, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r=0.851, p=0.004; r=0.580, p=0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r=0.795, p=0.033; r=0.774, p=0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry. PMID:23353117

Ross, Heather E; Guo, Ying; Coleman, Karlene; Ousley, Opal; Miller, Andrew H

2013-01-24

347

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

PubMed

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

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

2011-01-28

348

Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome  

PubMed Central

22q11 deletion syndrome (22q11DS) is characterised by aberrant development of the pharyngeal apparatus and the heart with haploinsufficiency of the transcription factor TBX1 being considered the major underlying cause of the disease. Tbx1 mutations in mouse phenocopy the disorder. In order to identify the transcriptional dysregulation in Tbx1-expressing lineages we optimised fluorescent-activated cell sorting of ?-galactosidase expressing cells (FACS-Gal) to compare the expression profile of Df1/Tbx1lacZ (effectively Tbx1 null) and Tbx1 heterozygous cells isolated from mouse embryos. Hes1, a major effector of Notch signalling, was identified as downregulated in Tbx1?/? mutants. Hes1 mutant mice exhibited a partially penetrant range of 22q11DS-like defects including pharyngeal arch artery (PAA), outflow tract, craniofacial and thymic abnormalities. Similar to Tbx1 mice, conditional mutagenesis revealed that Hes1 expression in embryonic pharyngeal ectoderm contributes to thymus and pharyngeal arch artery development. These results suggest that Hes1 acts downstream of Tbx1 in the morphogenesis of pharyngeal-derived structures.

van Bueren, Kelly Lammerts; Papangeli, Irinna; Rochais, Francesca; Pearce, Kerra; Roberts, Catherine; Calmont, Amelie; Szumska, Dorota; Kelly, Robert G.; Bhattacharya, Shoumo; Scambler, Peter J.

2010-01-01

349

Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio- facial/DiGeorge/22q11.2 deletion syndrome patients  

PubMed Central

Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2, could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype enrichment groups. Nine common SNPs (MAF >0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome.

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

2011-01-01

350

Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome.  

PubMed

BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. METHOD: Guardians of children with 22q11DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. RESULTS: Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11DS. CONCLUSION: Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS. PMID:23742203

Allen, T M; Hersh, J; Schoch, K; Curtiss, K; Hooper, S R; Shashi, V

2013-06-01

351

Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and\\/or mental retardation  

Microsoft Academic Search

BACKGROUND: Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing. RESULTS: 296 patients with MR and a normal karyotype (500–550

Bernd Auber; Verena Bruemmer; Barbara Zoll; Peter Burfeind; Detlef Boehm; Thomas Liehr; Knut Brockmann; Ekkehard Wilichowski; Loukas Argyriou; Iris Bartels

2009-01-01

352

Sub-Telomere Directed Gene Expression during Initiation of Invasive Aspergillosis  

PubMed Central

Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus.

Crabtree, Jonathan; Yu, Yan; Kim, Stanley; Chen, Dan; Loss, Omar; Cairns, Timothy; Goldman, Gustavo; Armstrong-James, Darius; Haynes, Ken; Haas, Hubertus; Schrettl, Markus; May, Gregory; Nierman, William C.; Bignell, Elaine

2008-01-01

353

Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams–Beuren syndrome neurocognitive profile  

Microsoft Academic Search

BackgroundWilliams–Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterised by vascular stenoses, distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile, and some endocrine and connective tissue abnormalities, caused by a recurrent deletion of 1.55 Mb including 26–28 genes at chromosomal region 7q11.23. The analysis of clinical–molecular correlations in a few reported atypical patients has been

A. Antonell; M. Del Campo; L. F. Magano; L. Kaufmann; J. Martinez de la Iglesia; F. Gallastegui; R. Flores; U. Schweigmann; C. Fauth; D. Kotzot; L. A. Perez-Jurado

2010-01-01

354

Genetic diversity study of the yeast Saccharomyces bayanus var. uvarum reveals introgressed subtelomeric Saccharomyces cerevisiae genes.  

PubMed

Intraspecies polymorphism of the yeast Saccharomyces bayanus var. uvarum was studied using the polymerase chain reaction with a microsatellite primer (GTG)(5). Sixty-nine strains of different origins were analyzed. There existed a correlation between PCR patterns of the strains and the source of their isolation: the type of wine and the particular winemaking region. Southern hybridization analysis revealed for the first time introgression between Saccharomyces cerevisiae and S. bayanus var. uvarum. Two strains isolated from alcoholic beverages in Hungary and identified by genetic analysis as S. bayanus var. uvarum were found to harbor a number of S. cerevisiae subtelomeric sequences: Y', SUC, RTM and MAL. PMID:21112388

Naumova, Elena S; Naumov, Gennadi I; Michailova, Yulia V; Martynenko, Nikolay N; Masneuf-Pomarède, Isabelle

2010-11-26

355

The effects of gender and catechol O-methyltransferase (COMT) Val108/158Met polymorphism on emotion regulation in velo-cardio-facial syndrome (22q11.2 deletion syndrome): An fMRI study.  

PubMed

Velo-cardio-facial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/male=9, Val/female=17, Met/male=9, Met/female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys did. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders. PMID:20123031

Coman, Ioana L; Gnirke, Matthew H; Middleton, Frank A; Antshel, Kevin M; Fremont, Wanda; Higgins, Anne Marie; Shprintzen, Robert J; Kates, Wendy R

2010-02-01

356

The effects of gender and Catechol O-Methyltransferase (COMT) Val108/158Met polymorphism on emotion regulation in Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome): a fMRI study  

PubMed Central

Velocardiofacial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/Male=9, Val/Female=17, Met/Male=9, Met/Female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders.

Coman, Ioana L.; Gnirke, Matthew H.; Middleton, Frank A.; Antshel, Kevin M.; Fremont, Wanda; Higgins, Anne Marie; Shprintzen, Robert J.; Kates, Wendy R.

2010-01-01

357

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity  

PubMed Central

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals.

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

358

Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?  

PubMed

The 22q11.2 deletion syndrome (22q11DS) is a widely recognized genetic model allowing the study of neuroanatomical biomarkers that underlie the risk for developing schizophrenia. Recent advances in magnetic resonance image analyses enable the examination of structural connectivity integrity, scarcely used in the 22q11DS field. This framework potentially provides evidence for the disconnectivity hypothesis of schizophrenia in this high-risk population. In the present study, we quantify the whole brain white matter connections in 22q11DS using deterministic tractography. Diffusion Tensor Imaging was acquired in 30 affected patients and 30 age- and gender-matched healthy participants. The Human Connectome technique was applied to register white matter streamlines with cortical anatomy. The number of fibers (streamlines) was used as a measure of connectivity for comparison between groups at the global, lobar and regional level. All statistics were corrected for age and gender. Results showed a 10% reduction of the total number of fibers in patients compared to controls. After correcting for this global reduction, preserved connectivity was found within the right frontal and right parietal lobes. The relative increase in the number of fibers was located mainly in the right hemisphere. Conversely, an excessive reduction of connectivity was observed within and between limbic structures. Finally, a disproportionate reduction was shown at the level of fibers connecting the left fronto-temporal regions. We could therefore speculate that the observed disruption to fronto-temporal connectivity in individuals at risk of schizophrenia implies that fronto-temporal disconnectivity, frequently implicated in the pathogenesis of schizophrenia, could precede the onset of symptoms and, as such, constitutes a biomarker of the vulnerability to develop psychosis. On the contrary, connectivity alterations in the limbic lobe play a role in a wide range of psychiatric disorders and therefore seem to be less specific in defining schizophrenia. PMID:23533586

Ottet, Marie-Christine; Schaer, Marie; Cammoun, Leila; Schneider, Maude; Debbané, Martin; Thiran, Jean-Philippe; Eliez, Stephan

2013-03-22

359

A Cross-Sectional Analysis of the Development of Response Inhibition in Children with Chromosome 22q11.2 Deletion Syndrome  

PubMed Central

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with cognitive impairments and significantly elevated risk for developing schizophrenia. While impairments in response inhibition are central to executive dysfunction in schizophrenia, the nature and development of such impairments in children with 22q11.2DS, a group at high risk for the disorder, are not clear. Here we used a classic Go/No-Go paradigm to quantify proactive (anticipatory stopping) and reactive (actual stopping) response inhibition in 47 children with 22q11.2DS and 36 typically developing (TD) children, all ages 7–14. A cross-sectional design was used to examine age-related associations with response inhibition. When compared with TD individuals, children with 22q11.2DS demonstrated typical proactive response inhibition at all ages. By contrast, reactive response inhibition was impaired in children with 22q11.2DS relative to TD children. While older age predicted better reactive response inhibition in TD children, there was no age-related association with reactive response inhibition in children with 22q11.2DS. Closer examination of individual performance data revealed a wide range of performance abilities in older children with 22q11.2DS; some typical and others highly impaired. The results of this cross-sectional analysis suggest an impaired developmental trajectory of reactive response inhibition in some children with 22q11.2DS that might be related to atypical development of neuroanatomical systems underlying this cognitive process. As part of a larger study, this investigation might help identify risk factors for conversion to schizophrenia and lead to early diagnosis and preventive intervention.

Shapiro, Heather M.; Wong, Ling M.; Simon, Tony J.

2013-01-01

360

Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF)  

PubMed Central

Introduction: There is evidence that inherited genetic variation affects both testicular germ cell tumor (TGCT) treatment outcome and risks of late-complications arising from cisplatin-based chemotherapy. Using a candidate gene approach, we examined associations of three genes involved in the cisplatin metabolism pathway, GSTP1, COMT, and TPMT, with TGCT outcome and cisplatin-induced neurotoxicity. Materials and Methods: Our study population includes a subset of patients (n = 137) from a genome-wide association study at the University of Pennsylvania that evaluates inherited genetic susceptibility to TGCT. All patients in our study had at least one course of cisplatin-based chemotherapy with at least 1 year of follow-up. A total of 90 markers in GSTP1, COMT, and TPMT and their adjacent genomic regions (±20 kb) were analyzed for associations with refractory TGCT after first course of chemotherapy, progression-free survival (PFS), overall survival (OS), peripheral neuropathy, and ototoxicity. Results: After adjustment for multiple comparisons, one Single nucleotide polymorphism (SNP), rs2073743, in the flanking region (±20 kb) of COMT was associated with refractory TGCT after initial chemotherapy. This SNP lies within the intron region of the Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). The G allele of rs2073743 predisposed patients to refractory disease with a relative risk of 2.6 (95% CI 1.1, 6.3; P = 0.03). Assuming recessive inheritance, patients with the GG genotype had 22.7 times higher risk (95% CI 3.3, 155.8; P = 0.04) of developing refractory disease when compared to those with the GC or CC genotypes. We found no association of our candidate genes with peripheral neuropathy, ototoxicity, PFS and OS. Discussion: This is the first study to suggest that germline genetic variants of ARVCF may affect TGCT outcome. The result of this study is hypothesis generating and should be validated in future studies.

Fung, Chunkit; Vaughn, David J.; Mitra, Nandita; Ciosek, Stephanie L.; Vardhanabhuti, Saran; Nathanson, Katherine L.; Kanetsky, Peter A.

2012-01-01

361

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents.  

PubMed

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy. PMID:22127856

Sundram, Frederick; Campbell, Linda E; Azuma, Rayna; Daly, Eileen; Bloemen, Oswald J N; Barker, Gareth J; Chitnis, Xavier; Jones, Derek K; van Amelsvoort, Therese; Murphy, Kieran C; Murphy, Declan G M

2010-03-05

362

An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.  

PubMed

Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. Genome-wide homozygosity mapping localized the gene to a 2 Mb region on chromosome 18q11.2 with an LOD score of 19.8 at theta=0. This region includes the laminin alpha3 gene (LAMA3), in which loss-of-expression mutations cause the lethal skin blistering disorder Herlitz junctional epidermolysis bullosa. Detailed investigation showed that this gene possesses a further 38 exons (76 exons in total) spanning 318 kb of genomic DNA, and encodes three distinct proteins, designated laminin alpha3a, alpha3b1 and alpha3b2. The causative mutation in 15 families was a frameshift mutation 151insG predicting a stop codon 7 bp downstream in an exon that is specific to laminin alpha3a. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication. Surprisingly, the 151insG mutation does not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing. PMID:12915477

McLean, W H Irwin; Irvine, Alan D; Hamill, Kevin J; Whittock, Neil V; Coleman-Campbell, Carrie M; Mellerio, Jemima E; Ashton, Gabrielle S; Dopping-Hepenstal, Patricia J H; Eady, Robin A J; Jamil, Tanvir; Phillips, Roderic J; Shabbir, S Ghulam; Haroon, Tahir S; Khurshid, Khawar; Moore, Jonathan E; Page, Brian; Darling, Jonathan; Atherton, David J; Van Steensel, Maurice A M; Munro, Colin S; Smith, Frances J D; McGrath, John A; Phillips, Rodney J

2003-07-15

363

Relationship between reaction time, fine motor control, and visual-spatial perception on vigilance and visual-motor tasks in 22q11.2 Deletion Syndrome.  

PubMed

22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and that these individuals have specific deficits in visual-motor integration. However, the extent to which attentional deficits, such as vigilance, influence impairments on visual motor tasks in 22q11DS is unclear. This study examines visual-motor abilities and reaction time using a range of standardised tests in 35 children with 22q11DS, 26 age-matched typically developing (TD) sibling controls and 17 low-IQ community controls. Statistically significant deficits were observed in the 22q11DS group compared to both low-IQ and TD control groups on a timed fine motor control and accuracy task. The 22q11DS group performed significantly better than the low-IQ control group on an untimed drawing task and were equivalent to the TD control group on point accuracy and simple reaction time tests. Results suggest that visual motor deficits in 22q11DS are primarily attributable to deficits in psychomotor speed which becomes apparent when tasks are timed versus untimed. Moreover, the integration of visual and motor information may be intact and, indeed, represent a relative strength in 22q11DS when there are no time constraints imposed. While this may have significant implications for cognitive remediation strategies for children with 22q11DS, the relationship between reaction time, visual reasoning, cognitive complexity, fine motor speed and accuracy, and graphomotor ability on visual-motor tasks is still unclear. PMID:22522207

Howley, Sarah A; Prasad, Sarah E; Pender, Niall P; Murphy, Kieran C

2012-04-21

364

Transcriptional activity of multiple copies of a subtelomerically located olfactory receptor gene that is polymorphic in number and location  

Microsoft Academic Search

We report here on the transcriptional activity of multiple copies of a subtelomerically located olfac- tory receptor (OR) gene, OR-A. Due to recent duplica- tion events, both the copy number and chromosomal location of OR-A vary among humans. Sequence analyses of 180 copies of this gene, derived from 12 chromosome ends in 22 individuals, show that the main coding exon

Elena Linardopoulou; Heather C. Mefford; Oanh Nguyen; Cynthia Friedman; Ger van den Engh; D. Greg Farwell; Marc Coltrera; Barbara J. Trask

2001-01-01

365

Subtelomeric ACS-containing Proto-silencers Act as Antisilencers in Replication Factors Mutants in Saccharomyces cerevisiae  

PubMed Central

Subtelomeric genes are either fully active or completely repressed and can switch their state about once per 20 generations. This meta-stable telomeric position effect is mediated by strong repression signals emitted by the telomere and relayed/enhanced by weaker repressor elements called proto-silencers. In addition, subtelomeric regions contain sequences with chromatin partitioning and antisilencing activities referred to as subtelomeric antisilencing regions. Using extensive mutational analysis of subtelomeric elements, we show that ARS consensus sequence (ACS)-containing proto-silencers convert to antisilencers in several replication factor mutants. We point out the significance of the B1 auxiliary sequence next to ACS in mediating these effects. In contrast, an origin-derived ACS does not convert to antisilencer in mutants and its B1 element has little bearing on silencing. These results are specific for the analyzed ACS and in addition to the effects of each mutation (relative to wild type) on global silencing. Another line of experiments shows that Mcm5p possesses antisilencing activity and is recruited to telomeres in an ACS-dependent manner. Mcm5p persists at this location at the late stages of S phase. We propose that telomeric ACS are not static proto-silencers but conduct finely tuned silencing and antisilencing activities mediated by ACS-bound factors.

Rehman, Muhammad Attiq; Wang, Dongliang; Fourel, Genevieve; Gilson, Eric

2009-01-01

366

Recurrent HERV-H-Mediated 3q13.2-q13.31 Deletions Cause a Syndrome of Hypotonia and Motor, Language, and Cognitive Delays.  

PubMed

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ?5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease. PMID:23878096

Shuvarikov, Andrey; Campbell, Ian M; Dittwald, Piotr; Neill, Nicholas J; Bialer, Martin G; Moore, Christine; Wheeler, Patricia G; Wallace, Stephanie E; Hannibal, Mark C; Murray, Michael F; Giovanni, Monica A; Terespolsky, Deborah; Sodhi, Sandi; Cassina, Matteo; Viskochil, David; Moghaddam, Billur; Herman, Kristin; Brown, Chester W; Beck, Christine R; Gambin, Anna; Cheung, Sau Wai; Patel, Ankita; Lamb, Allen N; Shaffer, Lisa G; Ellison, Jay W; Ravnan, J Britt; Stankiewicz, Pawe?; Rosenfeld, Jill A

2013-08-13

367

Rieger syndrome locus: a new reciprocal translocation t(4;12)(q25;q15) and a deletion del(4)(q25q27) both break between markers D4S2945 and D4S193.  

PubMed Central

Rieger syndrome (RS) is an autosomal dominant disorder of morphogenesis characterised by malformation of the anterior segment of the eye, dental hypoplasia, and failure of the periumbilical skin to involute. RS has been mapped to the 4q25-q27 chromosomal segment by a series of cytogenetic studies as well as by genetic linkage to DNA markers. It was first localised to chromosome 4q based on an association with a constitutional deletion of 4q23-q27. In this paper we localise the proximal breakpoint of this deletion from the original patient, and we describe a new family with a de novo balanced reciprocal translocation t(4;12)(q25;q15) segregating with full RS in two generations. Using FISH and the P1 artificial chromosomes (PACs) as probes, we have physically localised both the deletion and the translocation breakpoints between genetic markers which are known to be strongly linked to RS. We have mapped both the proximal deletion breakpoint and the translocation breakpoint within a region between two groups of PACs bearing the markers D4S2945 (on the centromeric side) and D4S193 and D4S2940 (on the telomeric side). We believe that these recombinant bacterial clones derived directly from genomic DNA (not subcloned from YACs) will be valuable complementary tools in the efforts to clone the RS gene and to construct a full transcriptional and sequence ready map of this region. Images

Flomen, R H; Gorman, P A; Vatcheva, R; Groet, J; Barisic, I; Ligutic, I; Sheer, D; Nizetic, D

1997-01-01

368

Ehlers-Danlos Syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen  

SciTech Connect

The authors have studied a patient with severe, dominantly inherited Ehlers-Danlos syndrome type IV. The results indicate that this patient carries a deletion of 3.3 kilobase pairs in the triple helical coding domain of one of the two alleles for the pro-..cap alpha..-chains of type III collagen (COL3A1). His cultured skin fibroblasts contain equal amounts of normal length mRNA and of mRNA shortened by approximately 600 bases, and synthesize both normal and shortened pro-..cap alpha..1(III)-chains. In procollagen molecules containing one or more shortened chains, a triple helix is formed with a length of only about 780 amino acids. The mutant procollagen molecules have decreased thermal stability, are less efficiently secreted, and are not processed as their normal counterpart. The deletion in this family is the first mutation to be described in COL3A1.

Superti-Furga, A.; Gugler, E.; Gitzelmann, R.; Steinmann, B.

1988-05-05

369

DNA Break Site at Fragile Subtelomeres Determines Probability and Mechanism of Antigenic Variation in African Trypanosomes  

PubMed Central

Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by ‘70 bp’-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in ‘active-site’ survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (?60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, ?H2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome.

Glover, Lucy; Alsford, Sam; Horn, David

2013-01-01

370

FSH dystrophy and a subtelomeric 4q haplotype: a new assay and associations with disease  

PubMed Central

Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4. Methods We developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles. Results All (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10?4), and 26% had homozygous 4qB163 alleles. Conclusions Our results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay.

Tsumagari, K; Chen, D; Hackman, J R; Bossler, A D; Ehrlich, M

2011-01-01

371

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes.  

PubMed

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS. PMID:23910792

Zarchi, Omer; Carmel, Miri; Avni, Chen; Attias, Josef; Frisch, Amos; Michaelovsky, Elena; Patya, Miriam; Green, Tamar; Weinberger, Ronnie; Weizman, Abraham; Gothelf, Doron

2013-08-01

372

The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17.  

PubMed Central

The human gene for cystathionine beta-synthase (CBS), the enzyme deficient in classical homocystinuria, has been assigned to the subtelomeric region of band 21q22.3 by in situ hybridization of a rat cDNA probe to structurally rearranged chromosomes 21. The homologous locus in the mouse (Cbs) was mapped to the proximal half of mouse chromosome 17 by Southern analysis of Chinese hamster X mouse somatic cell hybrid DNA. Thus, CBS/Cbs and the gene for alpha A-crystalline (CRYA1/Crya-1 or Acry-1) form a conserved linkage group on human (HSA) chromosome region 21q22.3 and mouse (MMU) chromosome 17 region A-C. Features of Down syndrome (DS) caused by three copies of these genes should not be present in mice trisomic for MMU 16 that have been proposed as animal models for DS. Mice partially trisomic for MMU 16 or MMU 17 should allow gene-specific dissection of the trisomy 21 phenotype. Images Figure 1 Figure 2 Figure 4

Munke, M; Kraus, J P; Ohura, T; Francke, U

1988-01-01

373

Genitourinary Anomalies in Mowat-Wilson Syndrome with Deletion\\/Mutation in the Zinc Finger Homeo Box 1B Gene (ZFHX1B)  

Microsoft Academic Search

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly

L. Garavelli; P. Cerruti-Mainardi; R. Virdis; S. Pedori; G. Pastore; M. Godi; S. Provera; A. Rauch; C. Zweier; M. Zollino; G. Banchini; N. Longo; D. Mowat; G. Neri; S. Bernasconi

2005-01-01

374

Learning about Velocardiofacial Syndrome  

MedlinePLUS

... of the syndrome. A special blood test called FISH (fluorescence in situ hybridization) is then done to ... not have the 22q11.2 deletion by standard FISH testing may have a smaller deletion that may ...

375

Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review.  

PubMed

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype. PMID:15908750

Garavelli, L; Cerruti-Mainardi, P; Virdis, R; Pedori, S; Pastore, G; Godi, M; Provera, S; Rauch, A; Zweier, C; Zollino, M; Banchini, G; Longo, N; Mowat, D; Neri, G; Bernasconi, S

2005-05-20

376

Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome)  

PubMed Central

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions, ?11.8 Mb, demonstrated mild cognitive impairment, with a full-scale IQ of 63 or higher (p < 0.001). Among these five patients, the two patients with the larger deletions (11.4, 11.8 Mb) had a selective impairment in freedom from distractability compared to the three patients with smaller deletions (?9.1 Mb). We propose the presence of a proximal critical region that contains a gene for global cognitive function and a distal critical region that contains a gene essential for auditory attention, which may be necessary for optimizing intellectual function. The proximal critical region is 300 kb and contains three annotated genes. One of these genes, BSX, encodes a brain-specific homeobox protein that in gene-targeted mice has been shown previously to have a role in regulating locomotory behavior via BSX-expressing neurons in the hypothalamus. The distal critical region, ~2.2 Mb, contains 18 annotated genes. One gene in this region, Neurogranin, has been demonstrated previously in mice to be critical for synapse plasticity and long-term potentiation. Taken together, our results implicate the presence of at least two loci in distal 11q that when deleted, cause global and selective deficits in neurocognitive function. These findings have important implications for genetic counseling and potential gene-specific therapies.

Coldren, C. D.; Lai, Z.; Shragg, P.; Rossi, E.; Glidewell, S. C.; Zuffardi, O.; Mattina, T.; Ivy, D. D.; Curfs, L. M.; Mattson, S. N.; Riley, E. P.; Treier, M.

2011-01-01

377

Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).  

PubMed

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions, deletions (11.4, 11.8 Mb) had a selective impairment in freedom from distractability compared to the three patients with smaller deletions (deleted, cause global and selective deficits in neurocognitive function. These findings have important implications for genetic counseling and potential gene-specific therapies. PMID:18855024

Coldren, C D; Lai, Z; Shragg, P; Rossi, E; Glidewell, S C; Zuffardi, O; Mattina, T; Ivy, D D; Curfs, L M; Mattson, S N; Riley, E P; Treier, M; Grossfeld, P D

2008-10-15

378

Molecular analysis of a novel subtelomeric repeat with polymorphic chromosomal distribution.  

PubMed

DNA from a 50-kb yeast artificial chromosome (YAC) containing one human telomere was characterized. Cloned sequences from the centromeric end of this YAC (designated yRM2001) localized to several human chromosomes by somatic hybrid panel mapping. The telomeric end of the YAC contained both (TTAGGG)n sequences and the previously characterized TelBam3.4 subterminal repeat element. A novel low-copy repeat element (designated HC1103) mapped 19 kb from the telomeric end of the YAC. This repeat was shown by fluorescence in situ hybridization to be present in several subtelomeric regions (3q, 12p, 15q, 19p, and 20p) and at an interstitial site (2q13-->q14) in all individuals studied, but to be polymorphically distributed at several other telomeres. The YAC vector-insert EcoRI cloning site was positioned 50 kb to 70 kb from chromosome termini in human genomic DNA using RecA-assisted restriction endonuclease (RARE) cleavage analysis. Our results suggest that the DNA segment cloned in yRM2001 contains a novel block of low-copy DNA consistently present at some human telomeres, but polymorphically distributed at others. PMID:7587396

Martin-Gallardo, A; Lamerdin, J; Sopapan, P; Friedman, C; Fertitta, A L; Garcia, E; Carrano, A; Negorev, D; Macina, R A; Trask, B J

1995-01-01

379

Toward closing rice telomere gaps: mapping and sequence characterization of rice subtelomere regions.  

PubMed

Despite the collective efforts of the international community to sequence the complete rice genome, telomeric regions of most chromosome arms remain uncharacterized. In this report we present sequence data from subtelomere regions obtained by analyzing telomeric clones from two 8.8 x genome equivalent 10-kb libraries derived from partial restriction digestion with HaeIII or Sau3AI (OSJNPb HaeIII and OSJNPc Sau3AI). Seven telomere clones were identified and contain 25-100 copies of the telomere repeat (CCCTAAA)(n) on one end and unique sequences on the opposite end. Polymorphic sequence-tagged site markers from five clones and one additional PCR product were genetically mapped on the ends of chromosome arms 2S, 5L, 10S, 10L, 7L, and 7S. We found distinct chromosome-specific telomere-associated tandem repeats (TATR) on chromosome 7 (TATR7) and on the short arm of chromosome 10 (TATR10s) that showed no significant homology to any International Rice Genome Sequencing Project (IRGSP) genomic sequence. The TATR7, a degenerate tandem repeat which is interrupted by transposable elements, appeared on both ends of chromosome 7. The TATR10s was found to contain an inverted array of three tandem repeats displaying an interesting secondary folding pattern that resembles a telomere loop (t-loop) and which may be involved in a protective function against chromosomal end degradation. PMID:15965650

Yang, Tae-Jin; Yu, Yeisoo; Chang, Song-Bin; de Jong, Hans; Oh, Chang-Sik; Ahn, Sang-Nag; Fang, Eric; Wing, Rod A

2005-06-18

380

The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2.  

PubMed

Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time. PMID:22419167

Ventura, Mario; Catacchio, Claudia R; Sajjadian, Saba; Vives, Laura; Sudmant, Peter H; Marques-Bonet, Tomas; Graves, Tina A; Wilson, Richard K; Eichler, Evan E

2012-03-14

381

Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency.  

PubMed

Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (~80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences. PMID:23685628

Wang, Tao; Wu, Hao; Li, Yujing; Szulwach, Keith E; Lin, Li; Li, Xuekun; Chen, I-Ping; Goldlust, Ian S; Chamberlain, Stormy J; Dodd, Ann; Gong, He; Ananiev, Gene; Han, Ji Woong; Yoon, Young-sup; Rudd, M Katharine; Yu, Miao; Song, Chun-Xiao; He, Chuan; Chang, Qiang; Warren, Stephen T; Jin, Peng

2013-05-19

382

Interstitial deletion of 20q in a patient with Waldenström macroglobulinemia following chemotherapy.  

PubMed

A 76-year-old male with a history of renal insufficiency was found to have anemia, an IgM kappa paraprotein on serum immunofixation studies, absence of lytic bone lesions, and findings in the bone marrow consistent with Waldenström macroglobulinemia (WM). Cytogenetic studies including fluorescence in situ hybridization (FISH) on the post-treatment bone marrow revealed the karyotype 46,XY,del(20)(q13.1q13.3). Less than 70 cases of karyotypic abnormalities in patients with WM have been reported, which have shown no abnormalities specific to WM. Monosomy or trisomy of chromosome 20 has been reported in approximately eight cases, but to our knowledge this is the first case report of an interstitial deletion of 20q, confirmed by FISH using chromosome 20 subtelomeric specific probes. Interstitial deletions of 20q are known to occur in polycythemia vera and other hematological malignancies, especially those of myeloid origin. PMID:11850077

Blann, Melissa M; Velagaleti, Gopalrao V N; Morgan, David L; Martinez, Rodolfo E; Conlin, Phillip A; Tonk, Vijay S

2002-01-15

383

A compound heterozygous missense mutation and a large deletion in the KCTD7 gene presenting as an opsoclonus-myoclonus ataxia-like syndrome.  

PubMed

Mutations in the potassium channel-related gene KCTD7 were described so far in a single family with progressive myoclonus epilepsy. We describe a unique phenotype: acute onset of myoclonus and ataxia, associated with abnormal opsoclonus-like eye movements; improvement of clinical symptoms under steroid treatment; and appearance of epileptic activity on EEG 2 years later without overt seizures. After excluding possible genetic causes, whole-genome exome sequencing was performed in order to identify the causative gene. One heterozygous missense mutation (R84W) was detected by exome sequencing and a large heterozygous deletion of exons 3 and 4 by MLPA analysis. The father is heterozygous for the R84W mutation and the mother is heterozygous for the exon 3+4 deletion. The mutation affects a highly conserved segment of the predicted protein, changing a basic amino acid into neutral. The large deletion probably results in a truncated protein. The different phenotype broadens the spectrum of KCTD7-related diseases. Therefore, patients diagnosed as having opsoclonus-myoclonus with an atypical course should be evaluated for KCTD7 mutations. PMID:22638565

Blumkin, Lubov; Kivity, Sara; Lev, Dorit; Cohen, Sarit; Shomrat, Ruth; Lerman-Sagie, Tally; Leshinsky-Silver, Esther

2012-05-26

384