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1.
De novo,heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability
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Michael J. Parker Alan E. Fryer Deborah J. Shears Katherine L. Lachlan Shane A. McKee Alex C. Magee Shehla Mohammed Pradeep C. Vasudevan Soo‐Mi Park Valérie Benoit Damien Lederer Isabelle Maystadt DDD study David R. FitzPatrick 《American journal of medical genetics. Part A》2015,167(10):2231-2237
De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. 相似文献
2.
Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases
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S. Baer A. Afenjar T. Smol A. Piton B. Gérard Y. Alembik T. Bienvenu G. Boursier O. Boute C. Colson M.‐P. Cordier V. Cormier‐Daire B. Delobel M. Doco‐Fenzy B. Duban‐Bedu M. Fradin D. Geneviève A. Goldenberg M. Grelet D. Haye D. Heron B. Isidor B. Keren D. Lacombe A.‐S. Lèbre G. Lesca A. Masurel M. Mathieu‐Dramard C. Nava L. Pasquier A. Petit N. Philip J. Piard S. Rondeau P. Saugier‐Veber S. Sukno J. Thevenon J. Van‐Gils C. Vincent‐Delorme M. Willems E. Schaefer G. Morin 《Clinical genetics》2018,94(1):141-152
Wiedemann‐Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high‐throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID. 相似文献
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Philip J. Ostrowski Anna Zachariou Chey Loveday Diana Baralle Edward Blair Sofia Douzgou Michael Field Alison Foster Claire Kyle Katherine Lachlan Sahar Mansour Swati Naik Gillian Rea Sarah Smithson Yves Sznajer Elizabeth Thompson Trevor Cole Katrina Tatton‐Brown 《American journal of medical genetics. Part C, Seminars in medical genetics》2019,181(4):638-643
BRWD3 has been described as a cause of X‐linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth‐intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity. 相似文献
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Sara Griffiths Chey Loveday Anna Zachariou Lucy‐Ann Behan Kate Chandler Trevor Cole Stefano D'Arrigo Andrea Dieckmann Alison Foster James Gibney Matthew Hunter Donatella Milani Chiara Pantaleoni Edna Roche Mark Sherlock Amanda Springer Susan M. White Childhood Overgrowth Collaboration Katrina Tatton‐Brown 《American journal of medical genetics. Part A》2019,179(4):588-594
Overgrowth‐intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen‐Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished. 相似文献
7.
Extending the phenotype associated with the CSNK2A1‐related Okur–Chung syndrome—A clinical study of 11 individuals
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Ceris I. Owen Ramsay Bowden Michael J. Parker Jo Patterson Joan Patterson Sue Price Ajoy Sarkar Bruce Castle Charulatha Deshpande Miranda Splitt Neeti Ghali John Dean Andrew J. Green Charlene Crosby Deciphering Developmental Disorders Study Katrina Tatton‐Brown 《American journal of medical genetics. Part A》2018,176(5):1108-1114
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Jehan Suleiman Korbinian M. Riedhammer Timothy Jicinsky Melinda Mundt Laurie Werner Mirjana Gusic Anna L. Burgemeister Hessa S. Alsaif Maha Abdulrahim Nabil N Moghrabi Manal Nicolas‐Jilwan Moeenaldeen AlSayed Weimin Bi Srirangan Sampath Fowzan S. Alkuraya Ayman W. El‐Hattab 《Human mutation》2019,40(11):1985-1992
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An overlapping phenotype of Osteogenesis imperfecta and Ehlers–Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing
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Luisa Mackenroth Björn Fischer‐Zirnsak Johannes Egerer Jochen Hecht Tilmann Kallinich Werner Stenzel Birgit Spors Arpad von Moers Stefan Mundlos Uwe Kornak Kerstin Gerhold Denise Horn 《American journal of medical genetics. Part A》2016,170(4):1080-1085
11.
A 15‐year‐long Southern blotting analysis of
FMR1
to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan
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C.‐C. Tzeng L.‐P. Tsai Y.‐K. Chang Y.‐J. Hung Y.‐Y. Chang Y.‐P. Su J.‐J. Jiang H.‐M. Liang 《Clinical genetics》2017,92(2):217-220
Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15‐year period. In total, 725 high‐risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low‐risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low‐risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156‐1/539). A total of 100 carriers were found to be in the high‐risk group, thus revealing a significantly higher frequency than the low‐risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre‐mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low‐risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high‐risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing. 相似文献
12.
A novel FBXO28 frameshift mutation in a child with developmental delay,dysmorphic features,and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype
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Chris Balak Newell Belnap Keri Ramsey Shelagh Joss Koen Devriendt Marcus Naymik Wayne Jepsen Ashley L. Siniard Szabolcs Szelinger Mary E. Parker Ryan Richholt Tyler Izatt Madison LaFleur Panieh Terraf Lorida Llaci Matt De Both Ignazio S. Piras Sampathkumar Rangasamy Isabelle Schrauwen David W. Craig Matt Huentelman Vinodh Narayanan 《American journal of medical genetics. Part A》2018,176(7):1549-1558
Chromosome 1q41‐q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41‐q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41‐q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3‐year‐old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41‐q42 MDS. Through a familial whole‐exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41‐q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41‐q42 gene deletion syndrome. 相似文献