4.2 Article

De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability

期刊

AMERICAN JOURNAL OF MEDICAL GENETICS PART A
卷 167, 期 10, 页码 2231-2237

出版社

WILEY
DOI: 10.1002/ajmg.a.37189

关键词

SYNGAP1; 6p21.3 microdeletion; intellectual disability; epilepsy; syndrome; hypertrichosis; strabismus; hip dysplasia; DDD study; behavioral phenotype

资金

  1. Health Innovation Challenge Fund [HICF-1009-003]
  2. Wellcome Trust Sanger Institute [WT098051]
  3. Cambridge South REC [10/H0305/83]
  4. Republic of Ireland REC [GEN/284/12]
  5. National Institute for Health Research
  6. Medical Research Council [MC_U127561093, MC_PC_U127561093] Funding Source: researchfish
  7. MRC [MC_U127561093, MC_PC_U127561093] Funding Source: UKRI

向作者/读者索取更多资源

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. (c) 2015 Wiley Periodicals, Inc.

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