Abstract
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.
Highlights
De novo mutations are an important cause of moderate and severe intellectual disability (ID)
Heterozygous, de novo loss-of-function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]
In 2009, Hamdan et al first reported the sequencing of SYNGAP1 in 94 apparently nonsyndromic individuals with intellectual disability; they found de novo mutations in three, firstdescribing this gene as a cause of nonsyndromic intellectual disability (ID) in humans [Hamdan et al, 2009]
Summary
De novo mutations are an important cause of moderate and severe intellectual disability (ID). In 2009, Hamdan et al first reported the sequencing of SYNGAP1 in 94 apparently nonsyndromic individuals with intellectual disability; they found de novo mutations in three, firstdescribing this gene as a cause of nonsyndromic intellectual disability (ID) in humans [Hamdan et al, 2009]. This group subsequently published eight further affected individuals through re-sequencing predominantly ID cohorts enriched for epilepsy [Hamdan et al, 2011a, b; Berryer et al, 2013]. Further patients have been described as part of large generation sequencing studies of individuals with ID [Vissers et al, 2010; de Ligt et al, 2012; Rauch et al, 2012; Redin et al, 2014]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
