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Am J Med Genet A. 2015 Oct;167A(10):2231-7. doi: 10.1002/ajmg.a.37189. Epub 2015 Jun 15.

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

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Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
Clinical Genetics Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
Wessex Clinical Genetics Service, University Hospitals Southampton, Southampton, UK.
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
Department of Genetic Medicine, Belfast City Hospital, Belfast, UK.
Department of Clinical Genetics, Guy's and St. Thomas' Hospital NHS Trust, London, UK.
Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, UK.
East Anglian Medical Genetics Service, Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Centre de Génétique Humaine, Institut de Pathologie et de Génétique (I.P.G.), Gosselies (Charleroi), Belgium.
DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (I.G.M.M.), University of Edinburgh, UK.


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.


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

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