title: De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.
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 Wiley Periodicals, Inc.
authors.affiliation: Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Clinical Genetics Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Fryer
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Shears
authors.affiliation: Wessex Clinical Genetics Service, University Hospitals Southampton, Southampton, UK.|Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lachlan
authors.affiliation: Department of Genetic Medicine, Belfast City Hospital, Belfast, UK.
authors.forename: Shane A
authors.initials: SA
authors.lastname: McKee
authors.affiliation: Department of Genetic Medicine, Belfast City Hospital, Belfast, UK.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Magee
authors.affiliation: Department of Clinical Genetics, Guy's and St. Thomas' Hospital NHS Trust, London, UK.
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Pradeep C
authors.initials: PC
authors.lastname: Vasudevan
authors.affiliation: East Anglian Medical Genetics Service, Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique (I.P.G.), Gosselies (Charleroi), Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Benoit
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique (I.P.G.), Gosselies (Charleroi), Belgium.
authors.forename: Damien
authors.initials: D
authors.lastname: Lederer
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique (I.P.G.), Gosselies (Charleroi), Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.affiliation: DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Ddd
authors.initials: D
authors.lastname: Study
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (I.G.M.M.), University of Edinburgh, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003248:Constipation / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D005260:Female; D020233:Gait Disorders, Neurologic / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D057895:Haploinsufficiency; D006579:Heterozygote; D006617:Hip Dislocation / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D013285:Strabismus / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D014430:Twins, Monozygotic; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
chemical_list: C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins
keywords: 6p21.3 microdeletion; DDD study; SYNGAP1; behavioral phenotype; epilepsy; hip dysplasia; hypertrichosis; intellectual disability; strabismus; syndrome