title: De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.
abstract: To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Keren
authors.initials: K
authors.lastname: Carss
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Olivera
authors.initials: O
authors.lastname: Spasic-Boskovic
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Archer
authors.affiliation: Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: North West Thames Regional Genetics Service (Kennedy Galton Centre), North West London Hospitals NHS Trust, Harrow, Middlesex HA1 3UJ, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Canham
authors.affiliation: North West Thames Regional Genetics Service (Kennedy Galton Centre), North West London Hospitals NHS Trust, Harrow, Middlesex HA1 3UJ, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.affiliation: Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: Department of Medical Genetics, Royal North Shore Hospital, St. Leonards, NSW 2298, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK; The Genome Centre, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: James A B
authors.initials: JA
authors.lastname: Floyd
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: flr24@cam.ac.uk.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
mesh_terms: D000293:Adolescent; D002648:Child; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D009154:Mutation
chemical_list: D008780:Methyltransferases; C000588437:SETD5 protein, human