2. Academic Validation
  3. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability

De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability

  • Am J Hum Genet. 2014 Apr 3;94(4):618-24. doi: 10.1016/j.ajhg.2014.03.006.
Detelina Grozeva 1,  Keren Carss 2,  Olivera Spasic-Boskovic 1,  Michael J Parker 3,  Hayley Archer 4,  Helen V Firth 5,  Soo-Mi Park 5,  Natalie Canham 6,  Susan E Holder 6,  Meredith Wilson 7,  Anna Hackett 8,  Michael Field 9,  James A B Floyd 10,  UK10K Consortium,  Matthew Hurles 2,  F Lucy Raymond 11
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
  • 2 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 3 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
  • 4 Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
  • 5 Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
  • 6 North West Thames Regional Genetics Service (Kennedy Galton Centre), North West London Hospitals NHS Trust, Harrow, Middlesex HA1 3UJ, UK.
  • 7 Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
  • 8 Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
  • 9 Department of Medical Genetics, Royal North Shore Hospital, St. Leonards, NSW 2298, Australia.
  • 10 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.
  • 11 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: flr24@cam.ac.uk.
PMID: 24680889 DOI: 10.1016/j.ajhg.2014.03.006
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.

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