2. Academic Validation
  3. Quantifying the contribution of recessive coding variation to developmental disorders

Quantifying the contribution of recessive coding variation to developmental disorders

  • Science. 2018 Dec 7;362(6419):1161-1164. doi: 10.1126/science.aar6731.
Hilary C Martin 1,  Wendy D Jones 2 3,  Rebecca McIntyre 2,  Gabriela Sanchez-Andrade 2,  Mark Sanderson 2,  James D Stephenson 2 4,  Carla P Jones 2,  Juliet Handsaker 2,  Giuseppe Gallone 2,  Michaela Bruntraeger 2,  Jeremy F McRae 2,  Elena Prigmore 2,  Patrick Short 2,  Mari Niemi 2,  Joanna Kaplanis 2,  Elizabeth J Radford 2 5,  Nadia Akawi 6,  Meena Balasubramanian 7,  John Dean 8,  Rachel Horton 9,  Alice Hulbert 10,  Diana S Johnson 7,  Katie Johnson 11,  Dhavendra Kumar 12,  Sally Ann Lynch 13,  Sarju G Mehta 14,  Jenny Morton 15,  Michael J Parker 16,  Miranda Splitt 17,  Peter D Turnpenny 18,  Pradeep C Vasudevan 19,  Michael Wright 17,  Andrew Bassett 2,  Sebastian S Gerety 2,  Caroline F Wright 20,  David R FitzPatrick 21,  Helen V Firth 2 14,  Matthew E Hurles 2,  Jeffrey C Barrett 1,  Deciphering Developmental Disorders Study
Affiliations

Affiliations

  • 1 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [email protected] [email protected].
  • 2 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • 3 Great Ormond Street Hospital for Children, National Health Service (NHS) Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.
  • 4 European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
  • 5 Department of Paediatrics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 6 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 7 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, OPD2, Northern General Hospital, Herries Rd., Sheffield, S5 7AU, UK.
  • 8 Department of Genetics, Aberdeen Royal Infirmary, Aberdeen, UK.
  • 9 Wessex Clinical Genetics Service, G Level, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK.
  • 10 Cheshire and Merseyside Clinical Genetic Service, Liverpool Women's NHS Foundation Trust, Crown Street, Liverpool L8 7SS, UK.
  • 11 Department of Clinical Genetics, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK.
  • 12 Institute of Cancer and Genetics, University Hospital of Wales, Cardiff, UK.
  • 13 Temple Street Children's Hospital, Dublin, Ireland.
  • 14 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 15 Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK.
  • 16 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
  • 17 Northern Genetics Service, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 18 Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
  • 19 Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
  • 20 University of Exeter Medical School, Institute of Biomedical and Clinical Science, Research, Innovation, Learning and Development (RILD), Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
  • 21 Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
PMID: 30409806 DOI: 10.1126/science.aar6731
Abstract

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

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