title: Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.
abstract: Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Akawi
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: McRae
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Morad
authors.initials: M
authors.lastname: Ansari
authors.affiliation: Sheffield Regional Genetics Services, Sheffield Children's National Health Service (NHS) Trust, Western Bank, Sheffield, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Balasubramanian
authors.affiliation: Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Moira
authors.initials: M
authors.lastname: Blyth
authors.affiliation: North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clayton
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.affiliation: South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Tomas W
authors.initials: TW
authors.lastname: Fitzgerald
authors.affiliation: Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Francis
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: George
authors.initials: G
authors.lastname: Gabriel
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: Gerety
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Goodship
authors.affiliation: Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hobson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Jones
authors.affiliation: West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: King
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klena
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK.
authors.forename: Ajith
authors.identifier: http://orcid.org/0000-0003-3878-2856
authors.initials: A
authors.lastname: Kumar
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lees
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Chris
authors.identifier: http://orcid.org/0000-0001-8087-4530
authors.initials: C
authors.lastname: Lelliott
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lord
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: McMullan
authors.affiliation: West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Regan
authors.affiliation: Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Osio
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: Piombo
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Prigmore
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Rajan
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosser
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sifrim
authors.affiliation: Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Audrey
authors.initials: A
authors.lastname: Smith
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Ganesh J
authors.initials: GJ
authors.lastname: Swaminathan
authors.affiliation: Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Turnpenny
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Whitworth
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Wright
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.identifier: http://orcid.org/0000-0002-1152-370X
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000145:classification / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D006113:United Kingdom
chemical_list: D018797:Cell Cycle Proteins; C587687:KIAA0586 protein, human; C487994:PRMT7 protein, human; D011484:Protein-Arginine N-Methyltransferases; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases; C471969:MMP21 protein, human; D053505:Matrix Metalloproteinases, Secreted