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Nat Genet. 2015 Nov;47(11):1363-9. doi: 10.1038/ng.3410. Epub 2015 Oct 5.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

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Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
Sheffield Regional Genetics Services, Sheffield Children's National Health Service (NHS) Trust, Western Bank, Sheffield, UK.
Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
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.
Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK.
West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK.
Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.
East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.


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.

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