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

Lookup NU author(s): Professor Judith Goodship


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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(1,2). 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.

Publication metadata

Author(s): Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME, DDD Study

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2015

Volume: 47

Issue: 11

Pages: 1363-1369

Print publication date: 01/11/2015

Online publication date: 05/10/2015

Acceptance date: 31/08/2015

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.3410


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Funder referenceFunder name
DFG German Research Foundation
MRC Human Genetics Unit program
National Institutes for Health Research, through the Comprehensive Clinical Research Network
UK Department of Health
Wellcome Trust
HICF-1009-003Health Innovation Challenge Fund
U01-HL098180US National Institutes of Health
WT098051Wellcome Trust Sanger Institute