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

Nadia Akawi, Jeremy McRae, Morad Ansari, Meena Balasubramanian, Moira Blyth, Angela F. Brady, Stephen Clayton, Trevor Cole, Charu Deshpande, Tomas W. Fitzgerald, Nicola Foulds, Richard Francis, George Gabriel, Sebastian S. Gerety, Judith Goodship, Emma Hobson, Wendy D. Jones, Shelagh Joss, Daniel King, Nikolai KlenaAjith Kumar, Melissa Lees, Chris Lelliott, Jenny Lord, Dominic McMullan, Mary O'Regan, Deborah Osio, Virginia Piombo, Elena Prigmore, Diana Rajan, Elisabeth Rosser, Alejandro Sifrim, Audrey Smith, Ganesh J. Swaminathan, Peter Turnpenny, James Whitworth, Caroline F. Wright, Helen V. Firth, Jeffrey C. Barrett, Cecilia W. Lo, David R. FitzPatrick, Matthew E. Hurles

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1363-1369
Number of pages7
JournalNature Genetics
Issue number11
Publication statusPublished - Nov 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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