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

Akawi, Nadia, McRae, Jeremy, Ansari, Morad, Balasubramanian, Meena, Blyth, Moira, Brady, Angela F., Clayton, Stephen, Cole, Trevor, Deshpande, Charu, Fitzgerald, Tomas W., Foulds, Nicola, Francis, Richard, Gabriel, George, Gerety, Sebastian S., Goodship, Judith, Hobson, Emma, Jones, Wendy D., Joss, Shelagh, King, Daniel, Klena, Nikolai, Kumar, Ajith, Lees, Melissa, Lelliott, Chris, Lord, Jenny, McMullan, Dominic, O'Regan, Mary, Osio, Deborah, Piombo, Virginia, Prigmore, Elena, Rajan, Diana, Rosser, Elisabeth, Sifrim, Alejandro, Smith, Audrey, Swaminathan, Ganesh J., Turnpenny, Peter, Whitworth, James, Wright, Caroline F., Firth, Helen V., Barrett, Jeffrey C., Lo, Cecilia W., FitzPatrick, David R., Hurles, Matthew E., and for the DDD Study, (2015) Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genetics, 47 (11). pp. 1363-1369.

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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(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.

Item ID: 60720
Item Type: Article (Research - C1)
ISSN: 1546-1718
Copyright Information: © 2015 Nature America, Inc.
Funders: MRC Human Genetics Unit, US National Institutes of Health (NIH), DFG German Research Foundation
Projects and Grants: NIH U01-HL098180
Date Deposited: 23 Oct 2019 12:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1114 Paediatrics and Reproductive Medicine > 111401 Foetal Development and Medicine @ 30%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060403 Developmental Genetics (incl Sex Determination) @ 35%
08 INFORMATION AND COMPUTING SCIENCES > 0801 Artificial Intelligence and Image Processing > 080109 Pattern Recognition and Data Mining @ 35%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%
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