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

2.50
Hdl Handle:
http://hdl.handle.net/11287/593972
Title:
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families
Authors:
Akawi, N.; McRae, J.; Ansari, M.; Balasubramanian, M.; Blyth, M.; Brady, A. F.; Clayton, S.; Cole, T.; Deshpande, C.; Fitzgerald, T. W.; Foulds, N.; Francis, R.; Gabriel, G.; Gerety, S. S.; Goodship, J.; Hobson, E.; Jones, W. D.; Joss, S.; King, D.; Klena, N.; Kumar, A.; Lees, M.; Lelliott, C.; Lord, J.; McMullan, D.; O'Regan, M.; Osio, Deborah; Piombo, V.; Prigmore, E.; Rajan, D.; Rosser, E.; Sifrim, A.; Smith, A.; Swaminathan, G. J.; Turnpenny, Peter D.; Whitworth, J.; Wright, C. F.; Firth, H. V.; Barrett, J. C.; Lo, C. W.; FitzPatrick, D. R.; Hurles, M. E.; D. D. D. study
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.
Citation:
Nat Genet. 2015 Nov;47(11):1363-9
Publisher:
Nature
Journal:
Nature genetics
Issue Date:
5-Oct-2015
URI:
http://hdl.handle.net/11287/593972
DOI:
10.1038/ng.3410
PubMed ID:
26437029
Additional Links:
http://dx.doi.org/10.1038/ng.3410
Type:
Journal Article
Language:
eng
ISSN:
1546-1718
Appears in Collections:
2015 RD&E publications; Clinical Genetics (Peninsula Genetics)

Full metadata record

DC FieldValue Language
dc.contributor.authorAkawi, N.en
dc.contributor.authorMcRae, J.en
dc.contributor.authorAnsari, M.en
dc.contributor.authorBalasubramanian, M.en
dc.contributor.authorBlyth, M.en
dc.contributor.authorBrady, A. F.en
dc.contributor.authorClayton, S.en
dc.contributor.authorCole, T.en
dc.contributor.authorDeshpande, C.en
dc.contributor.authorFitzgerald, T. W.en
dc.contributor.authorFoulds, N.en
dc.contributor.authorFrancis, R.en
dc.contributor.authorGabriel, G.en
dc.contributor.authorGerety, S. S.en
dc.contributor.authorGoodship, J.en
dc.contributor.authorHobson, E.en
dc.contributor.authorJones, W. D.en
dc.contributor.authorJoss, S.en
dc.contributor.authorKing, D.en
dc.contributor.authorKlena, N.en
dc.contributor.authorKumar, A.en
dc.contributor.authorLees, M.en
dc.contributor.authorLelliott, C.en
dc.contributor.authorLord, J.en
dc.contributor.authorMcMullan, D.en
dc.contributor.authorO'Regan, M.en
dc.contributor.authorOsio, Deborahen
dc.contributor.authorPiombo, V.en
dc.contributor.authorPrigmore, E.en
dc.contributor.authorRajan, D.en
dc.contributor.authorRosser, E.en
dc.contributor.authorSifrim, A.en
dc.contributor.authorSmith, A.en
dc.contributor.authorSwaminathan, G. J.en
dc.contributor.authorTurnpenny, Peter D.en
dc.contributor.authorWhitworth, J.en
dc.contributor.authorWright, C. F.en
dc.contributor.authorFirth, H. V.en
dc.contributor.authorBarrett, J. C.en
dc.contributor.authorLo, C. W.en
dc.contributor.authorFitzPatrick, D. R.en
dc.contributor.authorHurles, M. E.en
dc.contributor.authorD. D. D. studyen
dc.date.accessioned2016-01-19T12:38:08Zen
dc.date.available2016-01-19T12:38:08Zen
dc.date.issued2015-10-05en
dc.identifier.citationNat Genet. 2015 Nov;47(11):1363-9en
dc.identifier.issn1546-1718en
dc.identifier.pmid26437029en
dc.identifier.doi10.1038/ng.3410en
dc.identifier.urihttp://hdl.handle.net/11287/593972en
dc.description.abstractDiscovery 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.en
dc.language.isoengen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/ng.3410en
dc.titleDiscovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 familiesen
dc.typeJournal Articleen
dc.identifier.journalNature geneticsen

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.