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Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families
Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988033/ https://www.ncbi.nlm.nih.gov/pubmed/26437029 http://dx.doi.org/10.1038/ng.3410 |
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author | 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. |
author_facet | 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. |
author_sort | Akawi, Nadia |
collection | PubMed |
description | Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1,2. Here we analysed 4,125 families with diverse, rare, genetically heterogeneous developmental disorders and identified four novel autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (identifying probands with rare biallelic 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 the same recessive candidate gene. This new paradigm promises to catalyse discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations, and those caused predominantly by compound heterozygous genotypes. |
format | Online Article Text |
id | pubmed-5988033 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-59880332018-06-05 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. Nat Genet Article Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1,2. Here we analysed 4,125 families with diverse, rare, genetically heterogeneous developmental disorders and identified four novel autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (identifying probands with rare biallelic 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 the same recessive candidate gene. This new paradigm promises to catalyse discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations, and those caused predominantly by compound heterozygous genotypes. 2015-10-05 2015-11 /pmc/articles/PMC5988033/ /pubmed/26437029 http://dx.doi.org/10.1038/ng.3410 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title | Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title_full | Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title_fullStr | Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title_full_unstemmed | Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title_short | Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
title_sort | discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988033/ https://www.ncbi.nlm.nih.gov/pubmed/26437029 http://dx.doi.org/10.1038/ng.3410 |
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