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

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families
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 trios1, 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.
1061-4036
1363-1369
Akawi, Nadia
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McRae, Jeremy
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Ansari, Morad
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Balasubramanian, Meena
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Blyth, Moira
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Brady, Angela F.
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Cole, Trevor
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Deshpande, Charu
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Fitzgerald, Tomas W.
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Foulds, Nicola
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Francis, Richard
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Gabriel, George
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Gerety, Sebastian S.
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Joss, Shelagh
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King, Daniel
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Klena, Nikolai
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Kumar, Ajith
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Lees, Melissa
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Lelliott, Chris
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Lord, Jenny
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McMullan, Dominic
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Osio, Deborah
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Piombo, Virginia
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Prigmore, Elena
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Sifrim, Alejandro
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Smith, Audrey
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Swaminathan, Ganesh J.
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Turnpenny, Peter
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Whitworth, James
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Wright, Caroline F.
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Firth, Helen V.
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Barrett, Jeffrey C.
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Lo, Cecilia W.
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FitzPatrick, David R.
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Hurles, Matthew E.
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Akawi, Nadia
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McRae, Jeremy
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Ansari, Morad
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Balasubramanian, Meena
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Brady, Angela F.
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Clayton, Stephen
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Cole, Trevor
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Deshpande, Charu
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Fitzgerald, Tomas W.
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Foulds, Nicola
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Gerety, Sebastian S.
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King, Daniel
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Lees, Melissa
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Lelliott, Chris
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Lord, Jenny
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McMullan, Dominic
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O'Regan, Mary
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Osio, Deborah
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Piombo, Virginia
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Prigmore, Elena
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Rajan, Diana
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Rosser, Elisabeth
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Sifrim, Alejandro
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Smith, Audrey
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Swaminathan, Ganesh J.
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Turnpenny, Peter
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Whitworth, James
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Wright, Caroline F.
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Firth, Helen V.
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Barrett, Jeffrey C.
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Lo, Cecilia W.
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FitzPatrick, David R.
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Hurles, Matthew E.
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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. and Hurles, Matthew E. (2015) Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genetics, 47 (11), 1363-1369. (doi:10.1038/ng.3410).

Record type: Article

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 trios1, 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.

Full text not available from this repository.

More information

Accepted/In Press date: 5 October 2015
Published date: November 2015
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 382696
URI: https://eprints.soton.ac.uk/id/eprint/382696
ISSN: 1061-4036
PURE UUID: 4e592ecb-9175-454e-955c-9bd010106775

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Date deposited: 03 Nov 2015 12:50
Last modified: 15 Jul 2019 21:02

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Contributors

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

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