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

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.

SUBMITTER: Akawi N

PROVIDER: S-EPMC5988033 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Akawi Nadia N McRae Jeremy J Ansari Morad M Balasubramanian Meena M Blyth Moira M Brady Angela F AF Clayton Stephen S Cole Trevor T Deshpande Charu C Fitzgerald Tomas W TW Foulds Nicola N Francis Richard R Gabriel George G Gerety Sebastian S SS Goodship Judith J Hobson Emma E Jones Wendy D WD Joss Shelagh S King Daniel D Klena Nikolai N Kumar Ajith A Lees Melissa M Lelliott Chris C Lord Jenny J McMullan Dominic D O'Regan Mary M Osio Deborah D Piombo Virginia V Prigmore Elena E Rajan Diana D Rosser Elisabeth E Sifrim Alejandro A Smith Audrey A Swaminathan Ganesh J GJ Turnpenny Peter P Whitworth James J Wright Caroline F CF Firth Helen V HV Barrett Jeffrey C JC Lo Cecilia W CW FitzPatrick David R DR Hurles Matthew E ME

Nature genetics 20151005 11

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 d ...[more]

PMID: 26437029

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Project description:RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n?=?14) and previously reported (n?=?92) recessive RYR1 cases.Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.

Dataset Information

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

Publications

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

Similar Datasets

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