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.
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Protein Data Bank
We thank the families for their participation and patience. We are grateful to the Exome Aggregation Consortium for making their data available. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. The authors wish to thank the Sanger Mouse Genetics Project for generating and providing mouse phenotyping information, N. Karp for statistical input on the mouse data and V. Narasimhan for making the bcftools roh algorithm available. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. Work on the Mmp21-mutant mouse models was supported by US National Institutes of Health grant U01-HL098180 to C.W.L. V.P. was funded by a fellowship from the DFG German Research Foundation.
Integrated supplementary information
Videomicroscopy of the embryonic node from an Mmp21 Miri mutant shows robust ciliary motility and leftward fluid flow similar to that seen in the embryonic node of a wild-type littermate control. Flow videos are shown at 200% the speed of real time to facilitate the visualization of bead movement, while cilia motion videos are shown at 15% the speed of real time to allow for better visualization of nodal ciliary motion.
About this article
Neurology Genetics (2019)