Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Author:

Kaplanis JoannaORCID,Samocha Kaitlin E.ORCID,Wiel Laurens,Zhang Zhancheng,Arvai Kevin J.,Eberhardt Ruth Y.,Gallone Giuseppe,Lelieveld Stefan H.,Martin Hilary C.ORCID,McRae Jeremy F.,Short Patrick J.ORCID,Torene Rebecca I.,de Boer Elke,Danecek Petr,Gardner Eugene J.ORCID,Huang Ni,Lord JennyORCID,Martincorena Iñigo,Pfundt Rolph,Reijnders Margot R. F.,Yeung Alison,Yntema Helger G.,Study DDD,Vissers Lisenka E. L. M.,Juusola Jane,Wright Caroline F.ORCID,Brunner Han G.,Firth Helen V.,FitzPatrick David R.,Barrett Jeffrey C.,Hurles Matthew E.,Gilissen Christian,Retterer Kyle

Abstract

SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

Publisher

Cold Spring Harbor Laboratory

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