Evidence for 28 genetic disorders discovered by combining healthcare and research data

Joanna Kaplanis, Kaitlin E. Samocha, Laurens Wiel, Zhancheng Zhang, Kevin J. Arvai, Ruth Y. Eberhardt, Giuseppe Gallone, Stefan H. Lelieveld, Hilary C. Martin, Jeremy F. McRae, Patrick J. Short, Rebecca I. Torene, Elke Boer, Petr Danecek, Eugene J. Gardner, Ni Huang, Jenny Lord, Iñigo Martincorena, Rolph Pfundt, Margot R. F. Reijnders, Alison Yeung, Helger G. Yntema, Lisenka E. L. M. Vissers, Jane Juusola, Caroline F. Wright, Han G. Brunner, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles (), Christian Gilissen and Kyle Retterer
Additional contact information
Joanna Kaplanis: Wellcome Sanger Institute
Kaitlin E. Samocha: Wellcome Sanger Institute
Laurens Wiel: Radboud University Medical Center
Zhancheng Zhang: GeneDx
Kevin J. Arvai: GeneDx
Ruth Y. Eberhardt: Wellcome Sanger Institute
Giuseppe Gallone: Wellcome Sanger Institute
Stefan H. Lelieveld: Radboud University Medical Center
Hilary C. Martin: Wellcome Sanger Institute
Jeremy F. McRae: Wellcome Sanger Institute
Patrick J. Short: Wellcome Sanger Institute
Rebecca I. Torene: GeneDx
Elke Boer: Radboud University Medical Center
Petr Danecek: Wellcome Sanger Institute
Eugene J. Gardner: Wellcome Sanger Institute
Ni Huang: Wellcome Sanger Institute
Jenny Lord: Wellcome Sanger Institute
Iñigo Martincorena: Wellcome Sanger Institute
Rolph Pfundt: Radboud University Medical Center
Margot R. F. Reijnders: Radboud University Medical Center
Alison Yeung: Victorian Clinical Genetics Services
Helger G. Yntema: Radboud University Medical Center
Lisenka E. L. M. Vissers: Radboud University Medical Center
Jane Juusola: GeneDx
Caroline F. Wright: University of Exeter Medical School, Royal Devon & Exeter Hospital
Han G. Brunner: Radboud University Medical Center
Helen V. Firth: Wellcome Sanger Institute
David R. FitzPatrick: University of Edinburgh, Western General Hospital
Jeffrey C. Barrett: Wellcome Sanger Institute
Matthew E. Hurles: Wellcome Sanger Institute
Christian Gilissen: Radboud University Medical Center
Kyle Retterer: GeneDx

Nature, 2020, vol. 586, issue 7831, 757-762

Abstract: Abstract De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, 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 genes associated with developmental disorders.

Date: 2020
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DOI: 10.1038/s41586-020-2832-5

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