@article{c43bc8de2b8c4262b687f19a05e5b2e4,
title = "Evidence for 28 genetic disorders discovered by combining healthcare and research data",
abstract = "De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1,2. 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.",
keywords = "cancer, mutations, protein-truncating variants, selection, MUTATIONS, SELECTION, CANCER, PROTEIN-TRUNCATING VARIANTS",
author = "J. Kaplanis and K.E. Samocha and L. Wiel and Z.C. Zhang and K.J. Arvai and R.Y. Eberhardt and G. Gallone and S.H. Lelieveld and H.C. Martin and J.F. McRae and P.J. Short and R.I. Torene and {de Boer}, E. and P. Danecek and E.J. Gardner and N. Huang and J. Lord and I. Martincorena and R. Pfundt and M.R.F. Reijnders and A. Yeung and H.G. Yntema and L.E.L.M. Vissers and J. Juusola and C.F. Wright and H.G. Brunner and H.V. Firth and D.R. FitzPatrick and J.C. Barrett and M.E. Hurles and C. Gilissen and K. Retterer and {Deciphering Developmental Disorders Study}",
note = "Funding Information: Acknowledgements We thank the families and their clinicians for their participation and engagement, and our colleagues who assisted in the generation and processing of data. Inclusion of RadboudUMC data was in part supported by the Solve-RD project that has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement no. 779257. This work was in part financially supported by grants from the Netherlands Organization for Scientific Research (917-17-353 to C.G.). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER, which is funded by the Wellcome Trust. The full acknowledgements can be found at www.ddduk.org/access.html. The DDD study authors acknowledges the work of R. Kelsell. Finally, we acknowledge the contribution of an esteemed DDD clinical collaborator, M. Bitner-Glindicz, who died during the course of the study. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = oct,
day = "29",
doi = "10.1038/s41586-020-2832-5",
language = "English",
volume = "586",
pages = "757--762",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7831",
}