RT Journal Article
SR Electronic
T1 Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 258723
DO 10.1101/258723
A1 Joanna Kaplanis
A1 Kaitlin E. Samocha
A1 Laurens Wiel
A1 Zhancheng Zhang
A1 Kevin J. Arvai
A1 Ruth Y. Eberhardt
A1 Giuseppe Gallone
A1 Stefan H. Lelieveld
A1 Hilary C. Martin
A1 Jeremy F. McRae
A1 Patrick J. Short
A1 Rebecca I. Torene
A1 Elke de Boer
A1 Petr Danecek
A1 Eugene J. Gardner
A1 Ni Huang
A1 Jenny Lord
A1 Iñigo Martincorena
A1 Rolph Pfundt
A1 Margot R. F. Reijnders
A1 Alison Yeung
A1 Helger G. Yntema
A1 DDD Study
A1 Lisenka E. L. M. Vissers
A1 Jane Juusola
A1 Caroline F. Wright
A1 Han G. Brunner
A1 Helen V. Firth
A1 David R. FitzPatrick
A1 Jeffrey C. Barrett
A1 Matthew E. Hurles
A1 Christian Gilissen
A1 Kyle Retterer
YR 2019
UL http://biorxiv.org/content/early/2019/12/09/258723.abstract
AB De 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 299 significantly DD-associated genes, including 49 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 500 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.