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

Joanna Kaplanis ,Wendy Lam ,Shane Mckee ,Helger G Yntema ,Nicola Ragge ,Fiona Stewart ,S Abbs ,S M Park ,Elke De Boer ,Stefan H Lelieveld ,Mary Porteous ,Ni Huang ,Eugene J Gardner ,Joanne Comerford ,Petr Danecek ,Andrew P Jackson ,Reijnders Mrf ,Laurens Wiel ,Karen Low ,Kevin J Arvai ,Brendan Mullaney ,Geoff Woods ,Andrew J Green ,Elaine M Cleary ,N Cooper ,Denise Williams ,Jenny Lord ,Ruth Newbury‐Ecob ,Simon Holden ,Vivienne Mcconnell ,Lisa Bradley ,Anne Katrin Lampe ,Carolyn Dunn ,Swati Naik ,Ruth Armstrong ,Simon Bodek ,Mary O’driscoll ,David Goudie ,Alex Magee ,Catherine Mcwilliam ,Dominic Mcmullan ,Ruth Y Eberhardt ,Shirley Mcquaid ,Gillian Rea ,Sarah E Turton ,Alison Hills ,Caroline Clark ,Emma L Baple ,Joanne Mclean ,Andrew Norman ,Lily Islam ,Richard Sandford ,Deirdre Donnelly ,Rebecca Keelagher ,Ingrid Simonic ,Sílvia Borràs ,Eleni Mavrak ,Júlia Baptista ,D J Moore ,Julie Vogt ,Patrick J Morrison ,Kaitlin E Samocha ,Marc Tischkowitz ,Susan E Mcnerlan ,Trevor Cole ,Rolph Pfundt ,Jeremy F Mcrae ,Rebecca Torene ,Madeleine J Tooley ,Tabib Dabir ,Jenny Morton ,Alison Ross ,Sally Ann Lynch ,Zosia Miedzybrodzka ,Stephen Tennant ,Joanna Jarvis ,Deborah Osio ,Tara Azam ,Iñigo Martincorena ,Patrick Short ,Mervyn Humphreys ,Helen Cox ,Giuseppe Gallone ,Kai-Ren Ong ,Derek Lim ,Alan Donaldson ,Eileen Roberts ,Sarah Smithson ,Jonathan Berg ,John Dean ,Joan Paterson ,Eleanor Reavey ,Z Zhang ,Alison Yeung ,Hilary C Martin ,Lucy Raymond ,Evan Reid ,Lisa Cooper-Charles ,Ingrid Scurr ,Carole Brewer

doi:10.1038/s41586-020-2832-5

Abstract

Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD)1. However, known DD-associated genes only account for a minority of the observed excess of such DNMs1,2. 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, 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.

Highlights

It has previously been estimated that ~42-48% of patients with a severe developmental disorder (DD) have a pathogenic de novo mutation (DNM) in a protein coding gene[1,2]
We investigated whether some synonymous DNMs might be pathogenic by disrupting splicing
To assess the contribution of germline selection to recurrent DNMs, we initially focused on the 12 known germline selection genes, which all operate through activation of the RAS

Summary

De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). 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

Findings

Introduction

Discussion