Rare disease gene association discovery in the 100,000 Genomes Project
Abstract
Abstract Up to 80% of rare disease patients remain undiagnosed after genomic sequencing 1 , with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project 2 . A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator 3,4 UNC13A , schizophrenia with GPR17 , epilepsy with RBFOX3 , Charcot–Marie–Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK . Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease–gene association discovery.
Article Details
Authors (61)
Valentina Cipriani
Letizia Vestito
Emma F. Magavern
Julius O. B. Jacobsen
Gavin Arno
Elijah R. Behr
Katherine A. Benson
Marta Bertoli
Detlef Bockenhauer
Michael R. Bowl
Kate Burley
Li F. Chan
Patrick Chinnery
Peter J. Conlon
Marcos A. Costa
Alice E. Davidson
Sally J. Dawson
Elhussein A. E. Elhassan
Sarah E. Flanagan
Marta Futema
Daniel P. Gale
Sonia García-Ruiz
Cecilia Gonzalez Corcia
Helen R. Griffin
Sophie Hambleton
Amy R. Hicks
Henry Houlden
Richard S. Houlston
Sarah A. Howles
Robert Kleta
Iris Lekkerkerker
Siying Lin
Petra Liskova
Hannah H. Mitchison
Heba Morsy
Andrew D. Mumford
William G. Newman
Ruxandra Neatu
Edel A. O’Toole
Albert C. M. Ong
Alistair T. Pagnamenta
Shamima Rahman
Neil Rajan
Peter N. Robinson
Mina Ryten
Omid Sadeghi-Alavijeh
John A. Sayer
Claire L. Shovlin
Jenny C. Taylor
Omri Teltsh
Ian Tomlinson
Arianna Tucci
Clare Turnbull
Albertien M. van Eerde
James S. Ware
Laura M. Watts
Andrew R. Webster
Sarah K. Westbury
Sean L. Zheng
Mark Caulfield
Damian Smedley