Rare disease gene association discovery in the 100,000 Genomes Project
Cipriani V., Vestito L., Magavern EF., Jacobsen JOB., Arno G., Behr ER., Benson KA., Bertoli M., Bockenhauer D., Bowl MR., Burley K., Chan LF., Chinnery P., Conlon PJ., Costa MA., Davidson AE., Dawson SJ., Elhassan EAE., Flanagan SE., Futema M., Gale DP., García-Ruiz S., Corcia CG., Griffin HR., Hambleton S., Hicks AR., Houlden H., Houlston RS., Howles SA., Kleta R., Lekkerkerker I., Lin S., Liskova P., Mitchison HH., Morsy H., Mumford AD., Newman WG., Neatu R., O’Toole EA., Ong ACM., Pagnamenta AT., Rahman S., Rajan N., Robinson PN., Ryten M., Sadeghi-Alavijeh O., Sayer JA., Shovlin CL., Taylor JC., Teltsh O., Tomlinson I., Tucci A., Turnbull C., van Eerde AM., Ware JS., Watts LM., Webster AR., Westbury SK., Zheng SL., Caulfield M., Smedley D.
Abstract Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, 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 Project2. 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 regulator3,4 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.