Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population
Authors: Zanovello Matteo , Ibáñez Kristina , Brown Anna-Leigh , Sivakumar Prasanth , Bombaci Alessandro , Santos Liana , van Vugt Joke J F A , Narzisi Giuseppe , Karra Ramita , Scholz Sonja W , Ding Jinhui , Gibbs J Raphael , Chiò Adriano , Dalgard Clifton , Weisburd Ben ,   The American Genome Center (TAGC) consortium, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, The NYGC ALS Consortium, Ambrose John C , Arumugam Prabhu , Bevers Roel , Bleda Marta , Boardman-Pretty Freya , Boustred Christopher R , Brittain Helen , Caulfield Mark J , Chan Georgia C , Elgar Greg , Fowler Tom , Giess Adam , Hamblin Angela , Henderson Shirley , Hubbard Tim J P , Jackson Rob , Jones Louise J , Kasperaviciute Dalia , Kayikci Melis , Kousathanas Athanasios , Lahnstein Lea , Leigh Sarah E A , Leong Ivonne U S , Lopez Javier F , Maleady-Crowe Fiona , McEntagart Meriel , Minneci Federico , Moutsianas Loukas , Mueller Michael , Murugaesu Nirupa , Need Anna C , O’Donovan Peter , Odhams Chris A , Patch Christine , Pereira Mariana Buongermino , Perez-Gil Daniel , Pullinger John , Rahim Tahrima , Rendon Augusto , Rogers Tim , Savage Kevin , Sawant Kushmita , Scott Richard H , Siddiq Afshan , Sieghart Alexander , Smith Samuel C , Sosinsky Alona , Stuckey Alexander , Tanguy Mélanie , Tavares Ana Lisa Taylor , Thomas Ellen R A , Thompson Simon R , Tucci Arianna , Welland Matthew J , Williams Eleanor , Witkowska Katarzyna , Wood Suzanne M , Van Rheenen Wouter , Pulit Sara L , Dekker Annelot M , Khleifat Ahmad Al , Brands William J , Iacoangeli Alfredo , Kenna Kevin P , Kavak Ersen , Kooyman Maarten , McLaughlin Russell L , Middelkoop Bas , Moisse Matthieu , Schellevis Raymond D , Shatunov Aleksey , Sproviero William , Tazelaar Gijs H P , Van der Spek Rick A A , Van Doormaal Perry T C , Van Eijk Kristel R , Van Vugt Joke , Basak A Nazli , Blair Ian P , Glass Jonathan D , Hardiman Orla , Hide Winston , Landers John E , Mora Jesus S , Morrison Karen E , Newhouse Stephen , Robberecht Wim , Shaw Christopher E , Shaw Pamela J , Van Damme Philip , Van Es Michael A , Wray Naomi R , Al-Chalabi Ammar , Van den Berg Leonard H , Veldink Jan H , Hanna Michael G , Greensmith Linda , Phatnani Hemali , Veldink Jan H , Traynor Bryan J , Polke James , Houlden Henry , Fratta Pietro , Tucci Arianna 
Published: February 2023

Abstract
CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8–100%], specificity of 99% (95% CI 94.2–99.7%), and a positive predictive value of 97.4% (95% CI 84.4–99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309–1:4386, n = 117 734) X chromosomes—10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.