Unexpected frequency of the pathogenic <i>AR</i> CAG repeat expansion in the general population
Matteo Zanovello, Kristina Ibáñez, Anna‐Leigh Brown, Prasanth Sivakumar, Alessandro Bombaci, Liana Santos, Joke J.F.A. van Vugt, Giuseppe Narzisi, Ramita Karra, Sonja W. Scholz, Jinhui Ding, J. Raphael Gibbs, Adriano Chiò, Clifton L. Dalgard, Ben Weisburd, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, Freya Boardman-Pretty, C. R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, Robert B. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, Sarah E A Leigh, Ivonne U S Leong, Javier F Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A Odhams, Christine Patch, Mariana Buongermino Pereira, D. Perez-Gil, J. Pullinger, T. Rahim, Augusto Rendon, Tim Rogers, K. Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, Matthew J Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M Wood, Wouter van Rheenen, Sara L. Pulit, Annelot M. Dekker, Ahmad Al Khleifat, William J. Brands, Alfredo Iacoangeli, Kevin P. Kenna, Erşen Kavak, Maarten Kooyman, Russell L. McLaughlin, Bas Middelkoop, Matthieu Moisse, Raymond D. Schellevis, Aleksey Shatunov, William Sproviero, Gijs H.P. Tazelaar, Rick A A Van der Spek, Perry T C Van Doormaal, Kristel R. van Eijk, Joke J.F.A. van Vugt, A Nazli Basak, Ian P. Blair, Jonathan D. Glass, Orla Hardiman, Winston Hide, John E. Landers, Jesús S. Mora, Karen Morrison
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.