Unexpected frequency of the pathogenic <i>AR</i> CAG repeat expansion in the general population-Reference-Cited by-同舟云学术

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

Published:2023-02-17 Issue:7 Volume:146 Page:2723-2729
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Zanovello Matteo¹^ORCID,Ibáñez Kristina²,Brown Anna-Leigh¹,Sivakumar Prasanth¹,Bombaci Alessandro¹³,Santos Liana⁴,van Vugt Joke J F A⁵^ORCID,Narzisi Giuseppe⁶^ORCID,Karra Ramita⁷⁸,Scholz Sonja W⁸⁹^ORCID,Ding Jinhui⁷,Gibbs J Raphael⁷^ORCID,Chiò Adriano³,Dalgard Clifton¹⁰,Weisburd Ben¹¹,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 G¹,Greensmith Linda¹,Phatnani Hemali⁶,Veldink Jan H⁵,Traynor Bryan J⁷⁸,Polke James⁴,Houlden Henry¹⁴^ORCID,Fratta Pietro¹,Tucci Arianna¹²,

Affiliation:

1. Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK

2. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , London EC1M 6BQ , UK

3. ‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin , Turin 10126 , Italy

4. Neurogenetics Unit, National Hospital for Neurology and Neurosurgery , London WC1N 3BG , UK

5. Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University , Utrecht 3508 , The Netherlands

6. Center for Genomics of Neurodegenerative Disease, New York Genome Center , New York, NY 10013 , USA

7. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 , USA

8. Department of Neurology, Brain Sciences Institute , Baltimore, MD 21287 , USA

9. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 , USA

10. Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences , Bethesda, MD 20814 , USA

11. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MT 02142 , USA

Abstract

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.

Funder

UK Medical Research Council Clinician Scientist Fellowship

UK Medical Research Council Senior Clinical Fellowship and Lady Edith Wolfson Fellowship

UCLH NIHR Biomedical Research Centre

the Neurological Research Trust

KDUK

European Union’s Horizon 2020

National Institute on Aging

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)