Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 17, 2023
- Source ID
- 10.1093/brain/awad050
Entities
People
- A Nazli Basak
- Adam Giess
- Adriano Chiò
- Afshan Siddiq
- Ahmad Al Khleifat
- Aleksey Shatunov
- Alessandro Bombaci
- Alexander Sieghart
- Alexander Stuckey
- Alfredo Iacoangeli
- Alona Sosinsky
- Ammar Al-chalabi
- Ana Lisa Taylor Tavares
- Angela Hamblin
- Anna C Need
- Anna-leigh Brown
- Annelot M Dekker
- Arianna Tucci
- Athanasios Kousathanas
- Augusto Rendon
- Bas Middelkoop
- Ben Weisburd
- Bryan J. Traynor
- Chris A Odhams
- Christine Patch
- Christopher E Shaw
- Christopher R Boustred
- Clifton L Dalgard
- Dalia Kasperaviciute
- Daniel Perez-gil
- Eleanor Williams
- Ellen R A Thomas
- Ersen Kavak
- Federico Minneci
- Fiona Maleady-crowe
- Freya Boardman-pretty
- Georgia C Chan
- Gijs H P Tazelaar
- Giuseppe Narzisi
- Greg Elgar
- Helen Brittain
- Hemali Phatnani
- Henry Houlden
- Ian P Blair
- Ivonne U S Leong
- J. Raphael Gibbs
- James Polke
- Jan H Veldink
- Javier F Lopez
- Jesus S Mora
- Jinhui Ding
- John C Ambrose
- John E. Landers
- John Pullinger
- Joke F A van Vugt
- Joke Van Vugt
- Jonathan D. Glass
- Karen E. Morrison
- Katarzyna Witkowska
- Kevin P Kenna
- Kevin Savage
- Kristel R Van Eijk
- Kristina Ibáñez
- Kushmita Sawant
- Lea Lahnstein
- Leonard H Van Den Berg
- Liana Santos
- Linda Greensmith
- Louise J Jones
- Loukas Moutsianas
- Maarten Kooyman
- Mariana Buongermino Pereira
- Mark J Caulfield
- Marta Bleda
- Matteo Zanovello
- Matthew J Welland
- Matthieu Moisse
- Melis Kayikci
- Meriel Mcentagart
- Michael A Van Es
- Michael G Hanna
- Michael Mueller
- Mélanie Tanguy
- Naomi R Wray
- Nirupa Murugaesu
- Orla Hardiman
- Pamela J. Shaw
- Perry T C Van Doormaal
- Peter O’donovan
- Philip Van Damme
- Pietro Fratta
- Prabhu Arumugam
- Prasanth Sivakumar
- Ramita Karra
- Raymond D Schellevis
- Richard H Scott
- Rick A A Van Der Spek
- Rob Jackson
- Roel Bevers
- Russell L Mclaughlin
- Samuel C Smith
- Sara L Pulit
- Sarah E A Leigh
- Shirley Henderson
- Simon R Thompson
- Sonja W. Scholz
- Stephen Newhouse
- Suzanne M Wood
- Tahrima Rahim
- The American Genome Center (tagc) Consortium, Genomics England Research Consortium, Project Mine Als Sequencing Consortium, The Nygc Als Consortium
- Tim J P Hubbard
- Tim Rogers
- Tom Fowler
- William J Brands
- William Sproviero
- Wim Robberecht
- Winston Hide
- Wouter Van Rheenen
Organizations
- Broad Institute
- Medical Research Council
- National Hospital for Neurology and Neurosurgery
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- Queen Mary University of London
- Uniformed Services University of the Health Sciences
- University College London
- University of Turin
- Utrecht University