Unexpected frequency of the pathogenic AR 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 Dalgard, Ben Weisburd, Michael G Hanna, Linda Greensmith, Hemali Phatnani, Jan H Veldink, Bryan J TraynorJames Polke, Henry Houlden, Pietro Fratta, Arianna Tucci, Karen Morrison, The American Genome Center (TAGC) consortium, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, The NYGC ALS Consortium

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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.

Original languageEnglish
Pages (from-to)2723-2729
Number of pages7
Issue number7
Early online date17 Feb 2023
Publication statusPublished - 03 Jul 2023

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.


  • Humans
  • Male
  • Receptors, Androgen/genetics
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy
  • Polymerase Chain Reaction
  • Trinucleotide Repeat Expansion/genetics

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