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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
1 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2723-2729
Number of pages7
JournalBrain
Volume146
Issue number7
Early online date17 Feb 2023
DOIs
Publication statusPublished - 03 Jul 2023

Bibliographical note

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

Keywords

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

Cite this