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

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 1:30,303 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% C.I. 90.8-100%), specificity of 99% (95% C.I. 94.2-99.7%), and positive predictive value of 97.4% (95% C.I. 84.4-99.6%). We found the mutation frequency to be 1:3,182 (95% C.I. 1:2,309-1:4,386, n=117,734) X chromosomes – ten times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6,887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced prevalence, and/or pleomorphic clinical manifestations.

Brain. 2023 Feb 17;awad050. doi: 10.1093/brain/awad050. Online ahead of print.




Other Contributors

  • 1Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, WC1N 3BG London.
  • 2William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK.
  • 3“Rita Levi Montalcini” Department of Neuroscience, University of Turin, 10126 Turin, Italy.
  • 4Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, WC1N 3BG London, UK.
  • 5Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3508 Utrecht, The Netherlands.
  • 6New York Genome Center, New York, 10013 NY, USA.
  • 7Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892 MD, USA.
  • 8Department of Neurology, Brain Sciences Institute, Johns Hopkins Hospital, Baltimore, 21287 MD, USA.
  • 9Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892 MD, USA.
  • 10Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, 20814 Bethesda, MD.
  • 11Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142 MT, USA.