Details

Autor(en) / Beteiligte

• Zanovello, Matteo
• Ibáñez, Kristina
• Brown, Anna-Leigh
• Sivakumar, Prasanth
• Bombaci, Alessandro
• Santos, Liana
• van Vugt, Joke J F A
• Narzisi, Giuseppe
• Karra, Ramita
• Scholz, Sonja W
• Ding, Jinhui
• Gibbs, J Raphael
• Chiò, Adriano
• Dalgard, Clifton
• Weisburd, Ben
• Hanna, Michael G
• Greensmith, Linda
• Phatnani, Hemali
• Veldink, Jan H
• Traynor, Bryan J
• Polke, James
• Houlden, Henry
• Fratta, Pietro
• Tucci, Arianna

Titel

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

Ist Teil von

• Brain (London, England : 1878), 2023-07, Vol.146 (7), p.2723-2729

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. CAG repeat expansions in the AR gene cause spinal and bulbar muscular atrophy. Zanovello et al. establish a pipeline to detect AR CAG expansion from whole-genome sequencing data, and find the mutation frequency to be much higher than the reported disease prevalence, possibly due to underdiagnosis or pleomorphic manifestations.