Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.
Brain
; 146(7): 2723-2729, 2023 07 03.
Article
en En
| MEDLINE
| ID: mdl-36797998
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 130 000 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 13182 (95% CI 12309-14386, 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 16887 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Atrofia Muscular Espinal
/
Receptores Androgénicos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
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Male
Idioma:
En
Revista:
Brain
Año:
2023
Tipo del documento:
Article
País de afiliación:
Reino Unido