Zanovello, Matteo;
Ibáñez, Kristina;
Brown, Anna-Leigh;
Sivakumar, Prasanth;
Bombaci, Alessandro;
Santos, Liana;
van Vugt, Joke JFA;
... Tucci, Arianna; + view all
(2023)
Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.
Brain
, 146
(7)
pp. 2723-2729.
10.1093/brain/awad050.
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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 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.
| Type: | Article |
|---|---|
| Title: | Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awad050 |
| Publisher version: | https://doi.org/10.1093/brain/awad050 |
| Language: | English |
| Additional information: | © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | androgen receptor, bioinformatics, population genetics, spinal and bulbar muscular atrophy, whole-genome sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165321 |
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