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. Traynor; James Polke; Henry Houlden; Pietro Fratta; Arianna Tucci

doi:10.1093/brain/awad050

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^*, , , ,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	2723-2729
Number of pages	7
Journal	Brain
Volume	146
Issue number	7
DOIs	https://doi.org/10.1093/brain/awad050
Publication status	Published - 1 Jul 2023

Keywords

androgen receptor
bioinformatics
bulbar muscular atrophy
population genetics
spinal
whole-genome sequencing

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awad050Final published version, 642 KBLicence: CC BY

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Zanovello, M., Ibáñez, K., Brown, A. L., Sivakumar, P., Bombaci, A., Santos, L., van Vugt, J. J. F. A., Narzisi, G., Karra, R., Scholz, S. W., Ding, J., Gibbs, J. R., Chiò, A., Dalgard, C., Weisburd, B., Hanna, M. G., Greensmith, L., Phatnani, H., Veldink, J. H. (2023). Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population. Brain, 146(7), 2723-2729. https://doi.org/10.1093/brain/awad050

@article{02b2779d6b3344908353470e5f5d3f72,

title = "Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population",

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.",

keywords = "androgen receptor, bioinformatics, bulbar muscular atrophy, population genetics, spinal, whole-genome sequencing",

author = "Matteo Zanovello and Kristina Ib{\'a}{\~n}ez and Brown, {Anna Leigh} and Prasanth Sivakumar and Alessandro Bombaci and Liana Santos and {van Vugt}, {Joke J.F.A.} and Giuseppe Narzisi and Ramita Karra and Scholz, {Sonja W.} and Jinhui Ding and Gibbs, {J. Raphael} and Adriano Chi{\`o} and Clifton Dalgard and Ben Weisburd and Hanna, {Michael G.} and Linda Greensmith and Hemali Phatnani and Veldink, {Jan H.} and Traynor, {Bryan J.} and James Polke and Henry Houlden and Pietro Fratta and Arianna Tucci",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2023",

month = jul,

day = "1",

doi = "10.1093/brain/awad050",

language = "English",

volume = "146",

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Zanovello, M, Ibáñez, K, Brown, AL, Sivakumar, P, Bombaci, A, Santos, L, van Vugt, JJFA, Narzisi, G, Karra, R, Scholz, SW, Ding, J, Gibbs, JR, Chiò, A, Dalgard, C, Weisburd, B, Hanna, MG, Greensmith, L, Phatnani, H, Veldink, JH, Traynor, BJ, Polke, J, Houlden, H, Fratta, P, Tucci, A 2023, 'Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population', Brain, vol. 146, no. 7, pp. 2723-2729. https://doi.org/10.1093/brain/awad050

TY - JOUR

T1 - Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

AU - Zanovello, Matteo

AU - Ibáñez, Kristina

AU - Brown, Anna Leigh

AU - Sivakumar, Prasanth

AU - Bombaci, Alessandro

AU - Santos, Liana

AU - van Vugt, Joke J.F.A.

AU - Narzisi, Giuseppe

AU - Karra, Ramita

AU - Scholz, Sonja W.

AU - Ding, Jinhui

AU - Gibbs, J. Raphael

AU - Chiò, Adriano

AU - Dalgard, Clifton

AU - Weisburd, Ben

AU - Hanna, Michael G.

AU - Greensmith, Linda

AU - Phatnani, Hemali

AU - Veldink, Jan H.

AU - Traynor, Bryan J.

AU - Polke, James

AU - Houlden, Henry

AU - Fratta, Pietro

AU - Tucci, Arianna

PY - 2023/7/1

Y1 - 2023/7/1

N2 - 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.

AB - 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.

KW - androgen receptor

KW - bioinformatics

KW - bulbar muscular atrophy

KW - population genetics

KW - spinal

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85164209619&partnerID=8YFLogxK

U2 - 10.1093/brain/awad050

DO - 10.1093/brain/awad050

M3 - Article

C2 - 36797998

AN - SCOPUS:85164209619

SN - 0006-8950

VL - 146

SP - 2723

EP - 2729

JO - Brain

JF - Brain

IS - 7

ER -

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

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Keywords

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