Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:146 |
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| Enthalten in: |
Brain : a journal of neurology - 146(2023), 7 vom: 03. Juli, Seite 2723-2729 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zanovello, Matteo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.07.2023 Date Revised 12.09.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/brain/awad050 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353044792 |
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| 100 | 1 | |a Zanovello, Matteo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population |
| 264 | 1 | |c 2023 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 05.07.2023 | ||
| 500 | |a Date Revised 12.09.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 4 | |a androgen receptor | |
| 650 | 4 | |a bioinformatics | |
| 650 | 4 | |a population genetics | |
| 650 | 4 | |a spinal and bulbar muscular atrophy | |
| 650 | 4 | |a whole-genome sequencing | |
| 650 | 7 | |a Receptors, Androgen |2 NLM | |
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| 700 | 1 | |a Narzisi, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a Karra, Ramita |e verfasserin |4 aut | |
| 700 | 1 | |a Scholz, Sonja W |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Jinhui |e verfasserin |4 aut | |
| 700 | 1 | |a Gibbs, J Raphael |e verfasserin |4 aut | |
| 700 | 1 | |a Chiò, Adriano |e verfasserin |4 aut | |
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| 700 | 1 | |a Weisburd, Ben |e verfasserin |4 aut | |
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| 700 | 1 | |a Greensmith, Linda |e verfasserin |4 aut | |
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