دورية أكاديمية
Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population
| العنوان: | Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population |
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| المؤلفون: | 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, 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 |
| المساهمون: | 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, 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, Jame, Houlden, Henry, Fratta, Pietro, Tucci, Arianna |
| بيانات النشر: | Oxford University Press |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | androgen receptor, bioinformatics, population genetics, spinal and bulbar muscular atrophy, whole-genome sequencing |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/36797998; info:eu-repo/semantics/altIdentifier/wos/WOS:000980256600001; volume:146; issue:7; firstpage:2723; lastpage:2729; numberofpages:7; journal:BRAIN; https://hdl.handle.net/20.500.11768/159116Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85164209619; https://academic.oup.com/brain/article/146/7/2723/7043521?login=trueTest |
| DOI: | 10.1093/brain/awad050 |
| الإتاحة: | https://doi.org/20.500.11768/159116Test https://doi.org/10.1093/brain/awad050Test https://hdl.handle.net/20.500.11768/159116Test https://academic.oup.com/brain/article/146/7/2723/7043521?login=trueTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.7FF82288 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/brain/awad050 |
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