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

Autor:	Zanovello M; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Ibáñez K; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK., Brown AL; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Sivakumar P; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Bombaci A; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.; 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin 10126, Italy., Santos L; Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK., van Vugt JJFA; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3508, The Netherlands., Narzisi G; Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA., Karra R; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Neurology, Brain Sciences Institute, Baltimore, MD 21287, USA., Scholz SW; Department of Neurology, Brain Sciences Institute, Baltimore, MD 21287, USA.; Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Ding J; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA., Gibbs JR; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA., Chiò A; 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin 10126, Italy., Dalgard C; Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA., Weisburd B; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MT 02142, USA., Hanna MG; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Greensmith L; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Phatnani H; Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA., Veldink JH; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht 3508, The Netherlands., Traynor BJ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Neurology, Brain Sciences Institute, Baltimore, MD 21287, USA., Polke J; Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK., Houlden H; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.; Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK., Fratta P; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK., Tucci A; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2023 Jul 03; Vol. 146 (7), pp. 2723-2729.
DOI:	10.1093/brain/awad050
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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