A probable cis-acting genetic modifier of Huntington disease frequent in individuals with African ancestry

Dawson, J., Baine-Savanhu, F. K., Ciosi, M. , Maxwell, A. , Monckton, D. G. and Krause, A. (2022) A probable cis-acting genetic modifier of Huntington disease frequent in individuals with African ancestry. Human Genetics and Genomics Advances, 3(4), 100130. (doi: 10.1016/j.xhgg.2022.100130) (PMID:35935919) (PMCID:PMC9352962)

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Huntington disease (HD)is a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine encoding CAG repeat in the huntingtin gene. Recently, it has been established that disease severity in HD is best predicted by the number of pure CAG repeats rather than total glutamines encoded. Along with uncovering DNA repair gene variants as trans-acting modifiers of HD severity, these data reveal somatic expansion of the CAG repeat as a key driver of HD onset. Using high-throughput DNA sequencing, we have determined the precise sequence and somatic expansion profiles of the HTT repeat tract of 68 HD-affected and 158 HD-unaffected African ancestry individuals. A high level of HTT repeat sequence diversity was observed, with three likely African-specific alleles identified. In the most common disease allele (30 out of 68), the typical proline-encoding CCGCCA sequence was absent. This CCGCCA-loss disease allele was associated with an earlier age of diagnosis of approximately 7.1 years and occurred exclusively on haplotype B2. Although somatic expansion was associated with an earlier age of diagnosis in the study overall, the CCGCCA-loss disease allele displayed reduced somatic expansion relative to the typical HTT expansions in blood DNA. We propose that the CCGCCA loss occurring on haplotype B2 is an African cis-acting modifier that appears to alter disease diagnosis of HD through a mechanism that is not driven by somatic expansion. The assessment of a group of individuals from an understudied population has highlighted population-specific differences that emphasize the importance of studying genetically diverse populations in the context of disease.

Item Type:Articles
Additional Information:This work is supported by grants to J.D. from the National Research Foundation (UID: 115568), the Faculty Research Committee, and the National Health Laboratory Service Research Trust (94639). This work was also supported by a self-initiated Research Trust Grant to A.K. from the South African Medical Research Council and a travel grant from the National Research Foundation (UID: 110654) and funding to D.G.M. from the CHDI Foundation.
Glasgow Author(s) Enlighten ID:Maxwell, Mr Alastair and Monckton, Professor Darren and Ciosi, Dr Marc
Authors: Dawson, J., Baine-Savanhu, F. K., Ciosi, M., Maxwell, A., Monckton, D. G., and Krause, A.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Human Genetics and Genomics Advances
Publisher:Elsevier (Cell Press)
ISSN (Online):2666-2477
Published Online:11 July 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Human Genetics and Genomics Advances 3(4): 100130
Publisher Policy:Reproduced under a Creative Commons License

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