Increased frequency of repeat expansion mutations across different populations

Ibanez, Kristina, Jadhav, Bharati, Zanovello, Matteo, Gagliardi, Delia, Clarkson, Christopher, Facchini, Stefano, Garg, Paras, Martin-Trujillo, Alejandro, Gies, Scott, Galassi Deforie, Valentina, Dalmia, Anupriya, Hensman Moss, Davina J, Vandrovcova, Jana, Rocca, Clarissa, Moutsianas, Loukas, Marini-Bettolo, Chiara, Walker, Helen, Turner, Chris, Shoai, Maryam, Long, Jeffrey, EUROSCA network, Fratta, Pietro, Langbehn, Douglas, Tabrizi, Sarah, Caulfield, Mark, Cortese, Andrea, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, hardy, John, Houlden, Henry, Sharp, Andrew and Tucci, Arianna 2024. Increased frequency of repeat expansion mutations across different populations. Nature Medicine 30 , pp. 3357-3368. 10.1038/s41591-024-03190-5

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Abstract

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modeling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating underdiagnosis and/or incomplete penetrance. While some REDs are population specific, for example, Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (that is, Europeans, Africans, Americans, East Asians and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Nature Research
ISSN:	1078-8956
Date of First Compliant Deposit:	23 July 2024
Date of Acceptance:	11 July 2024
Last Modified:	10 Dec 2024 13:40
URI:	https://orca.cardiff.ac.uk/id/eprint/170838

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