Increased frequency of repeat expansion mutations across

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Authors

Kristina Ibañez, Bharati Jadhav, Matteo Zanovello, Delia Gagliardi, Christopher Clarkson, Stefano Facchini, Paras Garg, Alejandro Martin-Trujillo, Scott J Gies, Valentina Galassi Deforie, Anupriya Dalmia, Davina J Hensman Moss, Jana Vandrovcova, Clarissa Rocca, Loukas Moutsianas, Chiara Marini-Bettolo, Helen Walker, Chris Turner, Maryam Shoai, Jeffrey D Long, Pietro Fratta, Douglas R Langbehn, Sarah J Tabrizi, Mark J Caulfield, Andrea Cortese, Valentina Escott-Price, John Hardy, Henry Houlden, Andrew J Sharp, Arianna Tucci

Abstract

Nat Med. 2024 Oct 1. doi: 10.1038/s41591-024-03190-5. Online ahead of print.

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.

PMID:39354197 | DOI:10.1038/s41591-024-03190-5