G008 Population analysis of repeat expansions indicates increased frequency of pathogenic alleles across different populations
Year: 2024
Type: conference-abstract
Abstract: Background Repeat expansion disorders (REDs) include some of the most common inherited neurological diseases, affecting ~1 per 3,000 individuals. Prevalence studies of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and by technological limitations for screening large numbers of individuals. Aims We here study REDs frequency and distribution of different populations using a genomic-first approach. Methods We analyze REDs in 82,000 whole genome sequencing from two large-scale genomic dataset. We estimate RED prevalence globally and among different gene c ancestries (Europeans, Africans, South Asians, Americans and East Asians), and analyze the population-specific distribution of REDs. Results We found an overall disease allele frequency of REDs of ~1 in 300 individuals. Modelling disease prevalence using age at onset and survival, we show that the expected number of people with REDs is two to three times higher than currently reported figures, indica ng under-diagnosis and/or incomplete penetrance. While most REDs are represented in all broad gene c ancestries, the frequencies of intermediate alleles vary across populations, and correlate with the different frequency of expanded alleles. We study the sequence structure of HTT and show that they are associated with overall repeat lengths, which have variable proportions in different populations. Conclusion The finding that a much larger number of people in the general population carry pathogenic alleles of REDs has implications both for diagnosis and gene c counseling of RED, Variable prevalence of REDs in different populations might be explained at a molecular level by different alleles structures and distributions.
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, EUROSCA, network
Institutions: Queen Mary University of London, William Harvey Research Institute, Icahn School of Medicine at Mount Sinai, UCL Queen Square Institute of Neurology, University College London, UK Dementia Research Institute, St George's, University of London, Genomics England, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle University, National Hospital for Neurology and Neurosurgery, University of Iowa, Cardiff University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374536