G008 Population analysis of repeat expansions indicates increased frequency of pathogenic alleles across different populations

<h3>Background</h3> 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. <h3>Aims</h3> We here study REDs frequency and distribution of different populations using a genomic-first approach. <h3>Methods</h3> 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. <h3>Results</h3> 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. <h3>Conclusion</h3> 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.

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Published
2024-09-01
DOI
https://doi.org/10.1136/jnnp-2024-ehdn.230
Citations
1
Primary Topic
Molecular Biology Techniques and Applications
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article
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0.23
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article

G008 Population analysis of repeat expansions indicates increased frequency of pathogenic alleles across different populations

Kristina Ibáñez, Valentina Galassi Deforie, Bharati Jadhav, Andrea Cortese et al.
1 citations
Molecular Biology Techniques and Applications
0.23
article

G008 Population analysis of repeat expansions indicates increased frequency of pathogenic alleles across different populations

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

Abstract

<h3>Background</h3> 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. <h3>Aims</h3> We here study REDs frequency and distribution of different populations using a genomic-first approach. <h3>Methods</h3> 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. <h3>Results</h3> 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. <h3>Conclusion</h3> 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.

University of Iowa (US), St George's, University of London (GB), Queen Mary University of London (GB), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Foundation Center (US), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), Urology Foundation (GB), Child Health and Development Institute (US), UK Dementia Research Institute (GB), Muscular Dystrophy UK (GB), NIHR Newcastle Biomedical Research Centre (GB), Genomics England (GB), William Harvey Research Institute (GB), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), Cardiff University (GB), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 43%
Molecular Biology Techniques and Applications
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