Burden of Mendelian disorders in a large Middle Eastern biobank
<h3>Background</h3><p dir="ltr">Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.</p><h3>M...
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| منشور في: |
2024
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إضافة وسم
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| الملخص: | <h3>Background</h3><p dir="ltr">Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.</p><h3>Methods</h3><p dir="ltr">Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.</p><h3>Results</h3><p dir="ltr">We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.</p><h3>Conclusions</h3><p dir="ltr">This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.</p><h2>Other Information</h2><p dir="ltr">Published in: Genome Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13073-024-01307-6" target="_blank">https://dx.doi.org/10.1186/s13073-024-01307-6</a></p> |
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