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Ancestry-stratified variant classification in monogenic diabetes genes: Annotation coverage and differential curation burden

2026-08-23Artigo científico Acesso restrito
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datacite.subject.fosCiências Médicas
dc.contributor.authorDario, Paulo
dc.date.accessioned2026-09-30T13:50:04Z
dc.date.available2026-09-30T13:50:04Z
dc.date.issued2026-08-23
dc.description.abstractBackground: Variant databases ClinVar and gnomAD underpin clinical variant interpretation, but their composition is skewed toward European ancestry. Whether this produces systematic disadvantages for non-European patients with monogenic diabetes has not been examined at the database level with mutually exclusive ancestry groups. Objective: To quantify ClinVar annotation coverage and ancestry-stratified classification outcomes across monogenic diabetes genes, using mutually exclusive population-private variant groups. Methods: gnomAD v4.0 (genomes and exomes; 807,162 individuals) was cross-referenced with the ClinVar GRCh38 record (accessed June 29, 2026) for 16 monogenic diabetes (maturity-onset diabetes of the young [MODY]) genes, and variants were classified as population-private to European or non-European ancestry from ancestry-specific allele counts. Results: Across 54,865 gnomAD variants, 86.7% carried no ClinVar classification. The annotation gap was near-universal rather than ancestry-specific (unannotated fraction 89.4% European-private, 87.5% non-European-private). Among classified population-private variants, however, the pathogenic or likely pathogenic rate was 19.8% for European-private but only 8.6% for non-European-private variants (Fisher exact OR 2.6, 95% CI 2.1-3.3, p = 1 × 10- 1 8), with a higher uncertain-significance rate in non-European-private variants (52.1% vs. 45.8%). Conclusion: The dominant problem is therefore an annotation deficit affecting all ancestries; the ancestry inequity the data support is one of actionability, not of raw uncertain-significance rates. Closing it requires ClinVar submissions and population-specific sequencing from underrepresented populations.eng
dc.identifier.citationAnn Hum Genet. 2026 Aug 23. doi: 10.1111/ahg.70054. Online ahead of print
dc.identifier.doi10.1111/ahg.70054
dc.identifier.issn0003-4800
dc.identifier.pmid42634466
dc.identifier.urihttp://hdl.handle.net/10400.18/11356
dc.language.isoeng
dc.peerreviewedyes
dc.publisherWiley
dc.relation.hasversionhttps://onlinelibrary.wiley.com/doi/10.1111/ahg.70054
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectClinVar
dc.subjectAncestry
dc.subjectDiagnostic Disparity
dc.subjectgnomAD
dc.subjectMonogenic Diabetes
dc.subjectVariant Classification
dc.subjectDoenças Genéticas
dc.titleAncestry-stratified variant classification in monogenic diabetes genes: Annotation coverage and differential curation burdeneng
dc.typejournal article
dcterms.referenceshttps://github.com/Darocas76/monogenic-diabetes-variant-ancestry-analysis
dcterms.referenceshttps://doi.org/10.64898/2026.04.06.26350230
dspace.entity.typePublication
oaire.citation.startPage70054
oaire.citation.titleAnnals of Human Genetics
oaire.citation.volume0
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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