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Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes

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dc.contributor.authorBrünger, Tobias
dc.contributor.authorIvaniuk, Alina
dc.contributor.authorPérez Palma, Eduardo
dc.contributor.authorMontanucci, Ludovica
dc.contributor.authorCohen, Stacey
dc.contributor.authorSmith, Lacey
dc.contributor.authorParthasarathy, Shridhar
dc.contributor.authorHelbig, Ingo
dc.contributor.authorNothnagel, Michael
dc.contributor.authorMay, Patrick
dc.contributor.authorLal, Dennis
dc.date.accessioned2026-08-19T19:34:45Z
dc.date.available2026-08-19T19:34:45Z
dc.date.issued2025
dc.description.abstractBackground: The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels, where variants and expert-curated clinical phenotypes are available, we also assess whether phenotype patterns of multiple disorders for each gene are conserved across variant positions within the gene family. Results: Mapping 590,000 pathogenic and 1.9 million population variants onto 9928 genes grouped into 2054 paralogous families increases the number of residues with classifiable evidence 5.1-fold compared with gene-specific data alone. The presence of a pathogenic variant in a paralogous gene is associated with a positive likelihood ratio of 13.0 for variant pathogenicity. Across ten genes encoding voltage-gated sodium channels and 22 expert-curated disorders, we identify cross-paralog correlated phenotypes based on 3D structure spatial position. For example, multiple established loss-of-function related disorders across SCN1A, SCN2A, SCN5A, and SCN8A show overlapping spatial variant clusters. Finally, we show that phenotype integration in paralog variant selection improves variant classification. Conclusion: Conserved pathogenic missense variants in paralogous genes provide robust, quantifiable support for clinical variant interpretation, and phenotype-informed mapping further improves predictions.
dc.description.versionVersión Publicada
dc.identifier.citationBrünger T, Ivaniuk A, Pérez-Palma E, Montanucci L, Cohen S, Smith L, Parthasarathy S, Helbig I, Nothnagel M, May P, Lal D. Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes. Genome Biol. 2025 Jul 7;26(1):197. doi: 10.1186/s13059-025-03663-x.
dc.identifier.doihttps://doi.org/10.1186/s13059-025-03663-x
dc.identifier.urihttps://hdl.handle.net/11447/11023
dc.language.isoen
dc.subjectACMG
dc.subjectGenetics
dc.subjectMissense
dc.subjectSodium channel
dc.subjectVariant classification
dc.titleConserved missense variant pathogenicity and correlated phenotypes across paralogous genes
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceGenome biology
dspace.entity.typePublication
relation.isAuthorOfPublication31623ebd-7791-4ceb-b04c-c69d7496b40f
relation.isAuthorOfPublication.latestForDiscovery31623ebd-7791-4ceb-b04c-c69d7496b40f

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