Actionable Genotypes and Their Association with Life Span in Iceland

This population-based genomic study assessed the prevalence, pathogenicity, and survival impact of actionable variants in 73 genes from the ACMG Secondary Findings v3.0 list across 57,933 Icelanders. Manual curation identified 235 pathogenic or likely pathogenic variants in 53 genes, found in 2306 participants (4.0%). Cancer-related genotypes especially in BRCA2 and BRCA1, were associated with ~3-year reductions in median survival and increased cancer-attributed mortality. Selected cardiovascular variants (e.g. LDLR, MYBPC3) also modestly reduced lifespan. Conversely, most variants in the cardiovascular, metabolic, and miscellaneous groups showed limited survival impact. Variant impact on cause of death was confirmed via Icelandic Death Registry data. Additionally, 10 candidate variants outside the ACMG list (e.g. F5 Leiden, PKD1, GCK) showed strong disease associations and mortality implications, suggesting future inclusion. Findings support reporting actionable genotypes beyond diagnostic sequencing contexts to improve public health through targeted prevention.

This population-based genomic study assessed the prevalence, pathogenicity, and survival impact of actionable variants in 73 genes from the ACMG Secondary Findings v3.0 list across 57,933 Icelanders. Manual curation identified 235 pathogenic or likely pathogenic variants in 53 genes, found in 2306 participants (4.0%). Cancer-related genotypes especially in BRCA2 and BRCA1, were associated with ~3-year reductions in median survival and increased cancer-attributed mortality. Selected cardiovascular variants (e.g. LDLR, MYBPC3) also modestly reduced lifespan. Conversely, most variants in the cardiovascular, metabolic, and miscellaneous groups showed limited survival impact. Variant impact on cause of death was confirmed via Icelandic Death Registry data. Additionally, 10 candidate variants outside the ACMG list (e.g. F5 Leiden, PKD1, GCK) showed strong disease associations and mortality implications, suggesting future inclusion. Findings support reporting actionable genotypes beyond diagnostic sequencing contexts to improve public health through targeted prevention.