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The New England Journal of MedicineActionable Genotypes and Their Association with Life Span in Iceland

In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available.

A recent study conducted in Iceland has shed light on the association between actionable genotypes and life span. The study, which involved an extensive analysis of the genomes of 57,933 Icelanders, has provided valuable insights into the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list.

Study Design

  • The study assessed the prevalence of coding and splice variants in genes on the ACMG SF v3.0 list in the genomes of 57,933 Icelanders.
  • Pathogenicity was assigned to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants).
  • The relationship between these genotypes and life span was assessed, and the specific causes of death among carriers were further examined.

Key Findings

  • Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, 235 actionable genotypes in 53 genes were identified.
  • Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype.
  • Shorter median survival was found among persons carrying actionable genotypes than among noncarriers.
  • Carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions.
  • Evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span was found.

HCN Medical Memo
Up to two-thirds of African American individuals are homozygous (CC) for the “Duffy” antigen genotype rs2814778 associated with white blood cell counts (WBCs) below the conventional reference range, constituting the well-described syndrome of “Benign Ethnic Neutropenia”.

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