Prevalence of clinically actionable disease variants in exceptionally long-lived families

Paige Carlson, Mary K. Wojczynski, Todd Druley, Joseph H. Lee, Joseph M. Zmuda, Bharat Thyagarajan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear. Methods: We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher's exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases. Results: The proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families. Conclusion: Further research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.

Original languageEnglish (US)
Article number61
JournalBMC Medical Genomics
Issue number1
StatePublished - Apr 10 2020

Bibliographical note

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© 2020 The Author(s).


  • Incidental genetic findings
  • Long lived families
  • Pathogenic variants
  • Population studies


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