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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.

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