Articles

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

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

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.

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Also Published In

Title
BMC Medical Genomics
DOI
https://doi.org/10.1186/s12920-020-0710-5

More About This Work

Published Here
December 20, 2022

Notes

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