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

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

doi:10.1186/s12920-020-0710-5

Abstract

BackgroundPhenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear.MethodsWe 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.ResultsThe 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.ConclusionFurther research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.

Highlights

Generation sequencing (NGS) has revolutionized the genetic diagnosis for several diseases such as hearing loss, vision loss, cardiovascular disorders, and neurodegenerative disorders through testing of single genes, targeted gene panels, and whole exome sequencing [1, 2]
Since this study was limited to 44 centenarians of Ashkenazi Jewish descent, we evaluated the prevalence of established pathogenic and likely pathogenic variants in long-lived families of broad European descent in Long Life Family Study (LLFS), a family-based cohort study designed to evaluate genetic and environmental factors associated with exceptional survival to extend the generalizability of the previous study findings to a broader population
All 9 variants classified via American College of Medical Genetics and Genomics (ACMG) guidelines as likely pathogenic or pathogenic appeared in LLFS at similar frequencies to general population frequencies (Table 1)

Summary

Introduction

Generation sequencing (NGS) has revolutionized the genetic diagnosis for several diseases such as hearing loss, vision loss, cardiovascular disorders, and neurodegenerative disorders through testing of single genes, targeted gene panels, and whole exome sequencing [1, 2]. Large scale sequencing efforts are increasingly being used in several research studies that include participants in the general population without a strong family history or with subtle clinical presentations [3]. Carlson et al BMC Medical Genomics (2020) 13:61 penetrance of rare variants, in the absence of relevant family history, remains a major limitation in expanding large scale sequencing efforts beyond the narrowly defined clinical settings into the general population. Since this study was limited to 44 centenarians of Ashkenazi Jewish descent, we evaluated the prevalence of established pathogenic and likely pathogenic variants in long-lived families of broad European descent in Long Life Family Study (LLFS), a family-based cohort study designed to evaluate genetic and environmental factors associated with exceptional survival to extend the generalizability of the previous study findings to a broader population. Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear

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