Exome sequencing of three cases of familial exceptional longevity

Summary Exceptional longevity ( EL ) is a rare phenotype that can cluster in families, and co‐segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long‐lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants ( RFV s) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFV s in all three families, APOB . Interestingly, APOB is a component of lipoprotein particles together with APOE , and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFV s. We have also identified candidate longevity genes shared between two families (5–13) or within individual families (66–156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC 1A , NRG 1 , RAD 52, RAD 51, NCOR 1 , and ADCY 5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.