Table 1.
Characteristics of supercentenarians.
Figure 1.
Pipeline to test supercentenarians for enrichment of rare protein-altering variants or genes harboring them.
All female Caucasian supercentenarian genomes were annotated for protein-altering variants. (A) To test for enrichment of a single variant, we filtered against dbSNP131 and compared each remaining rare protein-altering variant against 1000G EUR. No single variant was significantly enriched. (B) To test for enrichment of a gene with rare protein-altering variants, we collapsed all variants in to their respective genes and filtered against 1000G EUR (MAF<0.015). We tested for enrichment against 34 control genomes from PGP using the RVT1 burden test or a gene-based Fisher’s Exact (for recessive model). No gene was significantly enriched for rare protein-altering variants in supercentenarians. We then Sanger validated TSHZ3 as the best candidate from our burden-test for follow-up.
Figure 2.
Rare protein-altering variants in TSHZ3 in the Georgia Centenarian cohort versus NHLBI cohort.
To see if TSHZ3 is enriched for rare protein-altering variants in long-lived individuals, Sanger sequencing was performed on TSHZ3 in 99 Caucasians with extreme longevity (age 98–105). There was not a significant enrichment comparing the allele frequency of all rare protein-altering variants in the centenarians (4.0%; black bar) to 4300 Caucasian controls from the NHLBI exome project (2.5%; white bar). Both cohorts were annotated for protein-altering variants and filtered against 1000G EUR (MAF<0.015).
Table 2.
Baseline statistics of follow-up cohorts.
Table 3.
Protein-altering variants in TSHZ3 in Georgia Centenarian cohort.
Figure 3.
A supercentenarian with a known pathogenic mutation implicated in cardiomyopathy.
(A) Sanger validation confirmed that one supercentenarian possessed a known pathogenic mutation in a splice acceptor site of Desmocollin-2 (DSC2), a component of the myocardial desmosome. (B) This rare mutation has been reported in 2 independent cases of Arrhythmogenic Right Ventricular Cardiomyopathy and has been shown to cause cryptic splicing and mRNA degradation [54], [55].