rs4987076

Whole genome sequencing of 44 Ashkenazi Jewish centenarians identified 216 coding variants annotated as pathogenic or likely pathogenic in ClinVar. The study found 130 rare variants (MAF <5%) reported to cause degenerative, neoplastic, and cardiac diseases with various inheritance patterns. Notably, several carriers had no clinical manifestations despite carrying variants linked to serious diseases (e.g., an APOE ε4 homozygote without Alzheimer's disease, a UBQLN2 P525S carrier without ALS). These findings suggest incomplete penetrance and reduced clinical significance for many reported disease mutations.

This functional study investigated the effects of NAT1 (N-acetyltransferase 1) genetic polymorphisms in the coding region and 3'-UTR on enzyme activity, mRNA, and protein levels using recombinant expression in COS-1 cells. The 1088T>A (rs1057126) and 1095C>A (rs15561) variants slightly reduced NAT1 catalytic activity and expression levels. A 9-base pair deletion in the 3'-UTR reduced activity, while the 445G>A (rs4987076), 459G>A (rs4986990), and 640T>G (rs4986783) coding region haplotype increased activity. These findings provide biological support for previously reported associations of 1088T>A and 1095C>A polymorphisms with birth defects including oral clefts and limb deficiency.