Spectrum and Prevalence of Rare Variants and Their Association with Familial Dysbetalipoproteinemia.

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare variants and FD. Genetic data from 4720 subjects were used to identify rare variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, = 0.034) and variants of uncertain significance (median 1.38 mmol/L, = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of variants may advance our understanding of the genetic basis of FD and underscore the importance of gene sequencing in patients with lipid metabolism disorders.