• Familial hypercholesterolemia (FH);
  • low-density lipoprotein receptor (LDLR);
  • in silico;
  • novel variants;
  • genetics


Familial hypercholesterolemia (FH) is an autosomal dominant disease with a frequency of 1:500 in its heterozygous form. To date, mutations in the low-density lipoprotein receptor gene (LDLR) are the only identified causes of FH in the Greek population, causing high levels of low-density lipoprotein (LDL) and total cholesterol and premature atherosclerosis. The Greek FH population is genetically homogeneous, but most previous studies screened for the most common mutations only. The study aimed to characterize and assess novel LDLR variants. LDLR was examined by whole-gene DNA sequencing in 561 FH patients from 262 families of Greek origin. Novel LDLR variants were analyzed in silico using various software predicting pathogenicity and changes in protein stability. Twelve novel LDLR variants were identified, six of which are putative disease-causing variants: c.977C>G in exon 7, c.1124A>C in exon 8, c.1381G>T in exon 10, c.628_643dup{636del}, c.661–673dup in exon 4, and 13 c.1987+1_+33del in intron 13. All six putative variants were confirmed in the hypercholesterolemic members of the family. The results show that in silico analysis is a valuable tool to predict potential pathogenicity of novel variants, especially for populations that have not been extensively studied. The identification of novel pathogenic variants will facilitate the molecular diagnosis of FH from early childhood.