Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum.

ABSTRACT

OBJECTIVE: Familial Hypercholesterolemia (FH) is a common lipid metabolism disease, resulting in premature atherosclerosis, even from childhood. We aimed to define the genetic basis of FH in children and their families, to refine the spectrum of Low-Density Lipoprotein Receptor gene (LDLR) mutations and identify genotype-to-phenotype correlations in patients of Greek origin. METHODS: LDLR was analyzed in 561 patients from 262 families, by whole-gene sequencing. RESULTS: Children with identified LDLR mutations showed higher lipid levels compared to non-carriers. Molecular analysis identified a mutation in 53.4% of index cases. Twenty six LDLR mutations were identified, including 19 point mutations, 2 nonsense mutations, 3 splice site mutations and 2 small insertions. Amongst patients with common mutations, carriers of c.1646G > A and c.1285G > A showed higher lipid levels, whereas carriers of c.858C > A and c.81C > G showed a milder phenotype. CONCLUSIONS: The spectrum of LDLR mutations in Greece is refined and expanded, with more patients analyzed by whole-gene sequencing. Although a quick screening method is feasible for the Greek population, whole-gene sequencing is essential to identify rare variants. Children with border line lipid levels and a family history of hypercholesterolemia should be considered for molecular diagnosis, since carriers of certain mutations show milder phenotypes and may be missed during clinical diagnosis.