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Familial hypercholesterolemia (FH) is a leading cause of premature atherosclerosis. Genetic defects in the LDLR, APOB and PCSK9 genes cause FH, and confirmation of a gene defect is essential for an indisputable diagnosis of the disease. FH is underdiagnosed and we aimed to revise the genetic defects that have been characterized in FH patients of Greek origin and define an effective, future strategy for genetic studies. A literature search was performed in MEDLINE and EMBASE on genetic studies with FH patients of Greek origin. To date, no APOB and PCSK9 mutations have been found in the Greek population. It must be noted however, that only a small number of patients has been screened for PCSK9 mutations. In total, 41 LDLR defects have been characterized, with 6 common mutations c.1646G>A (p.Gly546Asp), c.858C>A (p.Ser286Arg), c.81C>G (p.Cys27Trp), c.1285G>A (p.Va1429Met), c.517T>C (p.Cys173Arg), and c.1775G>A (p.Gly592G1u) that account for >80% of all mutations. Due to geographic isolation, founder mutations exist in a subpopulation in North West Greece and the Greek Cypriot population but not in the general population. Genetic testing should focus primarily on LDLR, and subsequently on PCSK9 and APOB. The Greek population is genetically homogeneous, which allows for a quick molecular diagnosis of the disease. Cascade screening is feasible and will certainly facilitate the identification of additional patients. (C) 2016 National Lipid Association. All rights reserved.

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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

{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.}