Abstract
BackgroundFamilial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.ResultsA total of 29 gene sequence variants were reported in 117(76.0%) of the studied subjects. Eight different mutations (1 large rearrangement, 1 short deletion, 5 missense mutations, and 1 splice site mutation), and 21 variants. Eight gene sequence variants were reported for the first time and they were noticed in familial hypercholesterolemic patients, but not in controls (p.Asp100Asp, p.Asp139His, p.Arg471Gly, c.1705+117 T>G, c.1186+41T>A, 1705+112C>G, Dup exon 12 and p.Trp666ProfsX45). The incidence of the p.Arg471Gly variant was 11%. Patients with pathogenic mutations were younger, had significantly higher incidences of cardiovascular disease, xanthomas, and family history of hyperlipidemia, together with significantly higher total cholesterol and low density lipoprotein levels than patients with non-pathogenic variants.ConclusionsTwenty-nine gene sequence variants occurred among FH patients; those with predicted pathogenicity were associated with higher incidences of cardiovascular diseases, tendon xanthomas, and higher total and low density lipoprotein levels compared to the rest. These results provide preliminary information on the mutation spectrum of this gene among patients with FH in Malaysia.
Highlights
Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene
Tendon xanthoma (TX) was present in 40.9%, and xanthelasma occurred in 25.3%
Eighty control subjects were recruited with a mean age of 39.3 years, a mean total cholesterol (TC) level of 5.0 mmol/l, and a mean low-density lipoprotein cholesterol (LDL-C) level of 2.9 mmol/l
Summary
Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Familial hypercholesterolemia (FH) is caused by defects in the low-density lipoprotein receptor (LDLR) gene, which give rise to a well-characterized clinical phenotype [1]. The plasma levels of low-density lipoprotein cholesterol (LDL-C) in FH heterozygotes are lower and more dependent on other genetic and environmental factors than those in FH homozygotes. The nature of the molecular defect has some impact on the severity of hypercholesterolemia, FH heterozygotes with the same LDLR mutation can have widely different plasma levels of LDL-C. In all patients with FH caused by LDLR defects, phenotype severity seems to depend more on environmental factors than on the type of mutation [3]. The clinical diagnosis is not always evident, especially in young patients without physical stigmata, and molecular diagnostic techniques would be helpful in these cases [4]
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