Introduction: Familial hypercholesterolemia (FH) is a common genetic disorder characterized by hypercholesterolemia and markedly increased risk of cardiovascular disease. A causal mutation is mostly identified in the low-density-lipoprotein cholesterol receptor (LDLR) gene or in the apolipoprotein B (APOB) gene, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function (gof) mutations account for a small minority (<1 %). Genetic work-up in a cohort of FH patients in Cape Town yielded several novel PCSK9 mutations.
Hypothesis: The majority of these PCSK9 mutations are gof, to be confirmed by genetic cascade screening.
Methods: Individuals referred to the lipid clinic of Groote Schuur Hospital between 1980 and 2016 with clinically diagnosed FH underwent genetic analysis of the LDLR, and if applicable the APOB and PCSK9 genes. Families, in whom a PCSK9 mutation of unknown significance was found, underwent genetic cascade screening as well as laboratory and clinical assessments.
Results: A mutated FH allele was identified in 1232 persons; 1154 were in the LDLR and 43 in APOB. In 37 patients (3%) a non-synonymous PCSK9 mutation was found. Seven patients carried 1 of 4 different mutations published as gof. The remaining 30 FH patients carried one of 7 PCSK9 mutations of uncertain significance. Cascade screening has thus far identified another 39 carriers of PCSK9 mutation of unknown significance. The most prevalent novel mutation (G516V) was found in 6 index patients. Another 13 carriers of G516V were found during genetic cascading. LDLc was higher and tendon xanthoma more frequent in these 13 carriers as compared to their 21 unaffected relatives, with LDLc of 6.0 ± 2.2 vs 3.4 ± 0.80 mmol/L (p<0.001) and xanthoma prevalence of 46% vs 14% (p=0,041).
Conclusions: In a large cohort of patients with clinical FH PCSK9 mutations accounted for up to 3% of cases. Analyzing PCSK9 is likely to contribute to molecular diagnosis in South African FH patients without LDLR or APOB mutations. Pathogenicity is established for at least one novel prevalent mutation. Ongoing studies will determine whether the 6 other PCSK9 mutations, R97H, G177D, V200A, H553R, A594D and W566R, are pathogenic as well.