Atherosclerosis. 2021 Feb;319:108117. doi: 10.1016/j.atherosclerosis.2021.01.008. PMID: 33508743.
In brief: This multi-centre study included 2866 children with familial hypercholesterolemia (FH) from 8 European countries. The mutation spectrum was assessed, as were associations between gene mutations and clinical characteristics and pre and post-treatment lipid concentrations. The most common causes of FH were LDL receptor gene (LDLR) mutations, which were associated with a higher family history of premature coronary heart disease (CHD).
Comment: FH, an autosomal dominant disorder, is the most common inherited cause of premature CHD, and affects ~1:250 people of Northern European descent. Four genes involved in the clearance of LDL-C from the blood are known to cause FH: LDLR, which encodes the LDL receptor; the apolipoprotein B gene (APOB); gain-of-function mutations in PCSK9, encoding proprotein convertase subtilisin/kexin type 9; and a recently reported single mutation in the APOE gene.
In this cohort of children with a clinical diagnosis of FH, 88% had a confirmed genetic diagnosis. In all countries, the most common cause of FH was a mutation in LDLR. Overall, 297 LDLR mutations were reported, with extreme heterogeneity across countries. The prevalence of APOB mutations differed across countries, and also within each countries, yet the mutation was the same in 97% of affected individuals. The prevalence of mutations in PCSK9 was the lowest (0.3% of all mutations).
Higher baseline LDL cholesterol levels were observed in carriers of large insertion/deletion mutations than in carriers of promoter, splicing and missense mutations. LDL cholesterol levels were higher in those with LDLR mutations than APOB mutations. Nevertheless, responses to lipid-lowering therapy were similar between carriers of the various mutations. Moreover, LDLR mutations did not differ significantly in the likelihood of pathogenicity, based on American College of Medical Genetics criteria. However, an analysis based on functional class of the mutation showed differences in the proportions of children who achieved the LDL cholesterol target levels.
As genetic testing is not a part of the diagnostic workup for FH in many low- and middle-income countries, the findings of this work are reassuring. Most cases are due to mutations in LDLR, and most patients respond to statin therapy, with a significant decrease in LDL cholesterol. Therefore, the important tasks are clinical and biochemical screening for early diagnosis and early treatment (1). For those patients who respond poorly to statin therapy, genetic tests can be extended.
Reference: 1. Vuorio A, Ramaswami U, Holven KB. Editorial: Genetics of Familial Hypercholesterolemia: New Insight. 2021; 12(666).