Improving the yield of genetic testing in familial hypercholesterolaemia

This editorial refers to ‘Selection of individuals for genetic testing for familial hypercholesterolaemia: development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia’, by J. Besseling et al ., doi:10.1093/eurheartj/ehw135. Heterozygous familial hypercholesterolaemia (FH) is a common autosomal dominant disorder of LDL cholesterol (LDL-C) metabolism with an estimated prevalence of 1/500 to 1/200 in Caucasian populations.1 It is caused by deleterious heterozygous mutations in genes affecting LDL receptor function ( LDLR , APOB , or PCSK9 ).1 As a consequence, LDL-C levels are elevated from birth, which leads to premature cardiovascular disease (CVD) in those affected.2 Early interventions with lifestyle changes and statin treatment substantially attenuate this excess risk.3 Unfortunately, despite the WHO (World Health Organization) recommendation for large-scale screening almost two decades ago, FH is still severely underdiagnosed.1 Genetic cascade screening of first-degree relatives is an effective way to improve the identification of affected subjects.4 However, cost represents a major barrier to its implementation in many countries. The cost of genetic testing in an FH proband ranges from ∼€1600 in the UK6 to ∼€3100 in the USA.5 Cost-effectiveness analyses based on lipid and/or genetic screening approaches have estimated the incremental cost-effectiveness ratio for FH cascade screening to lie between ∼€3200 and ∼€460 000/life year gained.5,6 This is thought to be determined by three key factors: (i) the cost-effectiveness of treatment once FH is identified; (ii) the prevalence of FH in the screened population; and (iii) the accuracy of the screening test.6 When using current diagnostic criteria to select patients for genetic testing, mutation detection rates are variable, …