What is the correct screening method for FH, depends on what you aim to find

This commentary refers to ‘LDL-cholesterol in newborns and children with genetically verified familial hypercholesterolaemia: implications for cholesterol-based screening’, by M. P. Bogsrud et al., https://doi.org/10.1093/eurheartj/ehaf815 and the discussion piece ‘Screening for familial hypercholesterolaemia’, by D. S. Wald and N. J. Wald, https://doi.org/10.1093/eurheartj/ehag080. We thank Wald et al. for their comment on our recent article on ‘LDL-cholesterol in newborns and children with genetically verified familial hypercholesterolaemia: implications for cholesterol-based screening’.1 Wald et al. state that ‘Population screening for FH relies on both cholesterol and mutation analysis’ with reference to their 2016 study, in which children 1–2 years of age were genetically screened by an FH gene panel, and only 43% had cholesterol levels above a 99.2 general population percentile.2 We agree with Wald that several children harbouring an FH mutation may present with only mildly elevated cholesterol levels at a single time-point measurement, which is also evident in our study. However, harbouring an FH mutation confers a substantially elevated risk even with cholesterol below the 99.2 percentile, as shown by Khera et al. in 2016.3 Individuals harbouring an FH mutation had a 2.2-fold increased risk of coronary artery disease, even at normal cholesterol levels. Furthermore, it is well known that cholesterol values might vary during the life course also among persons with FH. We previously showed that 8% of children with a pathogenic verified FH mutation had normal cholesterol levels at one-time measurement; however, after 8 years of follow-up, >70% of these children had initiated statin treatment, indicating that LDL-C had increased above treatment targets.4