LDL-cholesterol in newborns and children with genetically verified familial hypercholesterolaemia: implications for cholesterol-based screening

Cholesterol screening in children, with subsequent genetic testing of top percentile, has been suggested as an efficient universal screening approach in familial hypercholesterolaemia (FH). The potential cholesterol-based screening efficacy was investigated in a national genetically based screening programme.

Data were from the Norwegian national family cascade screening programme in FH children from 1998 to 2023. Cholesterol levels [umbilical cord in newborns (n = 113) and venous blood in children 1–12 years old (n = 1346)] in variant positive and variant negative children were compared.

LDL cholesterol (LDL-C) was higher in FH newborns vs non-FH newborns [1.22 (.48) vs .68 (.32) mmol/L, P < .001], but overlapped widely. Cut-off levels corresponding to the 95th and 85th percentile would only identify 55.7% and 75.4% of newborns with FH, respectively. Screening efficacy in newborns did not differ in subgroups: boys and girls, null and non-null variants, variant gene, and neither for total cholesterol nor for non-HDL cholesterol. In all other age groups (from 1 to 12 years), LDL-C discriminated highly between mutation FH and non-FH children. Cut-off levels corresponding to 95th and 85th percentile of LDL-C would identify 88.4% and 94.1% of 1–12-year-old children with FH, respectively.

Previous studies investigating lipid or genetic screening approaches for FH have limitations of only performing genetic testing in children with high LDL-C levels. The present study is the first to show the true LDL-C overlap in children with FH vs non-FH by utilizing unique data from a national family cascade screening programme. Cholesterol-based screening approaches for FH only seem feasible from 1 year of age onward.