Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC)

BACKGROUND AND AIMS Familial hypercholesterolaemia (FH) is an autosomal-dominant disease with frequency of 1/500 to 1/250 that leads to premature coronary heart disease. New approaches to identify FH mutation-carriers early are needed to prevent premature cardiac deaths. In a cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC), we evaluated the biochemical thresholds for FH screening in childhood, and modelled a two-stage biochemical and sequencing screening strategy for FH detection. METHODS From 5083 ALSPAC children with cholesterol measurement at age nine years, FH genetic diagnosis was performed in 1512 individuals, using whole-genome or targeted sequencing of known FH-causing genes. Detection rate (DR) and false-positive rate (FPR) for proposed screening thresholds (total-cholesterol > 1.53, or LDL-C > 1.84 multiples of the median (MoM)) were assessed. RESULTS Six of 1512 sequenced individuals had an FH-causing mutation of whom five had LDL-C > 1.84 MoM, giving a verification-bias corrected DR of 62.5% (95% CI: 25-92), with a FPR of 0.2% (95% CI: 0.1-0.4). The DR for the TC cut-point of 1.53 MoM was 25% (95% CI: 3.2-65.1) with a FPR of 0.4% (95% CI: 0.2-0.6). We estimated 13 of an expected 20 FH mutation carriers (and 13 of the 20 parental carriers) could be detected for every 10,000 children screened, with false-positives reliably excluded by addition of a next generation sequencing step in biochemical screen-positive samples. CONCLUSIONS Proposed cholesterol thresholds for childhood FH screening were less accurate than previously estimated. A sequential strategy of biochemical screening followed by targeted sequencing of FH genes in screen-positive children may help mitigate the higher than previously estimated FPR and reduce wasted screening of unaffected parents.