Abstract 15499: Biochemical and Genetic Newborn Screening for Familial Hypercholesterolemia

Introduction: Familial Hypercholesterolemia (FH) causes elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. Despite guidelines, universal screening rates remain low. Newborn screening could increase FH diagnostic rates.

Hypothesis: FH can be diagnosed from newborn dried blood spots for LDL-C, total cholesterol (TC), and apolipoprotein B (apoB), followed by selective genetic testing to identify pathogenic and likely pathogenic variants causing FH.

Methods: De-identified, residual newborn screening dried blood spots were analyzed for LDL-C, TC, and apoB with results expressed as multiples of the median (MoM). Mahalanobis distance (measuring MoM different from 1) was computed and the top 8% of distances selected for genetic testing (panel including LDLR , APOB , PCSK9 , LDLRAP1 , APOE , LIPA , ABCG5 , and ABCG8 ).

Results: A total of 10,004 specimens had biochemical testing, with 768 specimens selected for genetic testing. In total 15 variants were identified, 11 pathogenic and 4 likely pathogenic (Table 1). Composite Mahalanobis distance from LDL-C and apoB identified the most variants, followed by apoB alone and then LDL-C alone. TC alone identified the fewest number of variants (Table 2).

Conclusions: Testing newborn dried blood spots with biochemical and reflex genetic testing is feasible to detect FH. Genetic testing of about 8% of samples identified 1 in 667 newborns with FH, but more extensive genetic testing would likely detect more variants. Prospective studies are needed to correlate newborn results with LDL-C levels later in childhood.