Abstract 11554: Biochemical and Molecular Newborn Screening for Familial Hypercholesterolemia

Abstract

Introduction: Familial Hypercholesterolemia (FH) is a common genetic disorder resulting in elevated low-density lipoprotein cholesterol (LDL-C) causing premature atherosclerosis. Despite guidelines, universal screening rates remain low. Newborn screening could increase FH diagnostic rates. Hypothesis: Biochemical newborn screening for LDL-C, total cholesterol (TC), and apolipoprotein B (apoB) followed by selective molecular testing identifies pathogenic and likely pathogenic variants causing FH. Methods: De-identified, residual newborn screening bloodspots collected for routine screening at 24-48 hours of life were analyzed for LDL-C, TC, and apoB. Values are expressed as multiples of median (MoM). Mahalanobis distance, measuring how far MoM values differed positively from 1, was computed. Samples with the most extreme Mahalanobis distance were selected for molecular testing (panel includes LDLR , APOB , PCSK9 , LDLRAP1 , APOE , STAP1 , LIPA , ABCG5 , and ABCG8 ). Results: Distributions of apoB, TC, and LDL-C from 5,248 samples are shown below (figure). ApoB followed a Gamma distribution; TC and LDL-C followed non-normal but symmetric distributions. ApoB and LDL-C accounted for 93% of variance among biomarkers. Of the first 2500 samples, 192 samples were selected for molecular testing; a pathogenic variant for monogenic FH was detected in 1 sample and risk factors for polygenic FH in 4 samples (table below). Conclusions: Pathogenic or likely pathogenic variants for FH were identified with an incidence of 1 in 500 in the first 2500 newborn specimens tested. Further study will determine if this two-tiered screening strategy adequately detects FH in newborns.