Genetic Diagnosis of Familial Hypercholesterolemia in Residual Newborn Dried Blood Spots

Newborn screening for familial hypercholesterolemia (FH) would dramatically increase the diagnosis of a common, potentially fatal but highly treatable genetic condition in newborns and relatives.

To report the results of genetic testing of residual newborn screening dried blood spots (DBS) with biomarkers suggesting high risk for FH as an initial step toward development of multitier newborn screening for FH.

A cross-sectional study design from July 2021 to July 2022 was used to test residual DBS from newborns with sample collection between 24 and 72 hours of life for total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B. Principal component analysis identified biomarker combinations that accounted for the greatest variance. Mahalanobis distance was calculated to generalize the idea of a standardized z score of a single variable to several correlated variables; approximately 8% of samples with the greatest positive Mahalanobis distance were selected for genetic FH testing. The study included a population-based screening for newborns in Wisconsin. Study data were analyzed from July 2022 to June 2024.

Newborn residual DBS were tested for total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B, with a subset tested for pathogenic variants in 8 genes associated with FH.

Prevalence of pathogenic variants for FH in a population-based sample of newborn screening DBS.

Of 59 927 total newborns, DBS samples were obtained from 10 004 newborns (mean [SD] age, 27.8 [5.6] hours; 5142 male [51.4%]). From 10 004 specimens tested, principal component analysis demonstrated the combination of low-density lipoprotein cholesterol and apolipoprotein B accounted for the greatest variance, and 768 specimens were selected for genetic testing. A pathogenic variant for FH was found in 16 samples yielding a population-based prevalence of 1 in 625 (1.6 per 1000; 95% CI, 0.91-2.60 per 1000) newborns. Pathogenic variants were distributed throughout the entire range of Mahalanobis scores selected for genetic testing.

This cross-sectional study found that screening newborns for FH using first-tier biochemical testing with reflex second-tier genetic testing was feasible and, in this population, identified 1 in 625 newborns with FH. Further refinement and validation are needed before implementation in newborn screening. Routine newborn screening for FH would substantially increase diagnosis of this common, potentially fatal, yet readily treatable condition while providing opportunities for cascade screening.