A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening

Abstract

Background: A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population.

Methods: In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects.

Results: The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in DUOXA2, p.R885Q in DUOX2, p.Y439C in PCCB, p.R285Pfs*2 in SLC25A13, and p.R224Q in GALT.

Conclusions: Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.

Keywords: Epidemiology; Founder mutation; Incidence; Inherited metabolic disease; Newborn screening; Next-generation sequencing.

Fig. 1. Workflow for diagnosing inherited metabolic diseases. The study population represented about 22% of births (120,700/540,200) in Korea during the designated period. Using the integrated screening model, results were interpreted and divided into three groups: Association-Positive Cases (Cases with mutations in genes relevant to metabolites), Positive Cases with Discrepancy (Cases with mutations in genes irrelevant to metabolites), and Presumptive Positive Cases (Cases with only metabolite abnormalities). The numbers in brackets indicate the number of samples.

Abbreviations: 17α-OHP, 17α-hydroxyprogesterone; TSH, thyroid-stimulating hormone; FT4, free thyroxine; MS/MS, tandem mass spectrometry.

Fig. 2. Putative variant prioritization and pathogenicity classification. Pathogenic variants were prioritized based on conventional methods and the American College of Medical Genetics and Genomics criteria in (A) total samples (n=269), (B) association-positive cases (n=125), and (C) in positive cases with discrepancy (n=85). The numbers in brackets indicate the number of different types of variants.

Abbreviation: ACMG, American College of Medical Genetics and Genomics.