Application of Next-Generation Sequencing Following Tandem Mass Spectrometry to Expand Newborn Screening for Inborn Errors of Metabolism: A Multicenter Study

Abstract

This study explored the effectiveness of expanding newborn screening (NBS) by tandem mass spectrometry (TMS) and gene diagnosis by next-generation sequencing (NGS). First, we described the characteristics of gene variants in Jiangsu Province. We collected clinical data from three NBS centers. All infants followed a unified screening and diagnosis process. After obtaining informed consent, dried blood spots (DBSs) were collected and analyzed by TMS. If the results fell outside of the cut-off value, repeat analysis was performed. If the re-test results remained abnormal, the infant was recalled for further assessment. We performed targeted sequencing using the extended edition panel of inborn errors of metabolism (IEM) to detect 306 genes using the Illumina HiSeq 2500 platform. A total of 536,008 babies underwent NBS by TMS in three NBS centres. In total, 194 cases were eventually diagnosed with various types of inherited metabolic diseases, with an overall incidence of 1/2763. There were 23 types of diseases, including ten amino acid disorders (43.5%), eight organic acidaemias (34.8%) and five fatty acid oxidation defects (21.7%). In these infants, we clearly identified variants of disease-causing genes by next-generation sequencing (NGS). Most had two variants and others had one or three variants: 88% of gene variants were heterozygous and 12% were homozygous. There is a certain incidence of IEM in Jiangsu Province and it is necessary to carry out screening for 27 diseases. Meanwhile, NGS combined with TMS offers an enhanced plan for NBS for IEM.

Newborn Screening for Genetic Diseases: An Overview of Current and Future Applications

“…A total of 1033 neonates were tested by NGS, followed by validation analyses by Sanger sequencing of positive findings. They identified the disease-causing genes of 194 cases for an overall incidence of 1:2763, which was higher than previously reported and suggesting that NGS allowed to identify additional cases [36]. Aminoacidopathies accounted for 43.5% of case findings, while 34.8% were organic acidemias and 21.7% were fatty acid oxidation disorders.…”

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency

“…NBS in Norway is based on informed consent, and allows for genetic mass screening of selected disorders to be performed without formal genetic counseling. It has been very useful in cystic fibrosis screening ( 28 ), in screening for metabolic disorders with limited numbers of disease genes ( 68 – 71 ), and for SCID screening with multiple disease genes. Analysis of biobanked samples from patients with known PIDs to evaluate the test methods, were performed retrospectively.…”

Two Infants With Beta-Ketothiolase Deficiency Identified by Newborn Screening in China

“…In China, the combination of MS/MS and NGS is considered to be a superior method for newborn screening. Beginning in 2014, we screened for diseases in this way and have successfully diagnosed and intervened in many metabolic diseases (Yang et al, 2019). In this study, MS/MS results suggested the possibility of BKTD, but abnormalities in blood acylcarnitine are not specific to BKTD.…”