Abstract
Expanded newborn screening for inborn errors of metabolism (IEMs) by tandem mass spectrometry (MS/MS) could simultaneously analyze more than 40 metabolites and identify about 50 kinds of IEMs. Next generation sequencing (NGS) targeting hundreds of IMEs-associated genes as a follow-up test in expanded newborn screening has been used for genetic analysis of patients. The spectrum, prevalence, and genetic characteristic of IEMs vary dramatically in different populations. To determine the spectrum, prevalence, and gene mutations of IEMs in newborns in Suzhou, China, 401,660 newborns were screened by MS/MS and 138 patients were referred to genetic analysis by NGS. The spectrum of 22 IEMs were observed in Suzhou population of newborns, and the overall incidence (excluding short chain acyl-CoA dehydrogenase deficiency (SCADD) and 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD)) was 1/3,163. The prevalence of each IEM ranged from 1/401,660 to 1/19,128, while phenylketonuria (PKU) (1/19,128) and Mild hyperphenylalaninemia (M-HPA) (1/19,128) were the most common IEMs, followed by primary carnitine uptake defect (PCUD) (1/26,777), SCADD (1/28,690), hypermethioninemia (H-MET) (1/30,893), 3-MCCD (1/33,412) and methylmalonic acidemia (MMA) (1/40,166). Moreover, 89 reported mutations and 51 novel mutations in 25 IMEs-associated genes were detected in 138 patients with one of 22 IEMs. Some hotspot mutations were observed for ten IEMs, including PAH gene c.728G > A, c.611A > G, and c.721C > T for Phenylketonuria, PAH gene c.158G > A, c.1238G > C, c.728G > A, and c.1315+6T > A for M-HPA, SLC22A5 gene c.1400C > G, c.51C > G, and c.760C > T for PCUD, ACADS gene c.1031A > G, c.164C > T, and c.1130C > T for SCAD deficiency, MAT1A gene c.791G > A for H-MET, MCCC1 gene c.639+2T > A and c.863A > G for 3-MCCD, MMUT gene c.1663G > A for MMA, SLC25A13 gene c.IVS16ins3Kb and c.852_855delTATG for cittrullinemia II, PTS gene c.259C > T and c.166G > A for Tetrahydrobiopterin deficiency, and ACAD8 gene c.1000C > T and c.286C > A for Isobutyryl coa dehydrogenase deficiency. All these hotspot mutations were reported to be pathogenic or likely pathogenic, except a novel mutation of ACAD8 gene c.286C > A. These mutational hotspots could be potential candidates for gene screening and these novel mutations expanded the mutational spectrum of IEMs. Therefore, our findings could be of value for genetic counseling and genetic diagnosis of IEMs.
Highlights
Inborn errors of metabolism (IMEs) are a large group of monogenic diseases resulting in death and abnormalities of physical and neurological development at almost all stages of life
The sequencing library was quantified by Illumina DNA Standards and Primer Premix Kit (KAPA Biosystems, Boston, USA), and massively parallel sequenced on Illumina HiSeq 2500 system
PKU is an autosomal recessive genetic amino acid metabolic disorders (AAMDs) caused by deficiency of phenylalanine hydroxylase (PAH) (Blau et al, 2010)
Summary
Inborn errors of metabolism (IMEs) are a large group of monogenic diseases resulting in death and abnormalities of physical and neurological development at almost all stages of life. The introduction of tandem mass spectrometry (TMS) allows screening for more than 50 IMEs using dried blood spot in the neonatal period (Therrell et al, 2015). For the neonates screened to have IMEs, some serious clinical consequence could be prevented, including mild to severe irreversible mental retardation, lifelong disability, physical handicaps, coma, and early death, if early diagnosis and treatment were implemented (Therrell et al, 2015). Expanded newborn screening program covering dozens of diseases has been implemented in the majority of developed countries. Populationbased data are available in the United States (Centers for Disease Control and Prevention, 2008; Gallant et al, 2012; Hsu et al, 2013), Canada (Karaceper et al, 2016), United Kingdom (Sanderson et al, 2006), Germany (Lindner et al, 2008), France (Dhondt, 2010), Egypt (Hassan et al, 2016), Greece (Loukas et al, 2010), Saudi Arabia (Alfadhel et al, 2017), Australia (Wiley et al, 1999; Webster et al, 2003), South Korea (Yoon et al, 2005), Singapore (Lim et al, 2014), and Japan (Shibata et al, 2018)
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