Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population

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.

A rare mutation c.1663G>A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

“…Apart from our present study, there were another several articles that mentioned this mutation in a few cases, all of which were based on African populations. Wang et al described three patients, and noted that this was the most common mutation/a hotspot for mutations in MMUT in the Chinese population [7]. Chu et al…”

“…A recent global large size systematic literature review exposed that estimates of MMA (all types) detection rates were 1/126,582, 1/81967, 1/81967, and 1/16556 newborns in Asia-Paci c, Europe, North America and the Middle East and North Africa (MENA) regions, respectively [3]. The incidence of MMA in China varies signi cantly from region to region and was reported to be 1/38,667 in Shanghai [4], 1/46,531 in Zhejiang province [5], 1/6,032 in Henan province [6], 1/40166 in Jiangsu Suzhou district [7], 1/16,883 in Jiangsu Xuzhou district [8] and 1/5589 in Shandong Jining district [9]. The expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China.…”

A Korean child diagnosed with malonic aciduria harboring a novel start codon mutation following presentation with dilated cardiomyopathy

“…However, since 2003, early cases of MA have been diagnosed in the neonatal period owing to the introduction of nationwide newborn screening programs in many countries (Santer et al, 2003). MA is extremely rare with an estimated prevalence of less than 1 in 400,000 newborns occurring worldwide (Lee et al, 2017;Wang et al, 2019). In Korea, from 2006 to 2015, only six infants have been suspected of having MA as shown by the results of first tier newborn screening using TMS (Lee et al, 2017;Santer et al, 2003), resulting in a detection rate of 1/574,206.…”

A rare mutation c.1663G > A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

“…A recent global large size systematic literature review exposed that estimates of MMA (all types) detection rates were 1/126,582, 1/81,967, 1/81,967, and 1/16,556 newborns in Asia–Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively [ 3 ]. The incidence of MMA in China varies significantly from region to region and was reported to be 1/38,667 in Shanghai [ 4 ], 1/46,531 in Zhejiang province [ 5 ], 1/6,032 in Henan province [ 6 ], 1/40,166 in Jiangsu Suzhou district [ 7 ], 1/16,883 in Jiangsu Xuzhou district [ 8 ] and 1/5589 in Shandong Jining district [ 9 ]. The expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China.…”