Applying targeted next generation sequencing to dried blood spot specimens from suspicious cases identified by tandem mass spectrometry-based newborn screening

Qian, Jicheng; Wang, Xiaonan; Liu, Jia; Zhong, Junyuan; Le, Yanqun; Tellier, Laurent; Liu, Chao; Jiang, Pingping; Gao, Rui; Wang, Yuan

doi:10.1515/jpem-2017-0003

Cited by 15 publications

(12 citation statements)

References 37 publications

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“…It can simultaneously carry out large-scale parallel sequencing of millions of DNA molecules. It was also recently proven to be valuable in explaining abnormal metabolite concentrations in NBS, as it enables the differentiation between affected patients and mere heterozygotes and has improved the turnaround time of genetic analyses (Qian et al, 2017; Smon et al, 2018). In this study, we designed and established a panel for IEM gene diagnosis based on NGS, which included 306 IEM disease-related genes.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Wang

et al. 2019

Front. Genet.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yang

Wang

et al. 2019

Front. Genet.

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“…It is known that the genetic variants related to IEMs are mainly detected by Sanger sequencing and MassARRAY ( Wright et al, 2008 ; Zhu et al, 2010 ; Shibbani et al, 2014 ; Mutlu-Albayrak et al, 2015 ). Recently, next generation sequencing (NGS) started to be applied for the clinical genetic analysis of IEMs ( Qian et al, 2017 ; Smon et al, 2018 ). Sanger sequencing is the golden standard to determine the DNA sequence, which is applied for the known gene locus in genetic analysis.…”

Section: Discussionmentioning

confidence: 99%

Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population

et al. 2018

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The incidence of inborn errors of metabolisms (IEMs) varies dramatically in different countries and regions. Expanded newborn screening for IEMs by tandem mass spectrometry (MS/MS) is an efficient approach for early diagnosis and presymptomatic treatment to prevent severe permanent sequelae and death. To determine the characteristics of IEMs and IEMs-associated mutations in newborns in Jining area, China, 48,297 healthy neonates were recruited for expanded newborn screening by MS/MS. The incidence of IEMs was 1/1178 in Jining, while methylmalonic acidemia, phenylketonuria, and primary carnitine deficiency ranked the top 3 of all detected IEMs. Thirty mutations in nine IEMs-associated genes were identified in 28 confirmed cases. As 19 cases with the mutations in phenylalanine hydroxylase (PAH), solute carrier family 22 member 5 (SLC22A5), and methylmalonic aciduria (cobalamin deficiency) cblC type with homocystinuria (MMACHC) genes, respectively, it suggested that mutations in the PAH, SLC22A5, and MMACHC genes are the predominant causes of IEMs, leading to the high incidence of phenylketonuria, primary carnitine deficiency, and methylmalonic acidemia, respectively. Our work indicated that the overall incidence of IEMs is high and the mutations in PAH, SLC22A5, and MMACHC genes are the leading causes of IEMs in Jining area. Therefore, it is critical to increase the coverage of expanded newborn screening by MS/MS and prenatal genetic consulting in Jining area.

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“…Therefore, tNGS may be uniquely suited as a primary modality (first-tier) to detect disorders for which a biochemical analyte is not currently measurable from DBS, or to improve first-tier biochemical tests (e.g. to reduce false positives) by providing supportive confirmatory sequence data relevant to those conditions currently screened [ 6 , [8] , [9] , [10] , [11] , [12] , [13] , [14] ].…”

Section: Introductionmentioning

confidence: 99%

Targeted next generation sequencing for newborn screening of Menkes disease

Parad

Kaler

Mauceli

et al. 2020

Molecular Genetics and Metabolism Reports

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Purpose Population-based newborn screening (NBS) allows early detection and treatment of inherited disorders. For certain medically-actionable conditions, however, NBS is limited by the absence of reliable biochemical signatures amenable to detection by current platforms. We sought to assess the analytic validity of an ATP7A targeted next generation DNA sequencing assay as a potential newborn screen for one such disorder, Menkes disease. Methods Dried blood spots from control or Menkes disease subjects ( n = 22) were blindly analyzed for pathogenic variants in the copper transport gene, ATP7A. The analytical method was optimized to minimize cost and provide rapid turnaround time . Results The algorithm correctly identified pathogenic ATP7A variants, including missense, nonsense, small insertions/deletions, and large copy number variants, in 21/22 (95.5%) of subjects, one of whom had inconclusive diagnostic sequencing previously. For one false negative that also had not been detected by commercial molecular laboratories, we identified a deep intronic variant that impaired ATP7A mRNA splicing. Conclusions Our results support proof-of-concept that primary DNA-based NBS would accurately detect Menkes disease, a disorder that fulfills Wilson and Jungner screening criteria and for which biochemical NBS is unavailable. Targeted next generation sequencing for NBS would enable improved Menkes disease clinical outcomes, establish a platform for early identification of other unscreened disorders, and complement current NBS by providing immediate data for molecular confirmation of numerous biochemically screened condition.

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Applying targeted next generation sequencing to dried blood spot specimens from suspicious cases identified by tandem mass spectrometry-based newborn screening

Cited by 15 publications

References 37 publications

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

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

Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population

Targeted next generation sequencing for newborn screening of Menkes disease

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