Newborn screening with targeted sequencing: a multicenter investigation and a pilot clinical study in China

Hao, Chanjuan; Guo, Ruolan; Hu, Xuyun; Zhan, Qimin; Guo, Qi; Liu, Xuanshi; Liu, Yuanhu; Sun, Yihong; Zhang, Xiaofen; Jin, Feng; Wu, Xiujie; Cai, Ren; Zeng, Dingyuan; Hu, Xi‐Jiang; Xiao-hua, Wang; Ji, Xiaoping; Li, Wenjie; Xing, Quansheng; Mu, Lanfang; Jiang, Xiulian; Xue, Yunxing; Yang, Weimin; Zhang, Yan; Yin, Qianli; Ni, Xin; Li, Wei

doi:10.1016/j.jgg.2021.08.008

Cited by 26 publications

(20 citation statements)

References 39 publications

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“…Notably, with the development of detection methodologies, the detection range and cost of genotyping are continuously increasing and decreasing, respectively. For example, high-throughput sequencing, in which hundreds of genes, including G6PD, can be simultaneously and comprehensively examined, has very recently been used for expanded newborn screening (Luo, et al, 2020;Hao, et al, 2021). In this context, the cost for each target gene is limited.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China

Xia

Wang

et al. 2022

Front. Genet.

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is caused by pathogenic variants of G6PD that result in decreased G6PD activity, is an X-linked inherited inborn error of metabolism that occurs worldwide. Individuals with G6PD deficiency and heterozygous females with normal G6PD activity (i.e., all individuals with pathogenic G6PD variants) are at risk of developing hemolytic anemia under increased oxidative challenge. However, this risk can be minimized by timely diagnosis. Currently, two assays are used to diagnose G6PD deficiency in China: evaluation of enzymatic activity and targeted genotyping. In terms of identification of all individuals with pathogenic G6PD variants, the performance and cost of different diagnostic strategies (isolated or combined evaluation of G6PD activity and G6PD genotyping) can vary, and these factors should be comprehensively evaluated. In this study, we examined 555 infants (437 males and 118 females) who were positive for the newborn screening of G6PD deficiency. We first evaluated the diagnostic performances of enzymatic testing and targeted genotyping. Both assays attained 100% specificities and positive predictive values for both male and female infants. In contrast, the sensitivities and negative predictive values (NPVs) of the diagnostic tests were different for male and female infants. For male infants, the sensitivities were 99.8 and 98.3%, and the NPVs were 94.1% and 69.6%, for enzymatic testing and targeted genotyping, respectively. For female infants, the sensitivities were 62.5% and 97.9%, and the NPVs were 37.9% and 91.7%, for enzymatic testing and targeted genotyping, respectively. We also evaluated the cost of the five different diagnostic strategies. The combination of G6PD activity testing of all infants, followed by genotyping of female infants with normal G6PD activity, attained high diagnostic sensitivity (99.8%) at a low cost (8.60 USD per diagnosed case). In the future, simultaneous examination of G6PD activity and whole-exon or whole-gene G6PD sequencing could become a standard clinical practice. Our data provide references for clinical practice on the standardization of current and future interventions for G6PD deficiency in China.

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Section: Discussionmentioning

confidence: 99%

Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China

Xia

Wang

et al. 2022

Front. Genet.

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“…Recently, newborn genomic sequencing (nGS) brings new opportunities to further expand newborn screening (NBS), which is an important public health project. 1 From 2013, BabySeq, 2 NBSeq, 3 NC NEXUS, 4 STATseq, 5 NESTS 6 and NeoSeq 7 successively confirmed that nGS could further expand the genetic diseases that could not be found by traditional screening methods and was considered as another innovation in the field of NBS. However, there are still many problems to be discussed and solved before large-scale clinical practice.…”

Section: Introductionmentioning

confidence: 91%

Molecular Genetic Screening of Neonatal Intensive Care Units: Hyperbilirubinemia as an Example

Yang¹,

Wang²,

Zhou³

et al. 2022

TACG

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Objective To explore the clinical value of newborn genomic screening (nGS) for neonatal intensive care units (NICU) infants (taking neonatal hyperbilirubinemia as an example). Methods Dried blood spots (DBSs) were collected after 72 hours of birth. The tandem mass spectrometry (TMS) screening and Angel Care genomic screening (GS, based on Targeted next-generation sequencing) were performed at the same time. Results Ninety-six hyperbilirubinemia newborns were enrolled in this study and none was identified with inborn errors of metabolism (IEM) by TMS, while 6 infants (6.25%, 6/96) were suspected to have a genetic disorder by Angel Care, including 2 cases of glucose-6-phosphate dehydrogenase deficiency (G6PD), and 1 case of maple syrup urine disease type 1B (MSUD1B), autosomal recessive deafness 1A (DFNB1A), Leber hereditary optic neuropathy (LHON), thyroid dyshormonogenesis 6 (TDH6) each. In addition, 44 infants (45.8%) were detected having at least one variant which conferred a carrier status for a recessive childhood-onset disorder. A total of 33 out of 60 variants (55.0%) reported for carrier status were pathogenic (P), 24 (40.0%) were likely pathogenic (LP), and 3 variants were variant of uncertain significance (VUS). Top six common genes of carrier status were GJB2, DUOX2, PRODH, ATP7B, SLC12A3, SLC26A4 . Two newborns showed abnormalities in elementary screening of TMS, but were confirmed as false positive after recall. Their results of Angel Care did not found abnormality. Conclusion Using neonatal hyperbilirubinemia as an example, genome sequencing screening can find more evidence of genetic variation in NICU newborns, and “Angel Care” is an effective method.

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“…The turnaround time of a primary report, including the sequencing period of < 7 days, was within 11 days. 54 Luo et al. also designed a panel of 573 genes related to severe inherited disorders, and performed NGS on 1127 individuals who had undergone biochemical NBS.…”

Section: Genetic Testing‐based Nbsmentioning

confidence: 99%

Newborn screening for genetic disorders: Current status and prospects for the future

Ding

Han

2022

Pediatric Investigation

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Newborn screening (NBS) is a public health service aimed at identifying infants with severe genetic disorders, thus providing effective treatment early enough to prevent or ameliorate the onset of symptoms. Current NBS uses biochemical analysis of dried blood spots, predominately with timeresolved fluorescence immunoassay and tandem mass spectrometry, which produces some false positives and false negatives. The application of enzymatic activity-based testing technology provides a reliable screening method for some disorders. Genetic testing is now commonly used for secondary or confirmatory testing after a positive result in some NBS programs. Recently, next-generation sequencing (NGS) has emerged as a robust tool that enables large panels of genes to be scanned together rapidly. Rapid advances in NGS emphasize the potential for genomic sequencing to improve NBS programs. However, some challenges still remain and require solution before this is applied for population screening.

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Newborn screening with targeted sequencing: a multicenter investigation and a pilot clinical study in China

Cited by 26 publications

References 39 publications

Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China

Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China

Molecular Genetic Screening of Neonatal Intensive Care Units: Hyperbilirubinemia as an Example

Newborn screening for genetic disorders: Current status and prospects for the future

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