A pilot study of expanded newborn screening for 573 genes related to severe inherited disorders in China: results from 1,127 newborns

Luo, Xiaomei; Sun, Yu; Xu, Feng; Guo, Jun; Lin, Liang-In; Wang, Qisheng; Ye, Jun; Gu, Xuefan; Yu, Yongguo

doi:10.21037/atm-20-1147

Cited by 28 publications

(22 citation statements)

References 30 publications

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“…However, it is noteworthy that patients with PCD are also easily missed during NBS because the C0 levels at birth could be affected by the maternal concentration, and therefore, cannot reflect the true levels of the newborns themselves. Luo et al [ 22 ] recently conducted a pilot study in which genetic screening was performed on only 1127 neonates using targeted next-generation sequencing (NGS), and one PCD case of false-negative (C0 = 11.6 μmol/L) was identified. Therefore, NBS for PCD faces challenges, and combining NBS with genetic testing is crucial to improve screening efficiency.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Lin¹,

Lin²,

Chen³

et al. 2021

Orphanet J Rare Dis

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Background Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected through NBS. Results A total of 548 247 newborns were screened for PCD between January 2014 and June 2021; 1714 newborns with low free carnitine (C0) levels were called back and 49 patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China, was estimated to be 1 in 11 189 newborns. NBS results showed that the 49 patients had varying degrees of decreased C0 levels, whereas seven patients exhibited normal C0 levels during the recall review. All patients harbored biallelic pathogenic variants of the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in these 49 patients, and most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants had an allele frequency of 86.73%. The most common variant was c.760C > T (p.R254*) with an allele frequency of 31.63%, followed by c.51C > G (p.F17L) (17.35%) and c.1400C > G (p.S467C) (16.33%). The C0 level of patients with the N/N genotype was significantly lower than that of the M/M group. The C0 levels of patients with genotypes of R254*/R254* and R254*/F17L were far lower than those of patients with the R254*/S467C genotype. Conclusions This study presented more than 500,000 NBS data with the latest incidence of 1:11 189 in the Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population has been updated. Patients with null variants were associated with low C0 levels. Combining NBS with genetic testing is critical to improve screening efficiency because patients with PCD may have normal C0 levels during NBS and recall review.

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Section: Discussionmentioning

confidence: 99%

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Lin¹,

Lin²,

Chen³

et al. 2021

Orphanet J Rare Dis

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“…Using NBGS, 4 cases were diagnosed with MMA, PCD and WD that had been missed by C-NBS. It has been reported that the determination of MMA by MS/MS has been affected by several factors, and one case was missed due to the concentrations of C3 and C3/C0 decrease with age [ 46 , 47 ]. However, unlike metabolites, genetic screening was sufficiently accurate and specific for inborn disorders because it does not vary with age, season or maternal status.…”

Section: Discussionmentioning

confidence: 99%

Application of a next-generation sequencing (NGS) panel in newborn screening efficiently identifies inborn disorders of neonates

Huang

Zhu

et al. 2022

Orphanet J Rare Dis

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Background Newborn screening (NBS) has been implemented for neonatal inborn disorders using various technology platforms, but false-positive and false-negative results are still common. In addition, target diseases of NBS are limited by suitable biomarkers. Here we sought to assess the feasibility of further improving the screening using next-generation sequencing technology. Methods We designed a newborn genetic sequencing (NBGS) panel based on multiplex PCR and next generation sequencing to analyze 134 genes of 74 inborn disorders, that were validated in 287 samples with previously known mutations. A retrospective cohort of 4986 newborns was analyzed and compared with the biochemical results to evaluate the performance of this panel. Results The accuracy of the panel was 99.65% with all samples, and 154 mutations from 287 samples were 100% detected. In 4986 newborns, a total of 113 newborns were detected with biallelic or hemizygous mutations, of which 36 newborns were positive for the same disorder by both NBGS and conventional NBS (C-NBS) and 77 individuals were NBGS positive/C-NBS negative. Importantly, 4 of the 77 newborns were diagnosed currently including 1 newborn with methylmalonic acidemia, 1 newborn with primary systemic carnitine deficiency and 2 newborns with Wilson’s disease. A total of 1326 newborns were found to be carriers with an overall carrier rate of 26.6%. Conclusion Analysis based on next generation sequencing could effectively identify neonates affected with more congenital disorders. Combined with C-NBS, this approach may improve the early and accurate identification of neonates with inborn disorders. Our study lays the foundation for prospective studies and for implementing NGS-based analysis in NBS.

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“…Moreover, the PPV of NBS calculated based on the results of the G6PD activity measurements and genotyping did not differ significantly in our study, indicating the consistency of these two diagnostic methods. However, more comprehensive genotyping would be desirable in future studies or in clinical practice, particularly in the era of high-throughput sequencing where hundreds or even thousands of genes could be screened simultaneously at a reasonable cost (Luo et al, 2020). Simultaneous evaluation of G6PD activity and genotype will advance our knowledge of the genotype-phenotype correlations in G6PD deficiency.…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

Wang

Xia

et al. 2021

Front. Genet.

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Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymatic defect. The purpose of this study was to evaluate the profile of G6PD deficiency and investigate the factors associated with the accuracy of newborn screening (NBS) in Xiamen, China.Methods: A total of 99,546 newborns were screened by modified fluorescent spot test at the Women and Children’s Hospital, Xiamen University. High-risk neonates were recalled for diagnosis by either a measurement of G6PD activity or genetic testing for the presence of pathogenic G6PD variants using a quantitative G6PD enzymatic assay or the MeltPro® G6PD assay, respectively.Results: In the first-tier screening, 1,256 newborns were categorized as high risk. Of these, 1,051 were diagnosed with G6PD deficiency, indicating a prevalence of 1.39% in Xiamen, China. Among the 1,013 neonates who underwent genotyping, 851 carried hemizygous, heterozygous, homozygous, or compound heterozygous variants, for a positive predictive value (PPV) of 84.01%. In total, 12 variants and 32 genotypes were identified, and the six most common variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.871G>A, and c.392G>T, which accounted for approximately 94% of the identified alleles. Different variants showed characteristic enzymatic activities, although high phenotypic heterogeneity was observed for each variant. The use of cold-chain transportation significantly improved the PPV of NBS.Conclusions: We determined the profile of G6PD deficiency in Xiamen, including the prevalence, variant spectrum, and genotype-phenotype correlations and confirmed that maintaining a low temperature during sample transport is essential to ensure the high screening accuracy of NBS. Our data provides epidemiological, genotypic, phenotypic, and clinical practice references to standardize future interventions for G6PD deficiency.

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A pilot study of expanded newborn screening for 573 genes related to severe inherited disorders in China: results from 1,127 newborns

Cited by 28 publications

References 30 publications

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Application of a next-generation sequencing (NGS) panel in newborn screening efficiently identifies inborn disorders of neonates

Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

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