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

Abstract

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.

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

“…Based on NBS and diagnostic procedures in China (Wang, et al, 2021), infants with positive NBS results were recalled for diagnostic testing for G6PD deficiency. After obtaining informed consent from guardians, 555 infants (437 males and 118 females) with positive NBS results were recruited in 2020 in NBS center, Women and Children's Hospital of Xiamen University.…”

“…The reactions were performed on a SLAN-96 real-time PCR system (Hongshi, Shanghai, China). The PCR amplification and melting curve analyses have been described in detail in a previous report (Wang, et al, 2021).…”

“…Compared with G6PD activity testing, targeted genotyping has better sensitivity for diagnosing female heterozygotes (Xia, et al, 2016;Islam, et al, 2018). Previously, we reported the NBS program in Xiamen City and indicated a 1.39% prevalence of G6PD deficiency in this city (Wang, et al, 2021). Moreover, we noticed that in clinical practice of China, the diagnostic strategy (isolated or combined evaluation of G6PD activity and G6PD genotyping) varies and mainly depends on the opinions of physicians or the choice of guardians after genetic counseling.…”

“…However, the risk of hemolytic anemia can be minimized by timely diagnosis of G6PD deficiency because the intake of these foods and drugs can then be avoided. In China, newborn screening (NBS) for G6PD deficiency, in which a fluorescent spot test is used to evaluate G6PD activity in a dried blood spot sample (Wang, et al, 2021), is the first-tier test for the timely diagnosis of G6PD deficiency. As illustrated in our previous study, infants with positive screening results, who are considered at high risk for G6PD deficiency, are recalled and subjected to further diagnostic testing to identify the G6PD-deficient infants (Wang, et al, 2021).…”

“…In China, newborn screening (NBS) for G6PD deficiency, in which a fluorescent spot test is used to evaluate G6PD activity in a dried blood spot sample (Wang, et al, 2021), is the first-tier test for the timely diagnosis of G6PD deficiency. As illustrated in our previous study, infants with positive screening results, who are considered at high risk for G6PD deficiency, are recalled and subjected to further diagnostic testing to identify the G6PD-deficient infants (Wang, et al, 2021). In addition to G6PD-deficient infants, female infants with heterozygous pathogenic G6PD variants whose G6PD activity levels are normal should also be identified.…”