DataSheet1_Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China.docx

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.

葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是一种在全球范围内流行的X连锁遗传性先天性代谢缺陷病，其致病机制为G6PD基因致病性变异导致酶活性降低。携带G6PD致病性变异的个体，包括G6PD缺乏症患者与酶活性正常的杂合子女性，在氧化应激负荷增加时均存在发生溶血性贫血的风险，但通过及时诊断可有效降低该风险。目前我国用于G6PD缺乏症诊断的检测手段主要有两种：酶活性检测与靶向基因分型。针对所有携带G6PD致病性变异个体的检出需求，不同诊断策略（单独或联合开展G6PD酶活性检测与G6PD基因分型）的诊断效能与检测成本存在差异，需进行综合评估。本研究纳入555例新生儿G6PD缺乏症筛查阳性的婴儿（其中男性437例，女性118例），首先评估了酶活性检测与靶向基因分型的诊断性能。结果显示，两种检测方法对男女婴儿均实现了100%的特异度与阳性预测值；但二者的灵敏度与阴性预测值（NPVs）在不同性别婴儿间存在显著差异。其中，男性婴儿的酶活性检测灵敏度为99.8%，靶向基因分型灵敏度为98.3%，对应的阴性预测值分别为94.1%与69.6%；女性婴儿的酶活性检测灵敏度为62.5%，靶向基因分型灵敏度为97.9%，对应的阴性预测值分别为37.9%与91.7%。本研究同时评估了五种不同诊断策略的检测成本。其中，先对所有婴儿开展G6PD酶活性检测，再对酶活性正常的女性婴儿进行基因分型的联合策略，以较低成本实现了99.8%的高诊断灵敏度，单确诊病例成本仅为8.60美元。未来，同步开展G6PD酶活性检测与全外显子或全基因G6PD测序或将成为临床常规诊疗手段。本研究数据可为我国当前及未来G6PD缺乏症干预措施的标准化临床实践提供参考依据。