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中华妇幼临床医学杂志(电子版) ›› 2024, Vol. 20 ›› Issue (02) : 200 -208. doi: 10.3877/cma.j.issn.1673-5250.2024.02.011

儿童罕见病及基因检测

新生儿葡萄糖-6-磷酸脱氢酶缺乏症筛查及基因突变特征分析
张禾璇1,†(), 杨雪1, 王侣金1, 李林洁1, 刘兴宇1   
  1. 1. 贵阳市妇幼保健院优生遗传科，贵阳　550001
  • 收稿日期:2023-10-08 修回日期:2024-02-20 出版日期:2024-04-01
  • 通信作者: 张禾璇

Screening and genetic mutation analysis of glucose-6-phosphate dehydrogenase deficiency in neonates

Hexuan Zhang1,†(), Xue Yang1, Lyujin Wang1, Linjie Li1, Xingyu Liu1   

  1. 1. Department of Eugenics and Genetics, Guiyang Maternity and Child Health Care Hospital, Guiyang 550001, Guizhou Province, China
  • Received:2023-10-08 Revised:2024-02-20 Published:2024-04-01
  • Corresponding author: Hexuan Zhang
  • Supported by:
    Clinical Special Project of Science and Technology Plan of Department of Science and Technology of Guizhou Provine(LC[2022]005); High-Level Innovative Youth Health Talent Training Program of Guiyang Health and Family Planning Commission([2022]001); Guiyang Science and Technology Plan Project([2023]48-25, [2023]028)
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引用本文：

张禾璇, 杨雪, 王侣金, 李林洁, 刘兴宇. 新生儿葡萄糖-6-磷酸脱氢酶缺乏症筛查及基因突变特征分析[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(02): 200-208.

Hexuan Zhang, Xue Yang, Lyujin Wang, Linjie Li, Xingyu Liu. Screening and genetic mutation analysis of glucose-6-phosphate dehydrogenase deficiency in neonates[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2024, 20(02): 200-208.

目的

探讨贵阳地区新生儿葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症发病情况和基因突变特点。

方法

选择2020年9月1日至2022年6月30日在贵阳市所有助产机构出生，并进行G6PD筛查的89 715例活产新生儿为研究对象。采集其足跟血滤纸干血斑标本(DBS)，采用荧光分析法定量初筛G6PD活性。对于G6PD≤27 U/dL的G6PD缺乏症初筛呈阳性新生儿，召回至贵阳市新生儿疾病筛查中心，采集空腹肘静脉血1～2 mL，采用G6PD/6-磷酸葡萄糖脱氢酶(6PGD)比值法与多色探针荧光熔解曲线(MMCA)法基因突变检测，进行新生儿G6PD缺乏症诊断。本研究经贵阳市妇幼保健院伦理委员会批准(科研伦理审查批件2021-56号)，并与新生儿监护人签订临床研究知情同意书。

结果

本研究89 715例新生儿中，G6PD缺乏症初筛阳性率为1.40%(1 254/89 715)，其中男性新生儿的初筛阳性率为1.85%(888/47 983)，女性为0.88%(366/41 732)，男性新生儿G6PD缺乏症初筛阳性率显著高于女性，并且差异有统计学意义(χ2＝153.52，P<0.001)。这1 254例G6PD缺乏症初筛阳性新生儿的召回复查率为74.96%(940/1 254)。940例被召回复查新生儿中，被确诊为G6PD缺乏症者为895例，召回确诊率为95.21%(895/940)，其中男性确诊率为98.10%(673/686)，女性为87.40%(222/254)；经G6PD/6PGD比值法被确诊为G6PD缺乏症者为694例，召回确诊率为73.83%(694/940)，其中男性确诊率为82.51%(566/686)，显著高于女性的50.39%(128/254)，并且差异有统计学意义(χ2＝98.94，P<0.001)；经MMCA法基因突变检测被确诊为G6PD缺乏症者为846例，召回确诊率为90.00%(846/940)，其中男性确诊率为95.48%(655/686)，显著高于女性的75.20%(191/254)，差异有统计学意义(χ2＝84.74，P<0.001)。846例经基因突变检测确诊为G6PD缺乏症新生儿中，G6PD基因单一突变型为13种和复合杂合突变为6种，排名前4位G6PD基因热点突变类型依次为c.1024C>T(235例，占27.78%)，c.1388G>A(205例，占24.23%)，c.95A>G(163例，占19.27%)，c.1376G>T(152例，占17.97%)。

结论

贵阳地区新生儿G6PD缺乏症初筛阳性者中，召回复查率较低。该地区G6PD缺乏症新生儿排名前4位的G6PD基因突变类型以c.1024C>T、c.1388G>A、c.95A>G、c.1376G>T为主。开展G6PD活性筛查及相关诊断检测，有利于新生儿G6PD缺乏症的早诊断、早治疗。

关键词: 葡糖磷酸脱氢酶, 葡糖磷酸脱氢酶缺乏, 新生儿筛查, G6PD基因型, 基因突变, 多色探针熔解曲线分析法, 婴儿，新生
Objective

To explore the incidence and genetic mutation characteristics of glucose-6-phosphate dehydrogenase (G6PD) deficiency in neonates of Guiyang area.

Methods

A total of 89 715 neonates born in all delivery institutions in Guiyang from September 1, 2020 to June 30, 2022 and screened for G6PD deficiency were selected as research subjects. Dried blood spot of heel blood (DBS) were collected from all neonates, and fluorescence analysis method was used for the initial quantitative screening of G6PD activity. Neonates who were positive for initial screening of G6PD deficiency with G6PD≤27 U/dL were recalled to the Guiyang Neonatal Disease Screening Center. And 1-2 mL of fasting peripheral venous blood was collected from each of them, and G6PD/6-phosphogluconate dehydrogenase (6PGD) ratio method and multicolor melting curve analysis (MMCA) gene mutation detection were conducted to diagnose G6PD deficiency in neonates. This study was approved by the Ethics Committee of Guiyang Maternity and Child Health Care Hospital (Approval No. 2021-56) and clinical research informed consents were obtained from the guardians of neonates.

Results

Among the 89 715 neonates, the positive of initial screening rate for G6PD deficiency was 1.40% (1 254/89 715), with males at 1.85% (888/47 983) and females at 0.88% (366/41 732). The positive rate of initial screening for G6PD deficiency of male was statistically higher than that of female, and the difference was statistically significant (χ2=153.52, P<0.001). Among the 1 254 newborns who were positive for initial screening of G6PD deficiency, the recall rate was 74.96% (940/1 254). Of those 940 recalled neonates, 895 cases were diagnosed as G6PD deficiency, with a recall diagnosis rate of 95.21% (895/940), and the recall diagnosis rate of male was 98.10% (673/686), and the rate of female was 87.40% (222/254). For 940 recalled neonates, 694 cases were diagnosed as G6PD deficiency by G6PD/6PGD ratio method, and the diagnosis rate of G6PD/6PGD ratio method was 73.83% (694/940). The diagnosis rate of male neonates by G6PD/6PGD ratio method was 82.51% (566/686), which was significantly higher than 50.39% (128/254) of female neonates, and the difference was statistically significant (χ2=98.94, P<0.001). And 846 cases were diagnosed as G6PD deficiency by MMCA gene mutation detection, and the diagnosis rate of MMCA gene mutation detection was 90.00% (846/940). The diagnosis rate for male neonates by MMCA gene mutation detection was 95.48% (655/686), which was significantly higher than 75.20% (191/254) for female neonates, and the difference was statistically significant (χ2=84.74, P<0.001). Among the 846 neonates diagnosed with G6PD deficiency by gene testing, there were 13 types of single G6PD gene mutations and 6 types of compound heterozygous mutations. The top four hotspot mutation types were c. 1024C>T (235 cases, 27.78%), c. 1388G>A (205 cases, 24.23%), c. 95A>G (163 cases, 19.27%), and c. 1376G>T (152 cases, 17.97%).

Conclusions

Among neonates in Guiyang who are positive for initial screening of G6PD deficiency, the recall rate for re-examination is relatively low. The top four hotspot G6PD gene mutations in neonates with G6PD deficiency in Guiyang are c. 1024C>T, c. 1388G>A, c.95A>G, and c. 1376G>T. Conducting G6PD activity screening and related diagnostic tests is beneficial for the early diagnosis and treatment of G6PD deficiency in neonates.

Key words: Glucosephosphate dehydrogenase, Glucosephosphate dehydrogenase deficiency, Neonatal screening, G6PD genotype, Gene mutation, Multicolor melting curve analysis method, Infant, newborn
表1 被成功召回复查的940例G6PD缺乏症初筛结果呈阳性新生儿G6PD缺乏症确诊结果
性别 召回复查数(例) 确诊数(例)a 确诊率(%)a G6PD/6PGD比值法 基因突变检测
确诊数(例) 确诊率(%) 确诊数(例) 确诊率(%)
男 686 673 98.10 566 82.51 655 95.48
女 254 222 87.40 128 50.39 191 75.19
合计 940 895 95.21 694 73.83 846 90.00
图1　1例G6PD缺乏症新生儿(男性，生后20 d) G6PD基因纯合突变MMCA法检测图谱，其外周血样本在ROX通道有突变峰(橘色曲线)，而其余熔解峰均为野生峰(黑色曲线)，突变峰熔点(Tm值)为68.58 ℃(红色箭头所示)，野生峰Tm值为72.06 ℃(黄色箭头所示)，野生峰与突变峰熔点差值(ΔTm值)为3.48 ℃，判断为c.1024C>T纯合突变　 图2　1例G6PD缺乏症新生儿(女，生后18 d) G6PD基因杂合突变MMCA法检测图谱，其外周血样本在ROX通道既有野生峰(黑色曲线)又有突变峰(橘色曲线)，突变峰熔点(Tm值)为68.13 ℃(红色箭头所示)，野生峰Tm值为72.38 ℃(黄色箭头所示)，野生峰与突变峰熔点差值(ΔTm值)为4.25 ℃，判断为c.1024C>T杂合突变注：G6PD为葡萄糖-6-磷酸脱氢酶，MMCA为多色探针荧光熔解曲线
图3 1例G6PD缺乏症新生儿(女，生后20 d) G6PD基因复合杂合突变MMCA法检测图谱，其外周血样本在ROX、Cy5通道均有2个突变峰(橘色、红色曲线)，其余熔解峰为野生峰(黑色曲线)，根据野生峰与突变峰熔点差值(ΔTm值)，判断为c.1024C>T＋c.1376G>T复合杂合突变(图3A：ROX通道图谱；图3B：Cy5通道图谱)(箭头所示为突变峰、熔解峰Tm值)注：G6PD为葡萄糖-6-磷酸脱氢酶，MMCA为多色探针荧光熔解曲线
表2 846例经基因突变检测确诊为G6PD缺乏症新生儿的G6PD基因突变类型分布
G6PD基因突变类型 男性 女性 所有新生儿
半合子(例) 构成比(%) 杂合(例) 双杂合(例) 纯合(例) 构成比(%)a 合计(例)b 构成比(%)
c.1024C>T 191 29.16 40 0 4 23.04 235 27.78
c.1388G>A 168 25.65 33 0 4 19.37 205 24.23
c．1376G>T 120 18.32 29 0 3 16.75 152 17.97
c．95A>G 111 16.95 47 0 5 27.23 163 19.27
c．871G>A 25 3.82 3 0 1 2.10 29 3.42
c．487G>A 20 3.05 3 0 0 1.57 23 2.71
c．1004C>A 6 0.92 1 0 0 0.52 7 0.82
c．392G>T 8 1.22 2 0 0 1.05 10 1.18
c．1360C>T 3 0.45 2 0 0 1.05 5 0.59
c．592C>T 2 0.31 2 0 0 1.05 4 0.47
c．383T>C 0 0 1 0 0 0.52 1 0.12
c．493A>G 1 0.15 1 0 0 0.52 2 0.24
c．519C>T 0 0 1 0 0 0.52 1 0.12
c．1376G>T＋c.95A>G 0 0 0 1 0 0.52 1 0.12
c．1024G>T＋c.95A>G 0 0 0 2 0 1.05 2 0.24
c．1024C>T＋c.1388G>A 0 0 0 2 0 1.05 2 0.24
c．1024C>T＋c.1376G>T 0 0 0 1 0 0.52 1 0.12
c．1024C>T＋c.519C>T 0 0 0 1 0 0.52 1 0.12
c．1388G>A＋c.95A>G 0 0 0 2 0 1.05 2 0.24
合计 655 100.00 165 9 17 100.00 846 100.00
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