[Phenotypic and genotypic spectra of patients with glucose-6-phosphate dehydrogenase deficiency gene known pathogenic variants: a single-center study].

Objective: To analyze the hotspots of known pathogenic disease-causing variants of glucose-6-phosphate dehydrogenase (G6PD) and the phenotype spectrum of neonatal patients with known pathogenic disease-causing variants of G6PD. Methods: The known pathogenic disease-causing variants of G6PD were collected from Human Gene Mutation Database. Screening was performed for these variants among the 7 966 cases (2 357 neonatal, 5 609 non-neonatal) in the database of sequencing at Molecular Diagnosis Center, Children's Hospital of Fudan University. All these samples were from patients suspected with genetic disorder. The database contained Whole Exon Sequencing data and Clinical Exon Sequencing data. We screened out the patients with known pathogenic disease-causing variants of G6PD, analyzed the hotspot of G6PD and the phenotype spectrum of neonatal patients with known pathogenic disease-causing variants of G6PD. Results: (1) Among the next generation sequencing data of the 7 966 samples, 86 samples (1.1%) were detected as positive for the known pathogenic disease-causing variants of G6PD (positive samples set). In the positive sample set, 51 patients (33 males, 18 females) were newborn babies. Forty-three patients (26 males, 17 females) had the enzyme activity data of G6PD. (2) Among the 86 samples, Arg463His, Arg459Leu, Leu342Phe, Val291Met were the leading 4 disease-causing variants found in 72 samples (84%). (3) Male neonatal patients with the same variants had the statistically significant differences in enzyme activity: among 13 patients with Arg463His, enzyme activity of 9 patients was ranked as grade Ⅲ, 1 case ranked as Ⅳ, 3 cases had no activity data;among 10 patients with Arg459Leu, enzyme activity of 4 patients was ranked as Ⅱ, 4 cases ranked as Ⅲ, 2 cases had no activity data;among 2 patients with His32Arg, enzyme activity of one patient was ranked as Ⅱ, another was Ⅲ. Male neonatal patients with the same mutation and enzyme activity also had the statistically significant differences in phenotype spectrum: among 9 patients with Arg463His and level Ⅲ enzyme activity, 6 presented hyperbilirubinemia, 2 met the criteria for exchange transfusion therapy, 2 showed hemolysis;among 4 patients with Arg459Leu and level Ⅱ enzyme activity, 3 presented hyperbilirubinemia;among 4 patients with Arg459Leu and level Ⅲ enzyme activity, 2 presented hyperbilirubinemia, 1 met the standard of exchange transfusion therapy;among 3 patients with Val291Met and level Ⅲ enzyme activity, 1 presented hyperbilirubinemia. Conclusions: Arg463His, Arg459Leu, Leu342Phe, Val291Met were the hotspots variants for the G6PD. Patients with the same G6PD variants and sex present different phenotype, patients with the same G6PD variants, sex and enzyme activity also present different phenotype .目的： 分析葡萄糖-6-磷酸脱氢酶（G6PD）基因的热点致病变异和新生儿中携带G6PD基因致病变异人群的表型谱。 方法： 整理人类基因突变数据库中G6PD基因已知致病变异，分析2016年1月至2017年6月复旦大学附属儿科医院（以下简称复旦儿科）分子诊断中心测序数据库中的7 966例（2 357例为新生儿，5 609为非新生儿）临床怀疑遗传性疾病患儿的全外显子检测和临床外显子检测数据，获得携带G6PD基因已知致病变异的阳性样本集，分析G6PD基因热点致病变异。并分析G6PD基因致病变异阳性样本集中新生儿患儿的葡萄糖-6-磷酸酶活性特点和临床表型谱。 结果： （1）在复旦儿科7 966例二代测序数据中，共检出86例（1.1%）携带G6PD基因已知致病变异，为阳性样本集。阳性样本集中有新生儿患儿共51例（男33例，女18例），其43例有葡萄糖-6-磷酸脱氢酶酶活性检测数据（男26例，女17例)。（2) 86例中，检出最多的前四位致病变异为Arg463His、Arg459Leu、Leu342Phe、Val291Met，共72例（84%）。（3）携带相同致病变异的男性新生儿患儿葡萄糖-6-磷酸脱氢酶活性水平各异：携带Arg463His的13例患儿中有9例酶活性为Ⅲ类，1例酶活性为Ⅳ类，3例酶活性数据缺失；携带Arg459Leu的10例患儿中有4例酶活性为Ⅱ类，4例酶活性为Ⅲ类，2例酶活性数据缺失；携带His32Arg变异的2例患儿中1例酶活性为Ⅱ类，另1例为Ⅲ类。携带相同致病位点且酶活性一致的男性新生儿患儿临床表现差异明显：有9例携带Arg463His且酶活性为Ⅲ类，其中6例诊断高胆红素血症，2例达到换血标准，2例有溶血表现；有4例携带Arg459Leu且酶活性为Ⅱ类，其中3例诊断高胆红素血症；有4例携带Arg459Leu且酶活性为Ⅲ类，其中2例诊断高胆红素血症，1例达到换血标准；有3例携带Val291Met且酶活性为Ⅲ类，其中1例诊断高胆红素血症。 结论： Arg463His、Arg459Leu、Leu342Phe、Val291Met为G6PD基因的热点变异。携带相同G6PD致病变异同性别患儿的表型谱有较大差异，携带相同致病位点且酶活性一致的同性别患儿临床表现亦差异。.