Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population
Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population
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中国人群高苯丙氨酸血症候选基因突变谱及基因型-表型相关性
DOI：
10.1016/j.cca.2018.02.035
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
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作者：
Wang, Ruifang;Shen, Nan;Yu, Yongguo
背景：高苯丙氨酸血症(HPA)是一种遗传性代谢紊乱，由苯丙氨酸羟基酶(PAH)或四氢生物蝶呤缺乏引起。世界各地HPA的患病率差异很大。方法：报道了1020例中国HPA患者的HPA候选基因谱。应用Sanger测序、下一代测序(NGS)、多重连接依赖探针扩增(MLPA)和实时定量聚合酶链式反应(qRT-PCR)对HPA患者进行精确的分子诊断。结果：除经Sanger测序证实的915例HPA患者(89.7%)外，另有57例(5.6%)通过深入检测(NGS、MLPA和qRT-PCR)发现了致病变异。我们在PAH、PTS、QDPR和GCH1中分别鉴定出196个、42个、10个和2个变异。在这些基因中总共发现了47个新的变种。通过APV和GPV计算，发现新的GPV系统与大多数PAH缺陷患者的代谢表型有很好的相关性。结论：利用新的分子诊断方法发现了更多的HPA候选变异。新的APV和GPV系统可能对预测PAH缺乏患者的临床表型非常有益。
Background: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder that is caused by a deficiency of phenylalanine hydroxylase (PAH) or tetrahydrobiopterin. The prevalence of HPA varies widely around the world.Methods: A spectrum of HPA candidate genes in 1020 Chinese HPA patients was reported. Sanger sequencing, next generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time PCR (qRT-PCR) were applied to precisely molecular diagnose HPA patients. The allelic phenotype values (APV) and genotypic phenotype values (GPV) were calculated in PAH-deficient patients based on a recently developed formula.Results: Apart from genetic diagnoses confirmed in 915 HPA patients (89.7%) by Sanger sequencing, pathogenic variants were discovered in another 57 patients (5.6%) through deep detections (NGS, MLPA and qRT-PCR). We identified 196, 42, 10 and 2 variants in PAH, PTS, QDPR and GCH1, respectively. And a total of 47 novel variants were found in these genes. Through the APV and GPV calculations, it was found that the new GPV system was well correlated with metabolic phenotypes in most PAH-deficient patients.Conclusions: More HPA candidate variants were identified using new molecular diagnostic methods. The new APV and GPV system is likely to be highly beneficial for predicting clinical phenotypes for PAH-deficient patients.