近亲婚配所致四氢生物喋呤缺乏症家系的GCH1基因变异分析

Analysis of GCH1 gene variant in a consanguineous Chinese pedigree affected with tetrahydrobiopterin deficiency

目的分析1例表现为全面性发育迟缓的四氢生物蝶呤缺乏症患儿家系遗传学病因。方法对1例全面发育迟缓患儿进行临床和实验室检查分析,并应用高通量测序技术(高苯丙氨酸血症相关基因panel)对患儿进行基因变异检测,对可疑序列变异进行患儿及其家系成员的Sanger测序验证及生物学信息学分析。结果患儿血串联质谱检查结果:血苯丙氨酸浓度642.7μmol/L,血Phe/Tyr为5.42,提示高苯丙氨酸血症;尿喋呤分析结果为:新喋呤0.09 mmol/molCr,生物喋呤0.04 mmol/molCr,B%30.77%,提示四氢生物喋呤缺乏症;该家系中先证者父母为近亲结婚。基因测序结果显示先证者为GCH1基因c.353A>T纯合变异,家系中先证者的外曾祖母、曾祖母、外祖父、祖父、母亲、舅舅、父亲、哥哥均为GCH1基因c.353A>T携带者,表型正常,无多巴反应性肌张力障碍相关临床症状。结论GCH1基因c.353A>T纯合变异可能是先证者的遗传学病因,与先证者父母近亲婚配有关。

Objective To explore the genetic basis for a child featuring tetrahydrobiopterin deficiency and global developmental delay.Methods Clinical and laboratory examinations were carried out for the child.Genomic DNA of the patient was subjected to high-throughput sequencing to identify genetic variants associated with hyperphenylalaninemia.Candidate variants were verified by Sanger sequencing.Results The result of blood tandem mass spectrometry showed that the Phenylalanine in the blood was 642.7μmol/l,and the ratio of Phenylalanine/Tyrosine was 5.42.Analysis of urinary pterin:neopterin 0.09 mmol/mol Cr,biopterin 0.04 mmol/mol Cr,biopterin%77%,which suggested tetrahydrobiopterin deficiency.The parents of the proband were first cousins.DNA sequencing revealed that the proband has harbored homozygous c.353A>T variants in exon 2 of the GCH1 gene,for which his great grandmother,grandfather,mother,uncle,father and elder brother were heterozygous carriers with normal phenotype and no clinical symptoms associated with dopa responsive dystonia.Conclusion The homozygous c.353A>T variant of the GCH1 gene probably underlay the tetrahydrobiopterin deficiency in this pedigree of consanguineous marriage.