目的 探讨甘肃地区18例四氢生物蝶呤缺乏症(BH4D)患者的遗传学特征。 方法 选择2018年1月至2021年12月由甘肃省妇幼保健院医学遗传中心确诊的18例甘肃籍BH4D患者作为研究对象，对其进行全外显子组测序分析，并对候选变异进行Sanger测序家系验证。 结果 18例BH4D患者的36个等位基因均被成功检出，检出率为100.0%。其中16例是由PTS基因变异所致，2例是由QDPR基因变异所致。PTS基因共检测出10种不同的变异，其中热点变异为c.259C>T(34.38%)及c.286G>A(15.63%)。c.259C>T为已报道致病性变异，c.286G>A、c.166G>A、c.200C>T、c.272A>G、c.402A>C、c.421G>T、c.84-291A>G、c.317C>T为已报道的可能致病性变异。c.289_290insCTT既往未见报道，根据美国医学遗传学与基因组学学会变异相关指南评级为可能致病性变异(PM1＋PM2_Supporting＋PM3＋PP3＋PP4)。QDPR基因的c.478C>T和c.665C>T均被评级为临床意义未明变异(PM1＋PM2_Supporting＋PP3＋PP4)。 结论 基因检测明确了上述研究BH4D家系的基因变异情况，为及时准确的临床干预和患者家庭的遗传咨询和生育决策提供了依据。 Objective To explore the genetic basis of eighteen patients with tetrahydrobiopterin deficiency (BH4D) from Gansu Province. Methods Eighteen patients diagnosed with BH4D at Gansu Provincial Maternal and Child Health Care Hospital from January 2018 to December 2021 were selected as the study subjects. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing. Results All of the thirty-six alleles of the eighteen patients were successfully determined by molecular genetic testing. Sixteen patients were found to harbor variants of the PTS gene, and two had harbored variants of the QDPR gene. Ten variants were detected in the PTS gene, with the most common ones being c. 259C>T (34.38%) and c. 286G>A (15.63%). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 259C>T was classified as a pathogenic variant, whilst the c. 286G>A, c. 166G>A, c. 200C>T, c. 272A>G, c. 402A>C, c. 421G>T, c. 84-291A>G and c. 317C>T were classified as likely pathogenic variants. A novel c. 289_290insCTT variant was classified as likely pathogenic (PM1+ PM2_Supporting+ PM3+ PP3+ PP4). The two variants (c.478C>T and c. 665C>T) detected in theQDPR gene were both classified as variants of uncertain significance (PM1+ PM2_Supporting+ PP3+ PP4). Conclusion Genetic testing has clarified the pathogenic variants in these BH4D patients, which has enabled timely and accurate clinical intervention and treatment, and provided a reference for genetic counseling and reproductive guidance for their families.
Abstract
Objective To explore the genetic basis of eighteen patients with tetrahydrobiopterin deficiency (BH4D) from Gansu Province. Methods Eighteen patients diagnosed with BH4D at Gansu Provincial Maternal and Child Health Care Hospital from January 2018 to December 2021 were selected as the study subjects. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing. Results All of the thirty-six alleles of the eighteen patients were successfully determined by molecular genetic testing. Sixteen patients were found to harbor variants of the PTS gene, and two had harbored variants of the QDPR gene. Ten variants were detected in the PTS gene, with the most common ones being c. 259C>T (34.38%) and c. 286G>A (15.63%). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 259C>T was classified as a pathogenic variant, whilst the c. 286G>A, c. 166G>A, c. 200C>T, c. 272A>G, c. 402A>C, c. 421G>T, c. 84-291A>G and c. 317C>T were classified as likely pathogenic variants. A novel c. 289_290insCTT variant was classified as likely pathogenic (PM1+ PM2_Supporting+ PM3+ PP3+ PP4). The two variants (c.478C>T and c. 665C>T) detected in theQDPR gene were both classified as variants of uncertain significance (PM1+ PM2_Supporting+ PP3+ PP4). Conclusion Genetic testing has clarified the pathogenic variants in these BH4D patients, which has enabled timely and accurate clinical intervention and treatment, and provided a reference for genetic counseling and reproductive guidance for their families.
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