Dihidropyrimidinase (DHP) deficiency is an inherited inborn error of pyrimidine metabolism with a variable clinical presentation and even asymptomatic subjects. Dihydropyrimidinase is encoded by the DPYS gene, thus pathogenic mutations in this gene can cause DHP deficiency. To date, several variations in the DPYS gene have been reported but only 23 of them have been confirmed to be pathogenic. Therefore, the biochemical, clinical and genetic aspects of this disease are still unclear. Here, we report a 22-year-old woman with DHP deficiency. To identify the genetic cause of DHP deficiency in this patient, Whole Exome Sequencing (WES) was performed, which revealed a novel homozygote stop gain mutation (NM_001385: Exon 9, c.1501 A > T, p.K501X) in the DPYS gene. Sanger sequencing was carried out on proband and other family members in order to confirm the identified mutation. According to the homozygote genotype of the patient and heterozygote genotype of her parents, the autosomal recessive pattern of inheritance was confirmed. In addition, bioinformatics analysis of the identified variant using Mutation Taster and T-Coffee Multiple Sequence Alignment showed the pathogenicity of mutation. Moreover, mRNA expression level of DPYS gene in the proband’s liver biopsy showed about 6-fold reduction compared to control, which strongly suggested the pathogenicity of the identified mutation. This study identified a novel pathogenic stop gain mutation in DPYS gene in a DHP deficient patient. Our findings can improve the knowledge about the genetic basis of the disease and also provide information for accurate genetic counseling for the families at risk of these types of disorders.

中文翻译：

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病例报告：DPYS基因中的一种新的终止增益突变，导致双hidyryrimidinase缺乏症。

Dihidropyrimidinase（DHP）缺乏症是嘧啶代谢的遗传性先天性错误，临床表现变化，甚至无症状。二氢嘧啶酶由DPYS基因编码，因此该基因中的致病性突变可导致DHP缺乏。迄今为止，已经报道了DPYS基因的几种变异，但是仅证实其中有23种是致病的。因此，该病的生化，临床和遗传方面仍不清楚。在这里，我们报告了一名22岁的DHP缺乏症妇女。为了确定该患者DHP缺乏的遗传原因，进行了全外显子组测序（WES），该序列揭示了DPYS基因中的新的纯合子终止增益突变（NM_001385：Exon 9，c.1501 A> T，p.K501X） 。对先证者和其他家庭成员进行了Sanger测序，以确认鉴定出的突变。根据患者的纯合子基因型和父母的杂合子基因型，确定了遗传的常染色体隐性模式。此外，使用突变体法和T-Coffee多序列比对技术对鉴定出的变异进行生物信息学分析，显示了突变的致病性。此外，先证者肝活检中DPYS基因的mRNA表达水平与对照相比降低了约6倍，这强烈表明了所鉴定突变的致病性。这项研究确定了DHP缺陷患者DPYS基因中的新型致病性停止增益突变。