PDF(Pubmed)
Abstract：
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD), is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. Deleterious variants in the DPYD gene cause DPD deficiency, a rare autosomal recessive disorder. The clinical spectrum of affected individuals is wide ranging from asymptomatic to severely affected patients presenting with intellectual disability, motor retardation, developmental delay and seizures. DPD is also important as the main enzyme in the catabolism of 5-fluorouracil (5-FU) which is extensively used as a chemotherapeutic agent. Even in the absence of clinical symptoms, individuals with either complete or partial DPD deficiency face a high risk of severe and even fatal fluoropyrimidine-associated toxicity. The identification of causative genetic variants in DPYD is therefore gaining increasing attention due to their potential use as predictive markers of fluoropyrimidine toxicity.
METHODS: A male infant patient displaying biochemical features of DPD deficiency was investigated by clinical exome sequencing. Bioinformatics tools were used for data analysis and results were confirmed by MLPA and Sanger sequencing.
RESULTS: A novel intragenic deletion of 71.2 kb in the DPYD gene was identified in homozygosity. The deletion, DPYD(NM_000110.4):c.850 + 23455_1128 + 8811del, eliminates exons 9 and 10 and may have resulted from a non-homologous end-joining event, as suggested by in silico analysis.
CONCLUSIONS: The study expands the spectrum of DPYD variants associated with DPD deficiency. Furthermore, it raises the concern that patients at risk for fluoropyrimidine toxicity due to DPYD deletions could be missed during pre-treatment genetic testing for the currently recommended single nucleotide polymorphisms.
METHODS: A male infant patient displaying biochemical features of DPD deficiency was investigated by clinical exome sequencing. Bioinformatics tools were used for data analysis and results were confirmed by MLPA and Sanger sequencing.
RESULTS: A novel intragenic deletion of 71.2 kb in the DPYD gene was identified in homozygosity. The deletion, DPYD(NM_000110.4):c.850 + 23455_1128 + 8811del, eliminates exons 9 and 10 and may have resulted from a non-homologous end-joining event, as suggested by in silico analysis.
CONCLUSIONS: The study expands the spectrum of DPYD variants associated with DPD deficiency. Furthermore, it raises the concern that patients at risk for fluoropyrimidine toxicity due to DPYD deletions could be missed during pre-treatment genetic testing for the currently recommended single nucleotide polymorphisms.
摘要：
背景：二氢嘧啶脱氢酶（DPD），是嘧啶分解代谢途径中的初始和限速酶。DPYD基因中的有害变异导致DPD缺乏，一种罕见的常染色体隐性疾病。受影响的个体的临床范围很广，从无症状到患有智力障碍的严重受影响的患者，电机延迟，发育迟缓和癫痫发作。DPD作为5-氟尿嘧啶（5-FU）分解代谢中的主要酶也很重要，5-氟尿嘧啶（5-FU）被广泛用作化学治疗剂。即使没有临床症状，患有完全或部分DPD缺乏症的个体面临严重甚至致命的氟嘧啶相关毒性的高风险.因此,DPYD中的致病遗传变异体的鉴定由于其作为氟嘧啶毒性的预测标志物的潜在用途而获得越来越多的关注。
方法：通过临床外显子组测序研究了一名表现出DPD缺乏症生化特征的男婴患者。使用生物信息学工具进行数据分析，并通过MLPA和Sanger测序确认结果。
结果:鉴定出DPYD基因中71.2kb的新基因内缺失纯合性。删除，DPYD(NM_000110.4):c.850+23455_1128+8811del,消除外显子9和10，可能是由于非同源末端连接事件，正如硅分析所建议的那样。
结论：该研究扩大了与DPD缺乏相关的DPYD变异的范围。此外，这引起了人们的担忧,即由于DPYD缺失而有氟嘧啶毒性风险的患者在目前推荐的单核苷酸多态性的治疗前基因检测中可能被遗漏.
方法：通过临床外显子组测序研究了一名表现出DPD缺乏症生化特征的男婴患者。使用生物信息学工具进行数据分析，并通过MLPA和Sanger测序确认结果。
结果:鉴定出DPYD基因中71.2kb的新基因内缺失纯合性。删除，DPYD(NM_000110.4):c.850+23455_1128+8811del,消除外显子9和10，可能是由于非同源末端连接事件，正如硅分析所建议的那样。
结论：该研究扩大了与DPD缺乏相关的DPYD变异的范围。此外，这引起了人们的担忧,即由于DPYD缺失而有氟嘧啶毒性风险的患者在目前推荐的单核苷酸多态性的治疗前基因检测中可能被遗漏.
