I型常染色体隐性遗传戊二酸血症(GA-I)是一种罕见的遗传性代谢疾病,其特征是有机酸和神经系统症状增加。尽管GCDH基因中的许多变体已被鉴定为与GA-I的发病机理有关,基因型和表型之间的关系仍然不确定.在这项研究中,我们评估了两名湖北GA-I患者的遗传数据,中国,我们回顾了以前的研究结果,以阐明GA-I的遗传异质性并确定潜在的致病变异。在我们从两个不相关的中国家庭的外周血样本中提取基因组DNA后,我们使用靶捕获高通量测序结合Sanger测序来确定两个先证者中可能的致病变异.还搜索了电子数据库以进行文献综述。遗传分析显示,GCDH基因中的两个复合杂合变体有望在两个先证者(P1和P2)中导致GA-I,P1携带两个已知的变体(c.892G>A/p。A298T和c.1244-2A>C/IVS10-2A>C)和P2带有两个新变体(c.370G>T/p。G124W和c.473A>G/p。E158G)。在文献综述中,低排泄物中最常见的等位基因(即,GA排泄低的个体)为R227P,V400M,M405V,和A298T,随着临床表型严重程度的变化。总的来说,我们在一名中国患者中发现了两种新的GCDH基因候选致病变异,丰富了GCDH基因突变谱,为低排泄GA-I患者的早期诊断提供了坚实的基础。
Autosomal recessive glutaric acidaemia type I (GA-I) is a rare hereditary metabolic disease characterized by increased organic acids and neurologic symptoms. Although numerous variants in the GCDH gene have been identified to be connected with the pathogenesis of GA-I, the relationship between genotype and phenotype remains uncertain. In this study, we evaluated genetic data for two GA-I patients from Hubei, China, and we reviewed the previous research findings to clarify the genetic heterogeneity of GA-I and identify the potential causative variants. After we extracted genomic DNA from peripheral blood samples obtained from two unrelated Chinese families, we used target capture high-throughput sequencing combined with Sanger sequencing to determine likely pathogenic variants in the two probands. Electronic databases were also searched for the literature
review. The genetic analysis revealed two compound heterozygous variants in the GCDH gene expected to lead to GA-I in the two probands (P1 and P2), with P1 carrying two known variants (c.892G > A/p. A298T and c.1244-2A > C/IVS10-2A > C) and P2 harbouring two novel variants (c.370G > T/p.G124W and c.473A > G/p.E158G). In the literature
review, the most common alleles in low excretors (i.e., individuals with low excretion of GA) were R227P, V400M, M405V, and A298T, with variation in the severity of clinical phenotypes. Overall, we identified two novel GCDH gene candidate pathogenic variants in a Chinese patient, enriching the GCDH gene mutational spectrum and providing a solid foundation for the early diagnosis of GA-I patients with low excretion.