Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
Department of Biochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Metab Brain Dis. 2017 Oct;32(5):1417-1426. doi: 10.1007/s11011-017-0006-4. Epub 2017 Apr 7.
Glutaric acidemia I (GAI) is an autosomal recessive metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase enzyme (GCDH). Patients with GAI are characterized by macrocephaly, acute encephalitis-like crises, dystonia and frontotemporal atrophy. In this study, we investigated 18 Egyptian patients that were diagnosed with GAI based on their clinical, neuroradiological, and biochemical profiles. Of the 18 patients, 16 had developmental delay and/or regression, dystonia was prominent in 75% of the cases, and three patients died. Molecular genetics analysis identified 14 different mutations in the GCDH gene in the 18 patients, of the 14 mutations, nine were missense, three were in the 3'-Untranslated Region (3'-UTR), one was nonsense, and one was a silent mutation. Four novel mutations were identified (c.148 T > A; p.Trp50Arg, c.158C > A; p.Pro53Gln, c.1284C > G; p.Ile428Met, and c.1189G > T; p.Glu397*) that were all absent in 300 normal chromosomes. The 3'-UTR mutation (c.*165A > G; rs8012), was the most frequent mutation observed (0.5; 18/36), followed by the most common mutation among Caucasian patients (p.Arg402Trp; rs121434369) with allele frequency of 0.36 (13/36), and the 3'-UTR mutation (c.*288G > T; rs9384, 0.22; 8/16). The p.Arg257Gln mutation was found with allele frequency of ~0.17 (6/36). The marked homozygosity observed in our patients is probably due to the high level of consanguinity that is observed in 100% of the cases. We used nine in silico prediction tools to predict the pathogenicity (SIFT, PhD-SNP, SNAP, Meta-SNP, PolyPhen2, and Align GVGD) and protein stability (I-Mutant2.0, Mupro, and istable) of the nine missense mutants. The mutant p.Arg402Trp was predicted to be most deleterious by all the six pathogenicity prediction tools and destabilizing by all the three-stability prediction tools, and highly conserved by the ConSurf server. Using the clinical, biochemical, family history of the 18 patients, and the in silico analysis of the missense mutations, our study showed a mix of conclusive and inconclusive genotype-phenotype correlations among our patient's cohort and suggests the usefulness of using various sophisticated computational analysis to be utilized for future variant classifications in the genetic clinics.
谷氨酸血症 I (GAI) 是一种常染色体隐性遗传代谢疾病，由谷氨酰辅酶 A 脱氢酶 (GCDH) 缺乏引起。GAI 患者的特征是大头畸形、类似脑炎的急性危机、肌张力障碍和额颞叶萎缩。在这项研究中，我们研究了 18 名根据其临床、神经放射学和生化特征诊断为 GAI 的埃及患者。在 18 名患者中，有 16 名存在发育迟缓或倒退，75%的病例出现肌张力障碍，3 名患者死亡。分子遗传学分析在 18 名患者的 GCDH 基因中发现了 14 种不同的突变，其中 9 种是错义突变，3 种位于 3'-非翻译区（3'-UTR），1 种是无义突变，1 种是沉默突变。鉴定出 4 种新突变（c.148T>A;p.Trp50Arg、c.158C>A;p.Pro53Gln、c.1284C>G;p.Ile428Met 和 c.1189G>T;p.Glu397*），这 4 种突变在 300 个正常染色体中均不存在。最常见的突变是 3'-UTR 突变（c.*165A>G;rs8012），频率为 0.5（18/36），其次是在白种人群中最常见的突变（p.Arg402Trp;rs121434369），等位基因频率为 0.36（13/36），还有 3'-UTR 突变（c.*288G>T;rs9384，0.22；8/16）。p.Arg257Gln 突变的等位基因频率约为 0.17（6/36）。我们患者中观察到的明显纯合性可能是由于 100%的病例中存在高度的近亲结婚。我们使用了 9 种计算预测工具（SIFT、PhD-SNP、SNAP、Meta-SNP、PolyPhen2 和 Align GVGD）来预测 9 种错义突变的致病性（SIFT、PhD-SNP、SNAP、Meta-SNP、PolyPhen2 和 Align GVGD）和蛋白质稳定性（I-Mutant2.0、Mupro 和 istable）。突变体 p.Arg402Trp 被所有 6 种致病性预测工具预测为最具危害性，所有 3 种稳定性预测工具预测为不稳定，并且 ConSurf 服务器高度保守。通过对 18 名患者的临床、生化、家族史以及错义突变的计算分析，我们的研究显示，我们患者队列中的基因型-表型相关性存在明确和不确定的混合，并表明在遗传诊所中使用各种复杂的计算分析对未来的变异分类是有用的。
