Zaki Osama K, Priya Doss C George, Ali Salsabil A, Murad Ghadeer G, Elashi Shaima A, Ebnou Maryam S A, Kumar D Thirumal, Khalifa Ola, Gamal Radwa, El Abd Heba S A, Nasr Bilal N, Zayed Hatem
Department of Medical Genetics, Ain Shams Paediatrics Hospital, Cairo, Egypt.
Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
Hum Mol Genet. 2017 Aug 15;26(16):3105-3115. doi: 10.1093/hmg/ddx195.
Isovaleric acidaemia (IVA) is an autosomal recessive inborn error of leucine metabolism. It is caused by a deficiency in the mitochondrial isovaleryl-CoA dehydrogenase (IVD) enzyme. In this study, we investigated eight patients with IVA. The patients' diagnoses were confirmed by urinary organic acid analysis and the blood C5-Carnitine value. A molecular genetic analysis of the IVD gene revealed nine different variants: five were missense variants (c.1193G > A; p. R398Q, c.1207T > A; p. Y403N, c.872C > T; p. A291V, c.749G > C; p. G250A, c.1136T > C; p.I379T), one was a frameshift variant (c.ins386 T; p. Y129fs), one was a splicing variant (c.465 + 2T > C), one was a polymorphism (c.732C > T; p. D244D), and one was an intronic benign variant (c.287 + 14T > C). Interestingly, all variants were in homozygous form, and four variants were novel (p. Y403N, p. Y129fs, p. A291V, p. G250A) and absent from 200 normal chromosomes. We performed protein modelling and dynamics analyses, pathogenicity and stability analyses, and a physiochemical properties analysis of the five missense variants (p.Y403N, R398Q, p.A291V, p.G250A, and p.I379T). Variants p.I379T and p.R398Q were found to be the most deleterious and destabilizing compared to variants p.A291V and p.Y403N. However, the four variants were predicted to be severe by the protein dynamic and in silico analysis, which was consistent with the patients' clinical phenotypes. The p.G250A variant was computationally predicted as mild, which was consistent with the severity of the clinical phenotype. This study reveals a potentially meaningful genotype-phenotype correlation for our patient cohort and highlights the development and use of this computational analysis for future assessments of genetic variants in the clinic.
异戊酸血症（IVA）是一种常染色体隐性遗传的亮氨酸代谢先天性缺陷疾病。它由线粒体异戊酰辅酶A脱氢酶（IVD）缺乏引起。在本研究中，我们调查了8例IVA患者。通过尿有机酸分析和血液中C5 - 肉碱值确诊患者病情。对IVD基因进行分子遗传学分析发现了9种不同变异：5种为错义变异（c.1193G＞A；p.R398Q，c.1207T＞A；p.Y403N，c.872C＞T；p.A291V，c.749G＞C；p.G250A，c.1136T＞C；p.I379T），1种为移码变异（c.ins386 T；p.Y129fs），1种为剪接变异（c.465 + 2T＞C），1种为多态性变异（c.732C＞T；p.D244D），1种为内含子良性变异（c.287 + 14T＞C）。有趣的是，所有变异均为纯合形式，其中4种变异为新发现变异（p.Y403N、p.Y129fs、p.A291V、p.G250A），在200条正常染色体中未出现。我们对5种错义变异（p.Y403N、R398Q、p.A291V、p.G250A和p.I379T）进行了蛋白质建模与动力学分析、致病性与稳定性分析以及理化性质分析。与p.A291V和p.Y403N变异相比，p.I379T和p.R398Q变异被发现具有最强的有害性和不稳定性。然而，通过蛋白质动力学和计算机模拟分析预测这4种变异均为严重变异，这与患者的临床表型一致。p.G250A变异经计算机模拟预测为轻度变异，这与临床表型的严重程度相符。本研究揭示了我们患者队列中潜在有意义的基因型 - 表型相关性，并强调了这种计算机分析方法在临床未来遗传变异评估中的开发与应用。
