Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy

Abstract

Mitochondriopathies represent a wide spectrum of miscellaneous disorders with multisystem involvement, which are caused by various genetic changes. The establishment of the diagnosis of mitochondriopathy is often challenging. Recently, several mutations of the VARS2 gene encoding the mitochondrial valyl-tRNA synthetase were associated with early onset encephalomyopathies or encephalocardiomyopathies with major clinical features such as hypotonia, developmental delay, brain MRI changes, epilepsy, hypertrophic cardiomyopathy, and plasma lactate elevation. However, the correlation between genotype and phenotype still remains unclear. In this paper we present a male Caucasian patient with a recurrent c.1168G>A (p.Ala390Thr) and a new missense biallelic variant c.2758T>C (p.Tyr920His) in the VARS2 gene which were detected by whole exome sequencing (WES). VARS2 protein was reduced in the patient's muscle. A resulting defect of oxidative phosphorylation (OXPHOS) was proven by enzymatic assay, western blotting and immunohistochemistry from a homogenate of skeletal muscle tissue. Clinical signs of our patient included hyperlactatemia, hypertrophic cardiomyopathy (HCM) and pulmonary hypertension, which led to early death at the age of 47 days without any other known accompanying signs. The finding of novel variants in the VARS2 gene expands the spectrum of known mutations and phenotype presentation. Based on our findings we recommend to consider possible mitochondriopathy and to include the analysis of the VARS2 gene in the genetic diagnostic algorithm in cases with early manifesting and rapidly progressing HCM with hyperlactatemia.

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

“…CASP1 [185], FOXP3 [186], SOCS1 [187], GATA6 [188], IRF7 [189], POSTN (periostin) [190], CYP19A1 [191], CD36 [192], LYN (LYN proto-oncogene, Src family tyrosine kinase) [193], CD4 [194], LEPR (leptin receptor) [195], AR (androgen receptor) [196], FOXO1 [197] and PON2 [198] are a potential biomarkers for the detection and prognosis of PCOS. Udjus et al [199] Benjafield et al [200], Shetty et al [58], Kassan et al [201], Wetzl et al [202], Le Hiress et al [203], Pal-Ghosh et al [204], Niu, [205], Fan et al [206], Deng et al [207], Chen et al [208], Sardo et al [209], Seidel et al [210], Zhu et al [211], Omura et al [212], Hu et al [213], Castoldi et al [214], Yoshida et al [215], Palao et al [216], Kušíková et al [217], Decharatchakul et al [218], Ahmed et al [219], Merklinger et al [220], Lei et al [146], Liu et al [221], Chen et al [222], Tan et al [223], Shi et al [224], Ikonnikova et al [225], Shimodaira et al [226], Pravenec et al [227], Zhang et al [228], Shah et al [229], Cicekliyurt and Dermenci [230], Ong et al [98], Nowzari et al [163], Kim et al [231], Bonafiglia et al [232], Selle et al [233],Yoo et al [234], Kasacka et al [235], Wang et al [236], Huang et al [237], Caceres et al [238], Lei et al [239], Lu et al [240], Cui et al [241], Xiao et al [242], Hiramatsu et al [243], Oliver et al [244], Grabowski et al [245], Zhu et al [246] and Li et al [247] demonstrated that the altered expression of CASP1, EDNRA (endothelin receptor type A), F2RL1, FOXP3, TIMP4, CD74, PLK1, TGFB1, GATA6, IRF7, IRF9, BGN (biglycan), C...…”

Genetic variants related to systemic lupus erythematosus revealed using bioinformatics

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A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease

“…Oxidative phosphorylation (OXPHOS) was evaluated in fresh muscle and skin fibroblasts ( 14 ) ( Figure 2 ). Evaluation of OXPHOS in muscle (M. gastrocnemius right) revealed normal activities of the respiratory chain complexes I [24 mUnit/mg (18–59 mUnit/mg)], II [43 mUnit/mg, (28–69 mUnit/mg)], III [208 mUnit/mg, (149–480 mUnit/mg)], IV (cytochrome-C-oxidase) [214 mUnit/mg, (148–392 mUnit/mg)], V [92 mUnit/mg, (60–223 mUnit/mg)], and citrate synthase [122 mUnit/mg, (134–260 mUnit/mg)].…”