A novel compound heterozygous mutation in VARS2 in a newborn with mitochondrial cardiomyopathy: a case report of a Chinese family

Abstract

BackgroundGenetic defects in the mitochondrial aminoacyl-tRNA synthetase are important causes of mitochondrial disorders. VARS2 is one of the genes encoding aminoacyl-tRNA synthetases. Recently, an increasing number of pathogenic variants of VARS2 have been reported.Case presentationWe report the novel compound heterozygous pathogenic VARS2 mutations c.643 C > T (p. His215Tyr) and c.1354 A > G (p. Met452Val) in a female infant who presented with poor sucking at birth, poor activity, hyporeflexia, hypertonia, persistent pulmonary hypertension of newborn (PPHN), metabolic acidosis, severe lactic acidosis, expansion and hypertrophic cardiomyopathy. These heterozygous mutations were carried individually by the proband’s parents and elder sister; the two mutations segregated in the family and were the cause of the disease in the proband.The c.643 C > T (p. His215Tyr) mutation was not described in the ExaC, GNomAD and 1000 Genomes Project databases, and the frequency of c.1354 A > G (p. Met452Val) was < 0.001 in these gene databases.The two mutated amino acids were located in a highly conserved region of the VARS2 protein that is important for its interaction with the cognate tRNA. The two missense mutations were predicted by online tools to be damaging and deleterious.ConclusionsOur report expands the spectrum of known pathogenicVARS2 variants associated with mitochondrial disorders in humans.VARS2 deficiency may cause a severe neonatal presentation with structural cardiac abnormalities.

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

“…Position 390 is highly conserved (Figure 1D). Position 390 corresponds to the tRNA-synthetase domain and position 920 corresponds to the anticodon binding domain of the protein VARS2 (1,12). These findings support the pathogenicity of the variants found in our patient.…”

“…Dysfunction of the protein product is responsible for combined oxidative phosphorylation deficiency 20 (OMIM: # 615917) inherited in an autosomal recessive manner. Rare biallelic variants in the VARS2 gene have been associated with severe clinical features as mitochondrial encephalomyopathy or encephalocardiomyopathy in 23 affected individuals from 19 families worldwide (1,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In the present paper we describe a compound heterozygous case with a recurrent c.1168G>A (p.Ala390Thr) and a novel missense variant c.2758T>C (p.Tyr920His) in the VARS2 gene causing isolated hypertrophic cardiomyopathy, hyperlactatemia, and pulmonary hypertension leading to early death.…”

“…Recently, several mutations in VARS2 gene were associated with clinical features such as hypotonia, psychomotor delay, encephalopathy, cardiomyopathy, hyperlactatemia, but the correlation between genotype and phenotype remains unclear (1,15). To date, 19 families with more than 23 affected individuals have been described in the literature worldwide (1,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) whereby c.1100C>T (p.Thr367Ile) is the most common variant in the VARS2 gene present in 60.8% (14/23) of the published cases (see Table 2). Common features of homozygous carriers for variant c.1100C>T (p.Thr367Ile) include microcephaly, global psychomotor delay, and hypotonia, less often nystagmus, limb spasticity, and difficulties with feeding.…”

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

“…The present study reported that the clinical and molecular characterization of a Chinese pedigree with maternally inherited hypertension. Although many studies revealed the genetics of mitochondrial disorders, the molecular mechanism underlying hypertension remains unclear (22,23). Experimental studies identified a positive association between mtDNA mutations and hypertension (24,25).…”

Cardiomyopathies in China: A 2018–2019 state‐of‐the‐art review

“… 42 Several studies have focused on mitochondrial dysfunction and its role in HCM pathogenesis. 43 , 44 The previously reported pathogenic mutation of the tRNA-modifying enzyme GTPBP3 may contribute to mitochondrial dysfunction, altering embryonic heart development and reducing fractional shortening of ventricles in zebrafish. This study highlighted the role of defective nucleotide modifications of tRNAs in the pathogenesis of HCM.…”