Clinical, biochemical, and genetic features associated with <italic>VARS2</italic>‐related mitochondrial disease.

Abstract: In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl‐tRNA synthetases (mt‐aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi‐allelic functional variants in <italic>VARS2</italic>, encoding the mitochondrial valyl tRNA‐synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring <italic>VARS2</italic> mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of <italic>VARS2</italic> missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic <italic>VARS2</italic> variants and we recommend that this gene should be considered in early‐onset mitochondrial encephalomyopathies or encephalocardiomyopathies. [ABSTRACT FROM AUTHOR]