Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation.

Mitochondriopathies are a diverse group of disorders caused by disruption of typical mitochondrial function. Heterogenous in nature, many of these disorders arise due to variants in genes encoding key mitochondrial proteins involved in transcription and translation of mitochondrial machinery. One such gene, VARS2, encodes a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of valine to its cognate tRNA molecule. Bi-allelic variants in VARS2 have been linked to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. While associated clinical phenotypes vary, they can include developmental delays, axial hypotonia, limb spasticity, and epilepsy. Here, we describe three additional clinical cases of VARS2-related mitochondriopathy with sequencing-confirmed variants in VARS2 that illustrate the phenotypic variability of this disorder. These include three novel variants: Lys225Glu, Cys281Tyr, and Leu732Cysfs*29. We further assess the pathogenicity and severity of the effects of the variants underlying these cases in a Xenopus model of disease through assaying both cardiac function and brain size. In addition, we use this model of VARS2 loss of function to assess the therapeutic potential of previously proposed amino acid supplementation. Through this approach, we demonstrate that the beneficial effects of valine supplementation in VARS2 mitochondriopathy may be dependent on residual enzyme activity.