A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype

To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C>T p.Ala360Val, likely pathogenic, and c.1258G>A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.