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PARS2 (prolyl-tRNA synthetase 2) deficiency is associated with autosomal recessive mitochondrial disease (MONDO:0044970). Biallelic PARS2 variants were identified by whole-exome sequencing in three unrelated probands with clinical features of mitochondrial dysfunction. In a cohort of 113 pediatric patients, a novel PARS2 missense variant c.239T>C (p.Ile80Thr) was detected (PMID:27290639). Independent reports described a patient with coagulation factor abnormalities and global developmental delay carrying c.1091C>G (p.Pro364Arg) (PMID:32071833) and a lethal mitochondrial cardiomyopathy case with c.283G>A (p.Val95Ile) (PMID:39253392). All patients presented early-onset symptoms and biochemical evidence of impaired oxidative phosphorylation; segregation analysis confirmed compound heterozygosity under an autosomal recessive model.
Functional data are limited but suggest loss of prolyl-tRNA ligase activity leading to defective mitochondrial translation. Published studies report nonspecific metabolic perturbations and variable MRI findings, without cellular or animal model validation or rescue experiments. Thus, current evidence supports a Limited clinical validity per ClinGen: PARS2 variants are recurrent in AR cases, but larger cohorts and mechanistic assays are lacking. Additional functional and model organism studies are warranted. Key take-home: Include PARS2 in genetic panels for autosomal recessive pediatric mitochondrial presentations.
Gene–Disease AssociationLimited3 unrelated probands with biallelic PARS2 variants (PMID:27290639; PMID:32071833; PMID:39253392) Genetic EvidenceLimitedThree AR probands with compound heterozygous missense PARS2 variants Functional EvidenceLimitedPredicted loss of enzymatic activity without cellular/animal model or rescue data |