PARS2

Inheritance Pattern: AR

Disease ID:MONDO:0032752

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032752

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032752

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The *PARS2* gene encodes mitochondrial prolyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits. The *PARS2* gene was first reported in relation to autosomal recessive mitochondrial disease in 2015 (PMID: 25629079). While various names have been given to the constellation of features seen in those with *PARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *PARS2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one nonsense variant, one frameshift variant, and six unique missense variants from eight publications (PMIDs: 25629079, 27290639, 29410512, 28077841, 29915213, 32514400, 32071833, 30237576, 34585293). Affected individuals have been reported to have infantile-onset epileptic encephalopathy, microcephaly, brain MRI showing progressive volume loss of the frontal lobes, and cardiomyopathy. While reported cases showed a markedly consistent clinical phenotype, mitochondrial respiratory chain testing is often normal in various tissues. Family segregation data were reviewed and summarized (PMIDs: 27290639, 29410512), however the summed LOD score did not meet criteria to be considered evidence in this curation. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease. The final score for this gene-disease curation was 6.2, which falls between limited and moderate. This expert panel agreed to move this classification to moderate given the markedly consistent phenotype across multiple patients in the literature. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June,16 2022 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032752

Submitter: Ambry Genetics