PRORP

Inheritance Pattern: AR

Disease ID:MONDO:0030543

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030543

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PRORP* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 15, 2024. The *PRORP* gene (alternate names include *MRPP3* and *KIAA0391*) encodes a protein-only RNase P that is a component of human mitochondrial ribonuclease P which catalyzes the 5’ end maturation of mitochondrial precursor tRNAs. *PRORP* was first reported in relation to autosomal recessive primary mitochondrial disease in 2021 (PMID: 34715011). While various names have been given to the constellation of features seen in those with *PRORP*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the PRORP 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 nine variants (eight missense variants and one frameshift variant resulting in loss of function) in six probands from two publications (PMIDs: 34715011, 37558808). Clinical features in affected individuals were quite variable and include hearing loss, hypergonadotropic hypogonadism, mild intellectual disability, headaches, seizures, feeding difficulty, and lactic acidosis. Brain imaging showed periventricular nodular heterotopia, dysplastic corpus callosum, subcortical white matter loss, and Leigh syndrome spectrum disorder. Age of onset ranged from infancy to childhood. Of note, one case included in this curation also had isovaleric acidemia (hypomorphic variant), however this Expert Panel elected to include this case given functional analysis supportive of pathogenicity of the PRORP variants and given the phenotypic presentation in this case, Leigh syndrome spectrum disorder, is consistent with a primary mitochondrial disorder. Segregation was also included in this curation (PMID: 34715011). The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of *PRORP* as a component of human mitochondrial ribonuclease P, conditional knockout studies in mice (PMID: 27498866), and rescue studies in patient cells (PMID: 34715011). In summary, there is definitive evidence to support the relationship between *PRORP* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 15, 2024 (SOP Version 10).