MRPS22

Inheritance Pattern: AR

Disease ID:MONDO:0012718

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0009299

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012718

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPS22* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 18, 2022. The *MRPS22* gene encodes the mitochondrial ribosomal protein S22, a component of the small subunit of the mitochondrial ribosome. *MRPS22* was first reported in relation to autosomal recessive mitochondrial disease in 2007 (PMID: 17873122). While various names have been given to the constellation of features seen in those with *MRPS22*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MRPS22* 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 five unique variants: four missense variants and one frameshift variant from five probands across four publications. Familial segregation data were also included in scoring (PMIDs: 17873122, PMID:29566152). The condition was first described in two sisters with severe lactic acidosis, hypotonia, ascites, hyperammonemia, and hypertrophic cardiomyopathy. Both sisters died within the first month of life. Muscle biopsy respiratory chain activities were consistent with a mitochondrial translation defect (PMID: 17873122). Subsequent publications have shown there are two phenotypes caused by *MRPS22* pathogenic variants. The first is a neonatal profound lactic acidosis with multi-organ failure that is often fatal (PMIDs: 25663021, 21189481). The second phenotype involves premature ovarian insufficiency with or without peripheral neuropathy (PMID: 29566152). Given the association of premature ovarian insufficiency with other mitochondrial disorders of translation, such as deficiencies of the HARS2 and LARS2 mitochondrial tRNA aminoacyl synthetases, all cases were scored for this curation. Of note, a Turkish proband with mosaic Down syndrome and Leigh syndrome has been reported but was not considered in this curation, given a lack of functional evidence and the presence of other potential candidate variants (PMID: 28752220). This gene-disease association is also supported by known protein interaction with other proteins involved in mitochondrial translation, documented respiratory chain deficiencies and assembly defects in patient cell lines, and mouse and drosophila models which showed embryonic lethality or sterility (PMIDs: 17873122, 18539099, 21189481, 29566152). In summary, there is definitive evidence to support this gene-disease relationship. This curation reached a score of 11.7 which is between moderate and definitive, and the Mitochondrial Disease Gene Curation Expert Panel opted to score as definitive. This has been repeatedly demonstrated and has been upheld over time. 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 July 18, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0012718

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0020857

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012718

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0020857

Submitter: Labcorp Genetics (formerly Invitae)