MRPS25

Inheritance Pattern: Unknown

Disease ID:MONDO:0033570

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0004675

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0004675

Submitter: Franklin by Genoox

A subject with dyskinetic cerebral palsy and partial agenesis of the corpus callosum and some skeletal dysplasia. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPS25* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2024. The *MRPS25* gene encodes the mitochondrial ribosomal protein S25, a component of the small subunit of the mitochondrial ribosome. The first and only report of *MRPS25* in relation to autosomal recessive primary mitochondrial disease was in 2019 (PMID: 31039582), in a 25-year-old man with a history of chorea, dystonia, partial agenesis of corpus callosum, adrenal insufficiency, short stature, and microcephaly. Muscle biopsy in childhood was originally unremarkable but repeat biopsy at 19 years old showed COX-negative fibers and reduced activities of the mitochondrial respiratory chain enzymes. He had a homozygous missense variant in *MRPS25*. While various names could be given to the constellation of features seen in those with *MRPS25*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPS25 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 the one missense variant noted above in one case in one publication (PMID: 31039582). The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of *MRPS25* in mitochondrial translation and rescue studies performed in patient cells (PMID: 31039582). In summary, there is limited evidence to support this gene-disease relationship. 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 20, 2024 (SOP Version 10).