TMEM65

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TMEM65* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 15, 2024. The *TMEM65* gene encodes transmembrane protein 65 that localizes to inner mitochondrial membrane. However, the exact function of this protein remains uncharacterized. The first and only case report of *TMEM65*-related autosomal recessive primary mitochondrial disease was in 2017 (PMID: 28295037), While various names could be given to the constellation of features seen in those with *TMEM65*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TMEM65* 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 a single homozygous splice site variant in one proband from one publication (PMID: 28295037). This was a girl from a consanguineous family who had intrauterine growth restriction, microcephaly, global developmental delay, developmental regression, seizures, spasticity, and dysmorphic features. Brain imaging showed brain atrophy and signal changes in the white matter, cerebellum, and thalami. Decreased mitochondrial DNA content was noted in skeletal muscle and mitochondrial respiratory chain enzyme analysis in skeletal muscle showed reduced activities of complexes I+III, II+III, and IV. The mechanism of disease is loss of function. This gene-disease association is also supported by functional alteration in patient and non-patient cells, rescue in patient cells, and mouse and zebrafish models (PMIDs: 28295037, 33319071, 36257954, 26403541). 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 July 15, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: PanelApp Australia