Submission Details

The relationship between MSTO1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2023. MSTO1 encodes Misato mitochondrial distribution and morphology regulator 1, an outer mitochondrial membrane protein that plays a role in mitochondrial fusion.

The MSTO1 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2017 (PMID: 28544275), in two infants with cerebellar atrophy, developmental delay, myopathy, and elevated serum creatine kinase (CK) levels. Subsequent publications have shown a highly consistent phenotype of infantile onset (<2 years) cerebellar atrophy, myopathy, mild serum CK elevations, developmental delays, and ataxia with or without retinitis pigmentosa. Notably, at the same time of the initial report, a case with proposed dominant inheritance was reported (PMID:2855494), however, since no subsequent dominant cases have been reported (and 22 autosomal recessive cases with a clear and consistent phenotype have been reported), this GCEP elected to curate this gene-disease relationship as an autosomal recessive condition. The possibility of different mechanisms of action leading to both dominant and recessive inheritance cannot be excluded, but additional cases are needed to support autosomal dominant inheritance of MSTO1-related disease. Furthermore, while various names have been given to the constellation of features seen in those with MSTO1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MSTO1 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 13 unique variants (including one nonsense, one frameshift, two splicing, and nine missense variants) in eight probands (although more than 20 probands have been reported in the medical literature) across at least five publications from 2017-2021 (PMIDs: 28544275, 29339779, 30684668, 31463572, 33612823). Loss-of-function is implicated as a mechanism of disease. This gene-disease association is also supported by numerous Drosophila melanogaster models (PMIDs: 29255146, 9144213), functional alteration in non-patient cells showing mitochondrial fragmentation (PMID: 17349998), absence of wild type MSTO1 expression in affected patients but not controls (PMID: 31463572), and rescue of mitochondrial morphology and fusion deficits in patients’ cells transduced with wild type MSTO1 (PMID: 31463572).

In summary, there is definitive evidence to support the relationship between MSTO1 and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on on May 18, 2023.