Submission Details

The relationship between MGME1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2023. The MGME1 gene encodes metal-dependent single-stranded DNA (ssDNA) exonuclease which is involved in mitochondrial genome DNA replication termination and is essential for maintenance and stability of the mitochondrial DNA (mtDNA).

The MGME1 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23313956), in three individuals with ophthalmoplegia, myopathy, and respiratory failure. While various names could be given to the constellation of features seen in those with MGME1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MGME1 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 four unique variants reported in five probands from three publications (PMIDs: 23313956, 28711739, 37429773). Variants included one frameshift, two nonsense, and one missense. The c.456G>A (p.Trp152Ter) variant was identified in two families from Lebanon and Italy that shared a common haplotype and is a proposed founder variant (PMID: 23313956). In the few affected individuals reported to date, the disorder is characterized by progressive external ophthalmoplegia and neuromuscular symptoms including muscle wasting, proximal weakness, exercise intolerance, and respiratory distress. Other features may include profound emaciation, spinal deformities, gastrointestinal issues and cardiac phenotypes such as arrythmias and dilated cardiomyopathy. Brain MRI findings include cerebellar atrophy. As well as phenotypic heterogeneity, a range in age of onset is observed, ranging from infant onset to the fourth decade. At least three additional cases are reported in the medical literature (PMIDs: 25058219, 28097321, 32528171) but were not included in this curation given limited clinical details provided.

This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease. Abnormal replication of the mitochondrial genome has been demonstrated in patient fibroblasts and a Mgme1 knockout mouse model which also recapitulates aspects of primary mitochondrial disease (PMIDs: 23313956, 29572490, 35533204).

In summary, there is definitive evidence to support the relationship between MGME1 and primary mitochondrial disease. This relationship has been 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 August 7, 2023 (SOP Version 9).