Submission Details

The relationship between MT-TN and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 20, 2022. The MT-TN gene encodes the mitochondrial transfer RNA (tRNA) for asparagine, which is located from m.5657-5729 on the light strand of mitochondrial DNA (mtDNA). Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities.

MT-TN was first reported in relation to maternally inherited primary mitochondrial disease in 1993 (PMID: 8254046). While various names have been given to the constellation of features seen in those with MT-TN-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TN 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 seven unique missense variants identified in multiple probands across numerous publications (PMIDs: 8254046, 9372914, 7980504, 14518831, 11335700, 16908752, 23696415, 15564038, 16908752, 23375258, 31026515, 32869280). There are multiple recurrent variants, notably m.5703G>A and m.5728T>C. Invariably in all cases curated, MT-TN pathogenic variants were present at high levels of heteroplasmy in muscle tissue. Frequently, in other tissues, such as blood, saliva, hair, urine and fibroblasts, the variant was undetectable or at substantially lower heteroplasmy level, thus highlighting the diagnostic importance of muscle biopsy in those with MT-TN-related primary mitochondrial disease. A variant in MT-TN was first reported in a 27-year-old woman with a history of progressive external ophthalmoplegia (PEO) since 9 months of age, myopathy, decreased deep tendon reflexes, and thin body habitus. Subsequent publications have shown a consistent phenotype including ptosis, PEO, myopathy, neuropathy, with or without ataxia, muscle biopsy with COX-negative and ragged red fibers, and often either a complex IV deficiency in muscle or combined OXPHOS defect. One patient has been reported with basal ganglia calcifications and seizures in addition to myopathy and faltering growth (PMID:16908752). Interestingly, two patients have been reported with focal segmental glomerular sclerosis (FSGS), which is a renal manifestation of some primary mitochondrial diseases (PMIDs: 16908752, 23375258). Variant heteroplasmy was low in renal biopsy for one patient, raising the question as to whether FSGS is part of the MT-TN phenotype (PMID: 23375258). Multiple single fiber studies were performed in several affected individuals and were supportive of variant pathogenicity. Single nucleotide deletions have also been reported but were not scored as case evidence had already reached maximum score (PMID: 32869280).

This gene-disease association is also supported by its known biochemical function and m.5703G>A cybrid studies yielding evidence supporting pathogenicity (PMIDs: 30030363, 9372914).

In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 20, 2022 (SOP Version 9).