MGME1-Related Mitochondrial DNA Depletion Syndrome via the MGME1 Gene

Mitochondrial DNA depletion syndromes are characterized by deficiencies in the maintenance or integrity of the mitochondrial DNA (mtDNA) genome, resulting in a significant decrease in the abundance of mtDNA within the cell (El-Hattab et al. 2013. PubMed ID: 23385875). These diseases, which exhibit significant clinical and genetic heterogeneity, are caused by defects in nuclear-encoded genes.

MGME1-associated mtDNA depletion syndrome has been identified and characterized in affected individuals in only four families to date, and is thought to be an extremely rare form of this disorder (Kornblum et al. 2013. PubMed ID: 23313956; Taylor et al. 2014. PubMed ID: 25058219). Onset of this disorder typically ranges from late childhood to adulthood. Patients present with a multisystemic disorder that includes ptosis, external ophthalmoplegia, muscle weakness, emaciation, and impaired respiratory function. Additionally, respiratory chain complex I and/or IV activities may be decreased in affected individuals, and mtDNA depletion and multiple mtDNA deletions are present.

One patient with a homozygous protein-truncating variant was described in a different study; however, limited functional evidence was available regarding pathogenicity of the variant (Hebbar et al. 2017. PubMed ID: 28711739). In the Hebbar et al. manuscript, the proband presented with a different phenotype to those reported in the Kornblum et al. study, including early onset progressive ataxia, speech delay, and fundus albipunctatus.

There are currently no clinical treatments available for mtDNA depletion syndrome arising from MGME1 defects. Management of the disorder is supportive, and screening for potential future complications may be recommended. Molecular diagnosis may help determine the recurrence risk in families.

Mitochondrial DNA (mtDNA) depletion syndromes are caused by pathogenic variants in nuclear genes such as TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, TYMP, POLG, C10orf2, MGME1, MPV17, AGK, and FBXL4 (El-Hattab et al. 2013. PubMed ID: 23385875; Kornblum et al. 2013. PubMed ID: 23313956; Mayr et al. 2012. PubMed ID: 22284826; Gai et al. 2013. PubMed ID: 23993194). Of these, AGK, DGUOK, DNA2, POLG2, SLC25A4, and TK2 also present with myopathy, similar to the clinical presentation seen with MGME1-associated mtDNA depletion syndrome (El-Hattab et al. 2018. PubMed ID: 29517884). MGME1-associated mtDNA depletion syndrome is inherited as an autosomal recessive disorder (Kornblum et al. 2013. PubMed ID: 23313956).

Approximately 20 affected individuals with MGME1-associated mtDNA depletion syndrome have been documented (Kornblum et al. 2013. PubMed ID: 23313956; Taylor et al. 2014. PubMed ID: 25058219). All affected individuals carry pathogenic missense and/or nonsense variants in the MGME1 gene. No large CNV events have been reported to date. Additionally, to our knowledge, no causative variants have arisen de novo in any of the previously reported probands, and therefore all known pathogenic variants are known or suspected to have been inherited from a carrier parent.

To our knowledge, only two of the reported causative variants have also been identified in a large public population database: c.698A>G (p.Tyr233Cys, transcript NM_052865.3), which is present at a minor allele frequency of up to ~0.03% in one sub-population (gnomAD); and c.456G>A (p.Trp152*, transcript NM_052865.3), which is present at a minor allele frequency of up to ~0.0009% in one sub-population (gnomAD).

The MGME1 gene, located on chromosome 20p11.23, spans 5 exons and encodes for a mitochondrial RecB-type exonuclease (Nicholls et al. 2014. PubMed ID: 24986917). The loss of functional MGME1 enzyme interferes with mtDNA replication and repair within the cell, resulting in large deletions of the mtDNA genome, reduction of mtDNA copy number, and accumulation of mtDNA replication intermediates.

Mice lacking functional MGME1 develop mtDNA depletion and multiple mtDNA deletions (Matic et al. 2018. PubMed ID: 29572490). The Online Gene Essentiality (OGEE) database lists the MGME1 gene as nonessential for growth of human tissue culture cells (http://ogee.medgenius.info/).

Too few cases of MGME1-associated mitochondrial DNA (mtDNA) depletion syndrome have been documented to accurately estimate clinical sensitivity. To date, only ~20 cases have been reported in the literature, making MGME1-associated mtDNA depletion syndrome an extremely rare form of the disorder (Kornblum et al. 2013. PubMed ID: 23313956; Taylor et al. 2014. PubMed ID: 25058219). Analytical sensitivity should be high.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the MGME1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).