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MGME1-Related Mitochondrial DNA Depletion Syndrome via the MGME1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8891 MGME1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8891MGME181479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

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.

Genetics

Mitochondrial DNA (mtDNA) depletion syndromes are caused by pathogenic variants in nuclear genes such as TK2SUCLA2SUCLG1RRM2BDGUOKTYMPPOLGC10orf2MGME1MPV17AGK, 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/).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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).

Indications for Test

MGME1 sequencing should be considered for patients who present with mitochondrial DNA (mtDNA) depletion syndromes. Targeted testing is indicated for family members of patients who have known pathogenic variants in MGME1. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in MGME1.

Gene

Official Gene Symbol OMIM ID
MGME1 615076
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mitochondrial DNA depletion syndrome 11 AR 615084

Citations

  • El-Hattab et al. 2013. PubMed ID: 23385875
  • El-Hattab et al. 2018. PubMed ID: 29517884
  • Gai et al. 2013. PubMed ID: 23993194
  • Hebbar et al. 2017. PubMed ID: 28711739
  • Kornblum et al. 2013. PubMed ID: 23313956
  • Matic et al. 2018. PubMed ID: 29572490
  • Mayr et al. 2012. PubMed ID: 22284826
  • Nicholls et al. 2014. PubMed ID: 24986917
  • Online Gene Essentiality (OGEE).
  • Taylor et al. 2014. PubMed ID: 25058219

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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