MPV17-Related Hepatocerebral Form of Mitochondrial DNA Depletion Syndrome via the MPV17 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1247 MPV17$540.00 81405 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Due to the founder effect of the p.R50Q variant in the Native American Navajo population, clinical sensitivity is expected to be high in patients with Navajo ancestry who present with the hepatocerebral form of MDS (Karadimas et al. 2006). For the remainder of patients, however, too few cases have been described to estimate clinical sensitivity at this time.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 MPV17$990.00 81404 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Mitochondrial DNA Depletion Syndromes (MDSs) are a clinically and genetically heterogeneous group of diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen and Isohanni 2010; El-Hattab et al. 2013). Patients with the hepatocerebral form of MDS commonly develop severe hepatopathy, hypotonia, and psychomotor delay.

The MPV17-related hepatocerebral form of MDS has an early disease onset that ranges from infancy to childhood. Patients present with clinical features that include liver dysfunction (typically progressing to liver failure during infancy or early childhood), neurologic manifestations (peripheral neuropathy and leukoencephalopathy), metabolic abnormalities (lactic acidosis and hypoglycemia) and failure to thrive. Less frequent clinical presentations include renal tubulopathy, hypoparathyroidism, gastrointestinal dysmotility, cyclic vomiting, and diarrhea (El-Hattab et al. 2012; El-Hattab et al. 2013). 

Navajo neurohepatopathy, a recessive multisystem disorder that has a high incidence in the Native American Navajo population of the southwestern United States, is caused by a founder variant in MPV17 (Karadimas et al. 2006). This disease shares similar clinical, pathological, and biochemical features with the hepatocerebral form of MDS, but patients may present with additional symptoms such as acral mutilation, corneal anesthesia, ulceration, and scarring.

Rarely, MPV17 defects result in adult-onset peripheral neuropathy with or without hepatic involvement (Blakely et al. 2012; Garone et al. 2012). This particular form of disease is characterized by severe mtDNA depletion and cytochrome c oxidase (COX) deficiency in skeletal muscle.


The MPV17-related hepatocerebral form of MDS is an autosomal recessive disorder caused by pathogenic variants in the MPV17 gene (Spinazzola et al. 2006). MPV17 has 7 coding exons that encode a non-selective channel within the inner mitochondrial membrane that functions to maintain mitochondrial homeostasis by acting as a regulator of membrane potential (Antonenkov et al. 2015). Missense, nonsense, splicing site variants, and small deletion/insertions have been found across the whole coding region of MPV17. In addition, several large deletions have been reported (Spinazzola et al., 2008; Uusimaa et al. 2014). 

Associated with less severe phenotypes and extended survival in patients, the p.R50Q variant in exon 2 is the most commonly reported cause of MPV17-related disease due to a founder effect within the Navajo community (Karadimas et al. 2006). However, this variant has also arisen independently, if less frequently, in other populations (Spinazzola et al. 2006; Spinazzola et al. 2008).

The hepatocerebral form of MDS can also be caused by defects in POLG, DGUOK, and C10orf2.

Testing Strategy

Full gene sequencing of MPV17 is performed, with bidirectional sequencing of exons 2-8. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Candidates for this test include patients with the hepatocerebral form of MDS or Navajo neurohepatopathy. Testing is also indicated for family members of patients who have known MPV17 mutations.


Official Gene Symbol OMIM ID
MPV17 137960
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Navajo Neurohepatopathy 256810


Genetic Counselors
  • Antonenkov V.D. et al. 2015. The Journal of Biological Chemistry. 290: 13840-61. PubMed ID: 25861990
  • Blakely E. et al. 2012. Neuromuscular Disorders. 22:587-91. PubMed ID: 22508010
  • El-Hattab A. and Scaglia F. 2013. Neurotherapeutics. 10:186-98.  PubMed ID: 23385875
  • El-Hattab A. et al. 2012. MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 22593919
  • Garone C. et al. 2012. Archives of Neurology. 69:1648-51. PubMed ID: 22964873
  • Karadimas C. et al. 2006. American Journal of Human Genetics. 79:544-8. PubMed ID: 16909392
  • Spinazzola A. et al. 2006. Nature Genetics. 38: 570-5. PubMed ID: 16582910
  • Spinazzola A. et al. 2008. Archives of Neurology. 65:1108-13. PubMed ID: 18695062
  • Spinazzola A. et al. 2008. Neuromuscular Disorders. 18:315-8. PubMed ID: 18261905
  • Suomalainen A. and Isohanni P. 2010. Neuromuscular Disorders. 20:429-37. PubMed ID: 20444604
  • Uusimaa J. et al. 2014. European Journal of Human Genetics. 22: 184-91. PubMed ID: 23714749
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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