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Mitochondrial Genome Maintenance/Integrity Nuclear Genes Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
AGK 81479,81479
APTX 81405,81479
DGUOK 81405,81479
DNA2 81479,81479
FBXL4 81479,81479
MFN2 81406,81479
MGME1 81479,81479
MPV17 81405,81404
OPA1 81407,81406
OPA3 81479,81479
POLG 81406,81479
POLG2 81479,81479
RRM2B 81405,81479
SLC25A3 81479,81479
SLC25A4 81404,81479
SPG7 81406,81405
SUCLA2 81479,81479
SUCLG1 81479,81479
SUCLG2 81479,81479
TK2 81405,81479
TWNK 81404,81479
TYMP 81405,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10367Genes x (22)81479 81404(x3), 81405(x7), 81406(x4), 81407(x1), 81479(x29) $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

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 platform).

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

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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.


Genetic Counselors


  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

Abnormalities in the maintenance of the mitochondrial genome integrity represent a group of clinically and genetically heterogeneous disorders including mitochondrial DNA (mtDNA) depletion syndromes and disorders with multiple mtDNA deletions. These disorders are caused by defects in nuclear-encoded genes responsible for mtDNA maintenance.

Mitochondrial DNA depletion syndromes (MDS) are characterized by a quantitative abnormality of the mitochondrial genome, leading to impaired energy production in a single or multiple organs (Suomalainen et al. 2010; El-Hattab et al. 2013). MDS is clinically and genetically heterogeneous; and it is usually classified into four forms: myopathic (onset at infancy to early childhood; caused by mutations in TK2, RRM2B and AGK), encephalomyopathic (onset at neonatal to infancy; caused by SUCLA2, SUCLG1, RRM2B and possibly SUCLG2), hepatocerebral (onset at neonatal to childhood, caused by mutations in DGUOK, MPV17, POLG and TWNK/C10orf2) and neurogastrointestinal (onset at late childhood to adolescence; caused by mutations in TYMP). More detailed clinical features are presented in each individual gene’s test description.

The accumulation of multiple mtDNA deletions represents the other major abnormality in the maintenance of the mitochondrial genome integrity. It is typically seen in skeletal muscle of patients affected by adult-onset progressive external ophthalmoplegia (PEO), which is accompanied by ptosis and mitochondrial myopathy (see for example Fratter et al. 2010; more information can be found at Test #1255 for the TWNK gene). The autosomal recessive mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) disease is also associated with multiple mtDNA deletions (Nishino et al. 1999; more information can be found at Test #1242 for the TYMP gene).


Mitochondrial DNA depletion syndromes (MDS) are autosomal recessive disorders due to defects in nuclear genes responsible for mtDNA maintenance that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, SUCLG2, RRM2B, DGUOK and TYMP) or mtDNA replication (POLG, TWNK and MGME1) or other activities (MPV17, FBXL4 and AGK).

Disorders with multiple mtDNA deletions can be autosomal dominant or recessive. In adults, the accumulation of multiple mtDNA deletions in postmitotic tissues (such as skeletal muscle) results from defects in proteins involved in mtDNA replication (POLG, POLG2, TWNK and DNA2), deoxyribonucleotide metabolism (TK2, TYMP, SLC25A4 and RRM2B), and mitochondrial fusion (OPA1, OPA3, MFN2 and SPG7).

Of the 22 genes in the panel, 16 are also currently available at our Sanger sequencing test menu: TK2 (Test# 1245), SUCLA2 (Test# 1251), SUCLG1 (Test# 1249), RRM2B (Test# 1246), DGUOK (Test# 1243), MPV17 (Test# 1247), POLG (Test# 1241), TWNK (Test# 1255), TYMP (Test# 1242); POLG2 (Test# 1248), DNA2 (Test# 1253), MFN2 (Test# 1254), OPA1 (Test# 566), OPA3 (Test# 567), SLC25A3 (Test# 1252), SLC25A4 (Test# 1250). Please find more information under each individual test description. Sanger tests for the remaining genes in the panel may be offered at a later date.

The SUCLG2 gene (11 coding exons) encodes a GTP-specific beta-subunit of succinyl-CoA synthetase, which catalyzes the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP. No SUCLG2 mutations have been reported in human diseases. However, defects in genes encoding other subunits of succinyl-CoA synthetase (SUCLA2 and SUCLG1) have been reported to cause the encephalomyopathic form of MDS. Therefore, the SUCLG2 gene is included in this panel.

The FBXL4 gene (7 coding exons) encodes an F-box protein with a possible role in maintaining mtDNA integrity and stability. Loss-of-function and splice mutations in this protein cause mitochondrial encephalopathy with a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network in affected individuals (Bonnen et al. 2013; Gai et al. 2013).

The MGME1 gene (also known as C20orf72; 4 coding exons) encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. Loss-of-function mutations in MGME1 impair mtDNA replication and cause a multisystemic mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure (Kornblum et al. 2013).

The AGK gene (15 coding exons) encodes the acylglycerol kinase, which phosphorylates monoacylglycerols and diacylglycerols to lysophosphatidic acid and phosphatidic acid respectively. Frameshift and splicing mutation in the AGK gene, resulting in a deletion of a highly conserved C-terminal region, cause Sengers syndrome, also known as a subtype of myopathic form of MDS (Mayr et al. 2012; Calvo et al. 2012).

The SPG7 gene (17 coding exons) encodes the protein paraplegin, a mitochondrial metalloprotease protein, which is a member of the AAA protein family. SPG7 mutations in this gene cause autosomal recessive spastic paraplegia 7 (Casari et al. 1998). Mutations in this gene also cause chronic progressive external ophthalmoplegia due to defected mitochondrial DNA maintenance (Pfeffer et al. 2014).

The APTX gene (8 coding exons) encodes aprataxin, which is involved in mitochondrial single strand break repair (SSBR). APTX mutations cause ataxia-ocular apraxia 1 (AOA1) (Date et al. 2001; Moreira et al. 2001).

Clinical Sensitivity - Sequencing with CNV PGxome

A TWNK defect is likely in autosomal dominant PEO patients (Fratter et al. 2010). Fratter et al. identified 16 different TWNK mutations within 26 (16/26; 62%) unrelated patients with adPEO from United Kingdom and Germany. POLG mutations were identified in 136 out of 2,697 unrelated individuals (5%) with clinical presentations suggestive of POLG deficiency (Tang et al. 2011). RRM2B mutations account for approximately 13% of PEO and multiple mtDNA deletions in adults (Pitceathly et al. 2012). However, RRM2B mutation detection rate in patients with encephalomyopathic form of MDS or MNGIE is uncertain because these RRM2B mutations have been only reported in individual families. In a limited number of patients, biallelic TK2 mutations were found in 20% to 46% of patients with the myopathic form of MDS (Alberio et al. 2007; Spinazzola et al. 2009). TYMP mutations were identified in 92 out of 102 unrelated individuals worldwide (~ 90%) with clinical presentations suggestive of MNGIE disease (Garone et al. 2011). Three of 90 patients (3.3%) with multiple mtDNA deletions were found via DNA sequencing to have DNA2 pathogenic mutations (Ronchi et al. 2013). In a molecular screening of 980 cases with suspected hereditary optic neuropathy, 440 patients had molecular defects. Among these 440 patients, 295 had OPA1 mutations (67%), and 14 patients (3%) had OPA3 mutations (Ferre et al. 2009). SLC25A4 mutations accounted for approximately 4% of familial adPEO cases in a study of a limited number of PEO patients (Lamantea et al. 2002). In 68 patients affected by progressive external ophthalmoplegia (PEO) and negative for the previous known causative genes, 9 (~13%) were found to have compound heterozygous SPG7 mutations and 6 (~9%) have a single heterozygous SPG7 mutation (Pfeffer et al. 2014). The mutation detection rates of other genes (POLG2, DGUOK, MPV17, SUCLA2, SUCLG1, MFN2, SLC25A3, FBXL4, MGME1, AGK and APTX) in a large cohort of patients are unknown because these mutations were only reported in a limited number of patients (families). SUCLG2 mutations have not been reported yet.

No gross deletions or duplications have been reported in SUCLG1 thus far (Human Gene Mutation Database).

Testing Strategy

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

This panel provides 100% coverage of all coding exons of the genes 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 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

Candidates for this test are patients with mitochondrial DNA (mtDNA) depletion syndromes and/or disorders with multiple mtDNA deletions. This test especially aids in a differential diagnosis of similar phenotypes by analyzing multiple genes simultaneously.


Official Gene Symbol OMIM ID
AGK 610345
APTX 606350
DGUOK 601465
DNA2 601810
FBXL4 605654
MFN2 608507
MGME1 615076
MPV17 137960
OPA1 605290
OPA3 606580
POLG 174763
POLG2 604983
RRM2B 604712
SLC25A3 600370
SLC25A4 103220
SPG7 602783
SUCLA2 603921
SUCLG1 611224
SUCLG2 603922
TK2 188250
TWNK 606075
TYMP 131222
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Adult Onset Ataxia With Oculomotor Apraxia AR 208920
Charcot-Marie-Tooth Disease, Type 2A2 AD 609260
Dominant Hereditary Optic Atrophy AD 165500
Mitochondrial DNA depletion syndrome 11 AR 615084
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) AR 615471
Mitochondrial DNA Depletion Syndrome 2 (Myopathic Type) AR 609560
Mitochondrial DNA Depletion Syndrome 4B, Mngie Type AR 613662
Mitochondrial DNA Depletion Syndrome 5 (Encephalomyopathic with or without Methylmalonic Aciduria) AR 612073
Mitochondrial DNA Depletion Syndrome 7 AR 271245
Mitochondrial DNA Depletion Syndrome 9 (Encephalomyopathic With Methylmalonic Aciduria) AR 245400
Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, With Renal Tubulopathy AR 612075
Mitochondrial DNA-Depletion Syndrome 3, Hepatocerebral AR 251880
Mitochondrial Neurogastrointestinal Encephalomyopathy Syndrome AR 603041
Mitochondrial Phosphate Carrier Deficiency 610773
Navajo Neurohepatopathy AR 256810
Optic Atrophy And Cataract, Autosomal Dominant AD 165300
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 1 AD 157640
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 2 AD 609283
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 3 AD 609286
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 4 AD 610131
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 5 AD 613077
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6 AD 615156
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Recessive AR 258450
Progressive Sclerosing Poliodystrophy AR 203700
Sengers syndrome AR 212350
Sensory Ataxic Neuropathy, Dysarthria, And Ophthalmoparesis AR 607459
Spastic Paraplegia 7 AR, AD 607259

Related Test



  • Alberio S, Mineri R, Tiranti V, Zeviani M. 2007. Depletion of mtDNA: syndromes and genes. Mitochondrion 7: 6–12. PubMed ID: 17280874
  • Bonnen P. et al. 2013. American Journal of Human Genetics. 93: 471–81. PubMed ID: 23993193
  • Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, et al. 2012. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 4: 118ra10. PubMed ID: 22277967
  • Casari G, Fusco M De, Ciarmatori S, Zeviani M, Mora M, Fernandez P, Michele G De, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, et al. 1998. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973–983. PubMed ID: 9635427
  • Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, et al. 2001. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat. Genet. 29: 184–188. PubMed ID: 11586299
  • El-Hattab AW, Scaglia F. 2013. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 10: 186–198. PubMed ID: 23385875
  • Ferré M, Bonneau D, Milea D, Chevrollier A, Verny C, Dollfus H, Ayuso C, Defoort S, Vignal C, Zanlonghi X, Charlin J-F, Kaplan J, et al. 2009. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Hum. Mutat. 30: E692–705. PubMed ID: 19319978
  • Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, et al. 2010. The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology 74: 1619–1626. PubMed ID: 20479361
  • Gai X. et al. 2013. American Journal of Human Genetics. 93: 482–95. PubMed ID: 23993194
  • Garone C, Tadesse S, Hirano M. 2011. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 134: 3326–3332. PubMed ID: 21933806
  • Human Gene Mutation Database (Bio-base).
  • Kornblum C. et al. 2013. Nature Genetics. 45: 214–9. PubMed ID: 23313956
  • Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M. 2002. Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann. Neurol. 52: 211–219. PubMed ID: 12210792
  • Mayr J. et al. 2012. American Journal of Human Genetics. 90: 314–20. PubMed ID: 22284826
  • Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, Mendonça P, Costa M, Barros J, Yanagisawa T, Watanabe M, Ikeda Y, et al. 2001. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat. Genet. 29: 189–193. PubMed ID: 11586300
  • Nishino I, Spinazzola A, Hirano M. 1999. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283: 689–692. PubMed ID: 9924029
  • Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, et al. 2014. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 137: 1323–1336. PubMed ID: 24727571
  • Pitceathly R. et al. 2012. Brain 135: 3392–403. PubMed ID: 23107649
  • Ronchi D, Fonzo A Di, Lin W, Bordoni A, Liu C, Fassone E, Pagliarani S, Rizzuti M, Zheng L, Filosto M, Ferrò MT, Ranieri M, et al. 2013. Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability. Am. J. Hum. Genet. 92: 293–300. PubMed ID: 23352259
  • Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, Giordano I, Meznaric-Petrusa M, Baruffini E, Ferrero I, Zeviani M. 2009. Clinical and molecular features of mitochondrial DNA depletion syndromes. J. Inherit. Metab. Dis. 32: 143–158. PubMed ID: 19125351
  • Suomalainen A, Isohanni P. 2010. Mitochondrial DNA depletion syndromes--many genes, common mechanisms. Neuromuscul. Disord. 20: 429-437. PubMed ID: 20444604
  • Tang S, Wang J, Lee N-C, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong L-JC. 2011. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J. Med. Genet. 48: 669–681. PubMed ID: 21880868


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