Mitochondrial Complex V Deficiency Panel (Nuclear Genes)

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3463 ATP5F1A 81479,81479 Order Options and Pricing
ATP5F1E 81479,81479
ATPAF2 81479,81479
TMEM70 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3463Genes x (4)81479 81479 $890 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 PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Mitochondrial complex V deficiency is considered the rarest oxidative phosphorylation (OXPHOS) complex disorder, accounting for approximately one percent of all OXPHOS disease (Rodenburg 2011). Patients share a similar biochemical phenotype, with a significant decrease in the activity of mitochondrial complex V, mitochondrial adenosine triphosphate (ATP) synthase.

Severe neonatal-onset mitochondrial encephalopathy and/or cardiomyopathy are the most common clinical phenotypes associated with complex V nuclear gene defects. The majority of patients present with severe lactic acidosis and 3-methylglutaconic aciduria (Hejzlarová et al. 2014; Jonckheere et al. 2012). Additional clinical symptoms may include respiratory distress, hypotonia, ataxia, dysmorphism, and psychomotor delay or regression.

Genetics

Mitochondrial complex V deficiency is caused by defects in the mitochondrial adenosine triphosphate (ATP) synthase, the fifth multi-subunit oxidative phosphorylation (OXPHOS) complex (Jonckheere et al. 2012; Hejzlarová et al. 2014). Although over 20 genes have been implicated in the assembly, structure, and function of this complex, variants in only six of these genes (ATP5F1A, ATP5F1E, ATPAF2, TMEM70, MT-ATP6, and MT-ATP8) have been linked to disease. Depending on the cellular localization of the affected gene, this disorder may have an autosomal recessive or maternal mode of inheritance. Causative variants in the nuclear genes (ATP5F1A, ATP5F1E, ATPAF2, and TMEM70) are inherited in an autosomal recessive manner. In contrast, causative variants in the MT-ATP6 or MT-ATP8 genes, which are encoded by the mitochondrial genome, are inherited in a maternal manner.

This NextGen Panel covers the four nuclear genes (ATP5F1A, ATP5F1E, ATPAF2, and TMEM70) that have been associated with mitochondrial complex V deficiency. This panel does not cover MT-ATP6 or MT-ATP8.

TMEM70: Defects in the TMEM70 gene appear to be the most frequent cause of mitochondrial complex V deficiency, with approximately 50 cases described to date (Hejzlarová et al. 2014). TMEM70 is required to maintain normal expression levels of complex V, although the exact function of this mitochondrial transmembrane protein is unknown (Cizková et al. 2008). Approximately 15 pathogenic variants have been reported in the TMEM70 gene, the majority of which are missense or nonsense (Human Gene Mutation Database). However, several small deletions and insertions, splicing variants, and gross deletions have also been documented.

ATP5F1A: The ATP5A1 gene encodes for subunit α of the F1 catalytic complex in the mitochondrial ATP synthase. Two pathogenic missense variants have been identified in this gene (Jonckheere et al. 2013; Lieber et al. 2013).

ATP5F1E: The ATP5F1E gene encodes subunit ε of the F1 catalytic complex in the mitochondrial ATP synthase. Although the exact function of this protein is still unclear, ATP5E may play a role in F1 complex assembly (Havlíčková et al. 2010). Only one pathogenic variant, a homozygous missense change, has been reported in ATP5F1E (Mayr et al. 2010).

ATPAF2: The ATPAF2 gene (also referred to as Atp12p in the literature) encodes a chaperone protein thought to prevent aggregation of the F1 alpha subunit prior to its integration into the mitochondrial ATP synthase complex (Wang et al. 2001; Ackerman 2002). Only one pathogenic variant, a homozygous missense change, has been documented in this gene (De Meirleir et al. 2004; Meulemans et al. 2010).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in TMEM70 appear to be the most frequent cause of mitochondrial complex V deficiency associated with nuclear gene defects. In one cohort of nine complex V-deficient patients who tested negative for pathogenic variants in mtDNA, all nine patients (100%) carried homozygous or compound heterozygous pathogenic variants in TMEM70 (Diodato et al. 2015). Clinical sensitivities for ATP5F1A, ATP5F1E, and ATPAF2 are difficult to estimate, as only a few affected individuals have been described with defects in these genes.

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 full coverage as >20X NGS reads or Sanger sequencing.

Due to sequence similarity with other genomic sites, the entire coding region of ATP5F1A (12 exons), in addition to ~10 bp of adjacent noncoding sequence of each exon, is bi-directionally sequenced using Sanger sequencing technology.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test include patients with a deficiency of mitochondrial complex V, or those who present with symptoms consistent with complex V deficiency.

Genes

Official Gene Symbol OMIM ID
ATP5F1A 164360
ATP5F1E 606153
ATPAF2 608918
TMEM70 612418
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Ackerman S.H. et al. 2002. Biochimica et Biophysica Acta. 1555:101-5. PubMed ID: 12206899
  • Cizková A. et al. 2008. Nature Genetics. 40:1288-90. PubMed ID: 18953340
  • De Meirleir L. et al. 2004. Journal of Medical Genetics. 41:120-4. PubMed ID: 14757859
  • Diodato D. et al. 2015. JIMD Reports. 15:71-8. PubMed ID: 24740313
  • Havlíčková V. et al. 2010. Biochimica et Biophysica Acta. 1797:1124-9. PubMed ID: 20026007
  • Hejzlarová K. et al. 2014. Physiological Research. 63:S57-71. PubMed ID: 24564666
  • Human Gene Mutation Database (Bio-base).
  • Jonckheere A.I. et al. 2012. Journal of Inherited Metabolic Disease. 35:211-25. PubMed ID: 21874297
  • Jonckheere A.I. et al. 2013. Brain. 136:1544-54. PubMed ID: 23599390
  • Lieber D.S. et al. 2013. Neurology. 80:1762-70. PubMed ID: 23596069
  • Mayr J.A. et al. 2010. Human Molecular Genetics. 19:3430-9. PubMed ID: 20566710
  • Meulemans A. et al. 2010. Journal of Biological Chemistry. 285:4099-109. PubMed ID: 19933271
  • Rodenburg R.J. 2011. Journal of Inherited Metabolic Disease. 34:283-92. PubMed ID: 20440652
  • Wang Z.G. et al. 2001. Journal of Biological Chemistry. 276:30773-8. PubMed ID: 11410595

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.

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

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ORDER OPTIONS

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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.

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