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Mitochondrial Complex IV Deficiency via the COA8/APOPT1 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
8571 COA8 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8571COA881479 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.

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 complex IV (CIV) deficiency is characterized by a deficiency of the fourth oxidative phosphorylation (OXPHOS) complex of the mitochondrial respiratory chain (Fassone and Rahman 2012). Primary mitochondrial CIV deficiency is estimated to account for approximately one-fifth of all OXPHOS disorders (Skladal et al. 2003; Scaglia et al. 2004).

The majority of CIV-deficient patients present with a severe, early-onset disease within the first year of life. Similar to other OXPHOS disorders, recurrent lactic acidosis is a prevalent finding in affected individuals. Patients may display significant heterogeneity in additional clinical features, which can include encephalopathy, hypertropic cardiomyopathy, hypotonia, epilepsy, microcephaly, dystonia, psychomotor delay or impairment, nystagmus, respiratory insufficiency, ataxia, muscle weakness, and/or CIV-deficient Leigh or Leigh-like syndrome (Pecina et al. 2004; Darin et al. 2003; Alfadhel et al. 2011). Leigh syndrome (LS) is a severe, progressive encephalopathy characterized by psychomotor delay or regression; isolated or combined mitochondrial complex deficiencies; elevated levels of lactate in the blood and/or cerebral spinal fluid; bilateral symmetrical lesions in the brainstem and basal ganglia; and neurologic manifestations such as hypotonia or ataxia (Rahman and Thorburn 2015; Lake et al. 2015).

COA8/APOPT1-related CIV deficiency has been reported in at least five unrelated families to date (Melchionda et al. 2014). In contrast to the majority of CIV-deficient patients, patients with defects in COA8 displayed a slightly later age at onset (~2.5-5 years of age); in at least one individual, symptoms were subclinical through early adolescence. All affected individuals underwent a period of acute regression (loss of developmental milestones/speech, episodes with somnolence and seizure, and pyramidal signs that developed into spastic tetraparesis), but stabilized and/or partially recovered after several months or years. In all cases, a distinctive cavitating leukodystrophy involving the posterior cerebral white matter and corpus callosum was identified via MRI during the acute stage of disease. Long-term survival was reported in all patients.

Genetics

The cytochrome c oxidase enzyme, also referred to as mitochondrial complex IV (CIV) or COX, is the terminal oxidase of the mitochondrial respiratory chain. Over 30 genes are involved in the structure, assembly, or function of this enzyme (Kadenbach and Hüttemann 2015). Primary mitochondrial CIV deficiency has been linked to pathogenic variants in approximately half of these genes to date. Three CIV subunits (MT-CO1, MT-CO2, and MT-CO3), which form the catalytic core of the enzyme, are encoded by the mitochondrial genome. Pathogenic variants in MT-CO1, MT-CO2, and MT-CO3 are maternally inherited (Rak et al. 2016). Defects in the remaining nuclear-encoded genes, including COA8, exhibit autosomal recessive inheritance.

The biological function of COA8 is still under debate; this protein may have a pro-apoptotic role or may function in mitochondrial anti-ROS defense mechanisms (Yasuda et al. 2006; Melchionda et al. 2014). One missense, one nonsense, and one splicing variant have been identified as causative for COA8-related CIV deficiency, in addition to one small and one gross deletion (Melchionda et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

At this time, due to the limited number of reported cases (<10), the clinical sensitivity of COA8-related mitochondrial complex IV deficiency is difficult to estimate, although it is expected to be a rare cause of this disease. Four of the five reported variants in this gene are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the COA8 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

COA8 sequencing should be considered for patients who present with symptoms consistent with mitochondrial complex IV (CIV) deficiency or for individuals with a family history of mitochondrial CIV deficiency. We will also sequence the COA8 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
COA8 616003
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mitochondrial Complex IV Deficiency AR 220110

Related Tests

Name
TACO1-Related Leigh Syndrome (LS) via the TACO1 Gene
Mitochondrial Complex IV Deficiency via the COA3 Gene
Mitochondrial Complex IV Deficiency via the COX14 Gene
Mitochondrial Complex IV Deficiency via the COX20 Gene
Mitochondrial Complex IV Deficiency via the COX6B1 Gene
Mitochondrial Complex IV Deficiency via the FASTKD2 Gene
Mitochondrial Complex IV Deficiency via the SCO1 Gene

Citations

  • Alfadhel et al. 2011. PubMed ID: 21412973
  • Darin et al. 2003. PubMed ID: 14681757
  • Fassone and Rahman. 2012. PubMed ID: 22972949
  • Kadenbach and H├╝ttemann. 2015. PubMed ID: 26190566
  • Lake et al. 2015. PubMed ID: 25978847
  • Melchionda L. et al. 2014. American Journal of Human Genetics. 95:315-25. PubMed ID: 25175347
  • Pecina et al. 2004. PubMed ID: 15119951
  • Rahman and Thorburn. 2015. PubMed ID: 26425749
  • Rak et al. 2016. PubMed ID: 26846578
  • Scaglia et al. 2004. PubMed ID: 15466086
  • Skladal et al. 2003. PubMed ID: 12805096
  • Yasuda O. et al. 2006. Journal of Biological Chemistry. 281:23899-907. PubMed ID: 16782708

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.
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