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Mitochondrial Complex III Deficiency via the CYC1 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
8433 CYC1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8433CYC181479 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

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

Mitochondrial complex III (CIII) deficiency is characterized by a deficiency of the third oxidative phosphorylation complex, also referred to as the cytochrome bc1 complex (Fernández-Vizarra and Zeviani 2015). In one cohort, primary mitochondrial CIII deficiency accounted for approximately 5% of all oxidative phosphorylation (OXPHOS) disorders (Skladal et al. 2003).

The majority of CIII deficient patients manifest symptoms within the first year of life, although significant clinical and genetic heterogeneity may be observed among affected individuals. Similar to other OXPHOS disorders, a prevalent finding in patients with CIII deficiency is recurrent lactic acidosis, which may be triggered by infections. Additional clinical features may include severe psychomotor delay or impairment, ataxia, muscle weakness, respiratory insufficiency, and/or encephalomyopathy (Fernández-Vizarra and Zeviani 2015; Dallabona et al. 2016; Ardissone et al. 2015). A subset of CIII deficient patients are diagnosed with Leigh syndrome, a subacute necrotizing encephalopathy characterized by elevated levels of lactate in blood and cerebral spinal fluid; bilateral symmetric necrotic lesions in the basal ganglia, brain stem, thalamus, and/or spinal cord; psychomotor delay or regression; and neurologic manifestations such as hypotonia or ataxia (Atwal 2014; Barel et al. 2008).

CYC1-associated mitochondrial CIII deficiency has been identified in three unrelated individuals to date (Gaignard et al. 2013; Anastasio et al. 2016). All patients presented with severe, neonatal or infantile-onset recurrent metabolic acidosis with or without liver failure. In contrast to UQCRB- and UQCRC2-deficient patients who presented with transient hypoglycemia, all CYC1-deficient patients presented with severe hyperglycemia (Haut et al. 2003; Miyake et al. 2013; Gaignard et al. 2013; Anastasio et al. 2016).

Genetics

The mitochondrial respiratory chain complex III (CIII) is composed of 10 nuclear-encoded subunits and one mitochondrial-encoded subunit (MT-CYB), while several additional nuclear-encoded proteins are required for complex assembly (Fernández-Vizarra and Zeviani 2015). The resulting holoenzyme complex plays a critical role in redox-driven proton translocation, which ultimately results in synthesis of adenosine triphosphate (ATP).

Due to the many structural and accessory subunits required to support the assembly and function of the third complex, mitochondrial CIII deficiency is a genetically heterogeneous disorder, and at least 10 genes have been linked to this disease to date. 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 (BCS1L, CYC1, LYRM7, TTC19, UQCC2, UQCC3, UQCRB, UQCRC2, and UQCRQ) are inherited in an autosomal recessive manner. In contrast, causative variants in the MT-CYB gene, which is encoded by the mitochondrial genome, are inherited in a maternal manner.

The CYC1 gene encodes for the cytochrome c1 subunit of the mitochondrial CIII (Gaignard et al. 2013). Two pathogenic missense variants have been reported in patients with CYC1-associated mitochondrial CIII deficiency (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

At this time, due to the limited number of reported cases, the clinical sensitivity of CYC1-related mitochondrial complex III deficiency is difficult to estimate. All reported pathogenic variants in this gene are detectable by sequencing (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the CYC1 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

Candidates for this test include patients with a deficiency of mitochondrial complex III, or those who present with symptoms consistent with complex III deficiency. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CYC1.

Gene

Official Gene Symbol OMIM ID
CYC1 123980
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mitochondrial Complex III Deficiency, Nuclear Type 6 AR 615453

Related Tests

Name
Mitochondrial Complex III Deficiency Panel (Nuclear Genes)
Mitochondrial Complex III Deficiency via the LYRM7 Gene
Mitochondrial Complex III Deficiency via the TTC19 Gene
Mitochondrial Complex III Deficiency via the UQCC2 Gene
Mitochondrial Complex III Deficiency via the UQCC3 Gene
Mitochondrial Complex III Deficiency via the UQCRB Gene
Mitochondrial Complex III Deficiency via the UQCRQ Gene

Citations

  • Anastasio N. et al. 2016. JIMD Reports. DOI 10.1007/8904_2016_557. PubMed ID: 27074787
  • Ardissone A. et al. 2015. JIMD Reports. 22:115-20. PubMed ID: 25772319
  • Atwal P.S. et al. 2014. JIMD Reports. 14:43-5. PubMed ID: 24368687
  • Barel O. et al. 2008. American Journal of Human Genetics. 82:1211-6. PubMed ID: 18439546
  • Dallabona C. et al. 2016. Brain. 139:782-94. PubMed ID: 26912632
  • Fern├índez-Vizarra E., Zeviani M. 2015. Frontiers Genetics. 6:134. PubMed ID: 25914718
  • Gaignard P. et al. 2013. American Journal of Human Genetics. 93:384-9. PubMed ID: 23910460
  • Haut S. et al. 2003. Human Genetics. 113:118-22. PubMed ID: 12709789
  • Human Gene Mutation Database (Bio-base).
  • Miyake N. et al. 2013. Human Mutation. 34:446-52. PubMed ID: 23281071
  • Skladal D. et al. 2003. Clinical Pediatrics. 42:703-10. PubMed ID: 14601919

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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