Mitochondrial Complex III Deficiency Panel (Nuclear Genes)

Mitochondrial complex III (CIII) deficiency is characterized by a deficiency of the third oxidative phosphorylation complex, also referred to as cytochrome bc1 (Fernández-Vizarra and Zeviani 2015). Significant clinical and genetic heterogeneity is observed between affected individuals. Similar to other OXPHOS disorders, recurrent lactic acidosis is a prevalent finding in patients with CIII deficiency, particularly during infections. Additional clinical features may include severe psychomotor delay or impairment, ataxia, muscle weakness, respiratory insufficiency, encephalomyopathy, hypoglycemia, and/or Leigh or Leigh-like syndrome (Fernández-Vizarra and Zeviani 2015; Dallabona et al. 2016; Ardissone et al. 2015). The majority of CIII deficient patients present within the first year of life; however, several individuals with defects in the TTC19 gene presented with an adult-onset disorder initially characterized by psychiatric symptoms (Ardissone et al. 2015).

Pathogenic variants in BCS1L are the most frequent cause of mitochondrial CIII deficiency, and may account for several distinct disease manifestations, including GRACILE syndrome (Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death) or neonatal proximal tubulopathy and/or liver failure with or without encephalopathy (Fernández-Vizarra and Zeviani 2015). BCS1L-associated CIII deficiency may also present as Björnstad syndrome, a milder disorder characterized by sensorineural hearing loss and pili torti (Hinson et al. 2007).

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) (Sazanov 2015).

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. 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.

This NextGen Panel covers nine nuclear genes (BCS1L, CYC1, LYRM7, TTC19, UQCC2, UQCC3, UQCRB, UQCRC2, and UQCRQ) that have been associated with mitochondrial complex III deficiency. This panel does not cover MT-CYB.

Please visit individual gene test descriptions for more information regarding each of these genes.

Many of the genes in this NextGen Panel have only been linked to disease in one or two families to date, making clinical sensitivity difficult to estimate. In one cohort, isolated mitochondrial CIII deficiency accounted for approximately 5% of all oxidative phosphorylation (OXPHOS) disorders (Skladal et al. 2003).

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. 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).

One pre-coding variant (c.-147A>G) and one deep intronic variant (c.-50+155T>A) in the BSC1L gene are also covered in this test (Gil-Borlado et al. 2009; Visapää et al. 2002; Lynn et al. 2012).

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).