Mitochondrial Complex III Deficiency via the CYC1 Gene

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).

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).

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).

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).