Mitochondrial Complex IV Deficiency via the COA3 Gene

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).

Developmental delay, neuropathy, exercise intolerance, mildly elevated plasma lactate, dysmorphic features, obesity, and short stature have been associated with COA3-related mitochondrial complex IV deficiency (Ostergaard et al. 2015). 

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 COA3, exhibit an autosomal recessive mode of inheritance.

The COA3 gene, spanning 2 exons, encodes an assembly factor for mitochondrial complex IV (Ostergaard et al. 2015). Only two pathogenic variants in the COA3 gene have been described to date, including one missense variant and one single nucleotide duplication that results in a frameshift and premature protein termination (Ostergaard et al. 2015; Human Gene Mutation Database).

Due to the paucity of reported patients, clinical sensitivity for COA3-related mitochondrial complex IV deficiency is difficult to estimate at this time (Ostergaard et al. 2015). Both reported pathogenic variants in this gene are detectable by sequencing.

This test provides full coverage of all coding exons of the COA3 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).