Mitochondrial Complex IV Deficiency via the PET100 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, hypertrophic 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).

PET100-related CIV deficiency has been reported in affected individuals of seven families to date; in six of these families, a shared founder mutation was identified (Lim et al. 2014; Oláhová et al. 2015). Affected individuals presented with either fatal neonatal lactic acidosis or a severe Leigh-like disease within the first year of life. Seizures were evident in all cases reported to date.

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 PET100, exhibit autosomal recessive inheritance.

The PET100 gene encodes for a CIV assembly factor (Lim et al. 2014). One missense variant and one nonsense variant have been reported in the PET100 gene to date (Human Gene Mutation Database). The missense variant, which results in the substitution of the initiation codon for an isoleucine, is a founder mutation that was identified in patients with Lebanese ancestry (Lim et al. 2014).

At this time, due to the limited number of reported cases and the absence of large cohort studies, the clinical sensitivity of PET100-related mitochondrial complex IV deficiency is difficult to estimate. Analytical sensitivity is expected to be high, as all reported variants to date may be identified via sequencing.

This test provides full coverage of all coding exons of the PET100 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.