Mitochondrial Complex IV Deficiency Panel (Nuclear Genes)

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. PubMed ID: 22972949). Primary mitochondrial CIV deficiency is estimated to account for approximately one-fifth of all OXPHOS disorders (Skladal et al. 2003. PubMed ID: 12805096; Scaglia et al. 2004. PubMed ID: 15466086).

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. PubMed ID: 15119951; Darin et al. 2003. PubMed ID: 14681757; Alfadhel et al. 2011. PubMed ID: 21412973).

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. PubMed ID: 26425749; Lake et al. 2015. PubMed ID: 25978847; Tiranti et al. 1998. PubMed ID: 9837813). The French-Canadian form of CIV-deficient LS is the result of a founder mutation in the LRPPRC gene in the Saguenay-Lac-Saint-Jean population of northern Québec, Canada (Debray et al. 2011. PubMed ID: 21266382). Acute metabolic crises, which are rare in patients with SURF1-related LS, are common in patients with the French-Canadian form of disease.

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. PubMed ID: 26190566). 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. PubMed ID: 26846578). Defects in the remaining nuclear-encoded genes exhibit an autosomal recessive mode of inheritance.

This NextGen Panel covers sixteen nuclear genes (COA8/APOPT1, COA3, COA5, COA6, COX10, COX14, COX15, COX20, COX6B1, FASTKD2, LRPPRC, PET100, SCO1, SCO2, SURF1, and TACO1) that have been shown to be involved in primary mitochondrial CIV deficiency. This panel does not cover the mitochondrial genes MT-CO1, MT-CO2, or MT-CO3. Additionally, due to sequence similarity with other genomic sites, exon 6 of COX10 is not available at this time.

In the general population, pathogenic variants in the SURF1 gene appear to be the most frequent cause of CIV deficiency, with over 90 causative variants reported in this gene to date (Wedatilake et al. 2013. PubMed ID: 23829769; Human Gene Mutation Database). Pathogenic variants in the SCO2 gene are also prevalent, with approximately 25 unique variants reported.

A number of founder mutations have been documented for this disorder. In the Saguenay-Lac-Saint-Jean region of northern Québec, Canada, a founder mutation (Ala354Val) in the LRPPRC gene is responsible for the majority of cases (estimated carrier rate: 1 in 23) (Morin et al. 1993. PubMed ID: 8392291; Mootha et al. 2003. PubMed ID: 12529507). At least one pathogenic variant (Ser282Cysfs*9) in the SURF1 gene has been described among patients with Slavic ancestry (Böhm et al. 2006. PubMed ID: 16326995). In the Lebanese population, a pathogenic G>C change was identified within the initiation codon of the PET100 gene (Lim et al. 2014. PubMed ID: 24462369). Finally, the Glu140Lys change in the SCO2 gene is predominant among patients originating from Central-Eastern Europe (Pronicka et al. 2013. PubMed ID: 23719228).

Please visit individual gene test descriptions for more information regarding each of the genes included in this panel.

Clinical sensitivity is difficult to estimate for this panel, as previously published studies have utilized different clinical features for inclusion into their respective cohorts. Additionally, defects in many genes in this panel have only been identified in a few families to date.

In a group of 1,200 patients who presented under the broad category of ‘mitochondrial disorder’, 20 patients (~1.7%) harbored pathogenic variants in SURF1 (Mancuso et al. 2016. PubMed ID: 27020842). In a separate study of 605 patients who presented with a mitochondrial neuropathy, 7 patients (~1.2%) presented with SURF1 defects (Bindu et al. 2015. PubMed ID: 26341968). In another study of 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies, 1 patient (~0.7%) had causative variants in COX10 (Kohda et al. 2016. PubMed ID: 26741492).

However, in a more narrowly-defined cohort of 25 children with a Leigh syndrome diagnosis, 4 individuals (16%) had causative variants in SURF1 (Sonam et al. 2014. PubMed ID: 24262866). Finally, in a small cohort of 10 mitochondrial complex IV (CIV)-deficient patients, 4 patients (40%) harbored homozygous or compound heterozygous causative variants in SURF1, and one patient (10%) had a pathogenic homozygous missense variant in COX10. No plausible causative variants were identified in the SCO1 or SCO2 genes in the remaining five patients (Coenen et al. 2006. PubMed ID: 16948936).

Clinical sensitivity is expected to be high in individuals of certain ancestries due to founder effects. In a group of patients with French-Canadian Leigh syndrome (LS), 56/56 (100%) harbored pathogenic variants in LRPPRC; with one exception, all patients were homozygous for the Ala354Val change (Debray et al. 2011. PubMed ID: 21266382). In a different cohort of 180 children with CIV deficiency, 47 (~26%) carried causative variants in SURF1, primarily due to the Slavic founder variant (Ser282Cysfs*9) identified in the heterozygous or homozygous state in 31 individuals (~17%) (Böhm et al. 2006. PubMed ID: 16326995). Six additional patients (~3%) in the same cohort harbored pathogenic variants in the SCO2 gene. The Glu140Lys missense variant in SCO2 was identified in the homozygous or compound heterozygous state in 36 of 36 Polish patients (100%) (Pronicka et al. 2013. PubMed ID: 23719228). Finally, two of three CIV-deficient patients (66.7%) of Lebanese descent were homozygous for the causative p.Met1? variant in PET100 (Lim et al. 2014. PubMed ID: 24462369).

For COA8, COA3, COA5, COA6, COX14, COX15, COX20, COX6B1, FASTKD2, and TACO1, no large cohort studies have been reported, making clinical sensitivity difficult to estimate.

Gross deletions or insertions are expected to be a rare cause of complex IV deficiency in the COA8, COX10, SCO2, and SURF1 genes (Human Gene Mutation Database). No large deletions or insertions have been reported in the COA3, COA5, COA6, COX14, COX15, COX20, COX6B1, FASTKD2, LRPPRC, PET100, SCO1, or TACO1 genes to date.

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 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).