Mitochondrial Complex IV Deficiency via the COX10 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. 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, usually manifesting during an intercurrent illness followed by decompensation (Rahman and Thorburn. 2015. PubMed ID: 26425749). 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. 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).

COX10-associated CIV deficiency has been reported in fewer than 15 individuals to date, and is a rare form of CIV deficiency; one report indicates that COX10 likely contributes to less than 5% of CIV-deficient Leigh syndrome cases (Rahman and Thorburn. 2015. PubMed ID: 26425749). In contrast, SURF1-associated CIV deficiency likely contributes to ~50% of cases (Rahman and Thorburn. 2015. PubMed ID: 26425749).

Individuals affected with COX10-associated CIV deficiency typically present with neonatal or infantile-onset metabolic acidosis coupled with Leigh syndrome or hypertrophic cardiomyopathy (Coenen et al. 2004. PubMed ID: 15455402; Antonicka et al. 2003. PubMed ID: 12928484; Valnot et al. 2000. PubMed ID: 10767350; Kohda et al. 2016. PubMed ID: 26741492). Other manifestations may include respiratory failure, anemia, sensorineural deafness, ataxia, hypotonia, seizures, and/or nystagmus. Prognosis for this disease is often poor, with the majority of individuals passing away within the first few years of life. However, at least one individual was reported to survive into adulthood with fairly mild symptoms, including myopathy, demyelinating neuropathy, premature ovarian failure, short stature, hearing loss, pigmentary maculopathy, and renal tubular dysfunction (Pitceathly et al. 2013. PubMed ID: 24100867).

Treatment for COX10-associated CIV deficiency consists of supportive care, such as management of seizures with appropriate antiepileptic drugs, nutritional counseling, symptomatic treatment of acute episodes of acidosis, and/or routine surveillance by a cardiologist as needed (Rahman and Thorburn. 2015. PubMed ID: 26425749).

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, including COX10, exhibit autosomal recessive inheritance. Pathogenic variants in SURF1 are the most frequent cause of CIV deficiency, accounting for roughly half of cases (Rahman and Thorburn. 2015. PubMed ID: 26425749). Other less common nuclear genes associated with isolated CIV deficiency may include APOPT1, COA3, COA5, COA6, COX8A, COX14, COX15, COX20, COX6B1, FASTKD2, LRPPRC, PET100, SCO1, SCO2, and TACO1.

The majority of variants reported in the COX10 gene to date are missense, although one single nucleotide duplication and one large deletion have been reported (Human Gene Mutation Database). Most of the reported variants appear to be private familial variants, although a common 17p12 deletion, which disrupts the last two exons in COX10, has been reported in multiple families and is also responsible for hereditary neuropathy with liability to pressure palsies (HNPP), an autosomal dominant disorder of variable expressivity and incomplete penetrance. HNPP is a result of haploinsufficiency of the nearby PMP22 gene (Kohda et al. 2016. PubMed ID: 26741492; Bird et al. 2014. PubMed ID: 20301566; Inoue et al. 2001. PubMed ID: 11381029). Another missense variant in COX10, p.Asp336Val, was previously reported in two separate families (Antonicka et al. 2003. PubMed ID: 12928484; Pitceathly et al. 2013. PubMed ID: 24100867) and is present at a minor allele frequency of up to ~0.017% in non-Finnish Europeans in the gnomAD database (https://gnomad.broadinstitute.org/variant/17-14110205-A-T).

The COX10 gene encodes a mitochondrial complex IV assembly factor that plays a key role in the mitochondrial heme biosynthetic pathway (Glerum and Tzagoloff. 1994. PubMed ID: 8078902). Specifically, COX10 functions as a farnesyltransferase that transfers a farnesyl group to protoheme (heme B) to generate heme O.

Carriers of most COX10 pathogenic variants appear to be asymptomatic for CIV deficiency, although carriers of the large 17p12 deletion may present with autosomal dominant HNPP as a result of haploinsufficiency of the nearby PMP22 gene (Rahman and Thorburn. 2015. PubMed ID: 26425749; Inoue et al. 2001. PubMed ID: 11381029). In an immortalized skin fibroblast cell line lacking COX10 activity, which was established from a homozygous mouse model for the floxed COX10 gene, authors of one study demonstrated complete loss of detectable mitochondrial complex IV activity in the resulting tissue, as well as a reduction in the levels of mitochondrial complex I and abnormal mitochondrial morphology (Diaz et al. 2006. PubMed ID: 16782876). The OGEE (Online Gene Essentiality) database lists the COX10 gene as a conditional essential gene for tissue culture (http://ogee.medgenius.info/browse/).

Due to the paucity of reported patients (<15), clinical sensitivity for COX10-related mitochondrial complex IV deficiency is difficult to estimate at this time, although it is likely to be a rare cause of this disease. Only one large CNV, a deletion of the last two exons of COX10, has been reported as a cause of disease in at least one affected individual who harbored a second plausible causative variant (Kohda et al. 2016. PubMed ID: 26741492). However, this relatively common 17p12 deletion has been seen in multiple families in association with autosomal dominant hereditary neuropathy with liability to pressure palsies due to haploinsufficiency of the nearby PMP22 gene (Inoue et al. 2001. PubMed ID: 11381029).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides coverage of all coding exons of the COX10 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).

Please note that one exon (exon 6) shares high sequence similarity with a pseudo-exon within CDRT1 on chromosome 17. Due to the shared sequence similarity, this exon is covered using gene-specific primers via Sanger sequencing.

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).