Mitochondrial Complex V Deficiency via the TMEM70 Gene

Primary mitochondrial complex V (CV) deficiency is considered the rarest oxidative phosphorylation (OXPHOS) complex disorder, accounting for approximately one percent of all OXPHOS disease (Rodenburg 2011). Although patients share a similar biochemical phenotype, displaying a significant decrease in the activity of mitochondrial complex V, the phenotypic disease spectrum can be broad (Hejzlarová et al. 2014; Jonckheere et al. 2012). Defects in CV-associated nuclear genes often result in a severe, neonatal-onset mitochondrial encephalopathy and/or cardiomyopathy. In contrast, pathogenic variants in genes encoded by the mitochondrial genome (such as MT-ATP6 or MT-ATP8) may lead to NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh syndrome), or bilateral striatal necrosis.

Patients with pathogenic variants in the TMEM70 gene usually present during the neonatal stage with CV deficiency, lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy (Magner et al. 2015). Other symptoms may include hypotonia, respiratory distress, developmental delay, facial dysmorphism, pulmonary arterial hypertension, and/or microcephaly. TMEM70-associated CV deficiency may be more prevalent in patients with Roma ancestry due to the presence of a founder pathogenic variant in this population.

Primary mitochondrial CV deficiency is caused by defects in the mitochondrial adenosine triphosphate (ATP) synthase, the fifth multi-subunit oxidative phosphorylation (OXPHOS) complex (Jonckheere et al. 2012; Hejzlarová et al. 2014). Although over 20 genes have been implicated in the assembly, structure, or function of the mitochondrial ATP synthase, variants in only six of these genes (ATP5A1, ATP5E, ATPAF2, TMEM70, MT-ATP6, and MT-ATP8) have been linked to 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 (ATP5A1, ATP5E, ATPAF2, and TMEM70) are inherited in an autosomal recessive (AR) manner. In contrast, causative variants in the MT-ATP6 or MT-ATP8 genes, which are encoded by the mitochondrial genome, are inherited in a maternal manner.

TMEM70 is required to maintain normal expression levels of complex V, although the exact function of this mitochondrial transmembrane protein is unknown (Cízková et al. 2008). Defects in the TMEM70 gene appear to be the most frequent cause of mitochondrial CV deficiency, with over fifteen unique variants reported in this gene to date (Hejzlarová et al. 2014; Magner et al. 2015). The majority of pathogenic changes in this gene are missense or nonsense variants, although several small deletions, insertions, and splicing variants have been described (Human Gene Mutation Database). Two large deletions in TMEM70 have also been reported (Jonckheere et al. 2011; Tort et al. 2011).

The pathogenic splicing variant, c.317-2A>G, is prevalent in the Roma population, although this variant has also been occasionally identified in patients of non-Roma origin (Magner et al. 2015).

Defects in TMEM70 appear to be the most frequent cause of mitochondrial complex V deficiency, with over fifteen variants reported (Human Gene Mutation Database). No large cohort studies have been described to date, however, making clinical sensitivity difficult to estimate.

This test provides full coverage of all coding exons of the TMEM70 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).