Mitochondrial Complex V Deficiency via the ATP5F1A (ATP5A1) Gene

Mitochondrial complex V 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, with 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 complex V-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.

To date, ATP5F1A-associated mitochondrial complex V deficiency has been documented in only four patients from two different families (Jonckheere et al. 2013; Lieber et al. 2013). Two of the affected individuals presented as neonates with isolated complex V deficiency, severe encephalopathy, intractable seizures, nystagmus, hypoplastic lungs, and renal cysts (Jonckheere et al. 2013). Clinical features of the remaining two neonates included a combined oxidative phosphorylation deficiency, mtDNA depletion, failure to thrive, microcephaly, encephalopathy, hypotonia, pulmonary hypertension, and heart failure (Leiber et al. 2013).

Mitochondrial complex V 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, and function of the mitochondrial ATP synthase, variants in only six of these genes (ATP5F1A, 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 (ATP5F1A, ATP5E, ATPAF2, and TMEM70) are inherited in an autosomal recessive 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.

The ATP5F1A gene encodes for subunit α of the F₁ catalytic complex in the mitochondrial ATP synthase. To date, only two pathogenic missense variants have been identified as a cause of ATP5F1A-associated mitochondrial complex V deficiency (Jonckheere et al. 2013; Lieber et al. 2013).

Defects in ATP5F1A appear to be a rare cause of mitochondrial complex V deficiency, as only four patients from two separate families have been described (Jonckheere et al. 2013; Lieber et al. 2013). In contrast, defects in TMEM70 appear to be the most frequent cause of this disorder, with over fifteen pathogenic variants reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ATP5F1A 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).