Submission Details

The relationship between ATPAF2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The ATPAF2 gene encodes the ATP synthase mitochondrial F1 complex assembly factor 2. Defects of this protein lead to complex V deficiency.

The ATPAF2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2004 (PMID: 14757859). While various names have been given to the constellation of features seen in those with ATPAF2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the ATPAF2 phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two homozygous missense variants in two cases from two publications (PMIDs: 14757859, 30369941). Additional cases have been reported (PMIDS: 34440436, 30919572) but insufficient clinical and biochemical details were provided precluding consideration in this curation. The first reported individual was a child who presented shortly after birth with dysmorphic features (large mouth, prominent nasal bridge, micrognathia, rocker bottom feet), and flexion contractures of the limbs associated with camptodactylia as well as hypertonicity, poor suck, hepatomegaly, and hypoplastic kidneys. Metabolic screening showed increased urinary lactate, fumarate, methylglutaconic acid, and amino acids and cerebrospinal fluid lactate was mildly elevated at 2.9 mmol/l. Brain magnetic resonance imaging (MRI) revealed marked cortical–subcortical atrophy, dysgenesis of the corpus callosum with absent anterior genu and rostrum, and hypoplasia of white matter, along with basal ganglia and thalamic atrophy. This child also had severe developmental delay, seizures, and faltering growth, and died at the age of 14 months from recurrent infection. Complex V deficiency was noted in muscle and liver (PMID: 14757859). The second individual had intellectual disability, ataxia, exercise intolerance, 3-methylglutaconic aciduria, and complex V deficiency in muscle and fibroblasts (PMID: 30369941).

Loss of function resulting in a complex V deficiency is the mechanism of disease. This gene-disease association is also supported by known biochemical function and model systems in mice (knock-out mouse model is embryonic lethal) and Saccharomyces cerevisiae (PMIDs: 35330152, 34375736, 2142305).

In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 4, 2022 (SOP Version 8).