Submission Details

The relationship between BOLA3 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 24, 2023. The BOLA3 gene encodes bola family member 3, a mitochondrial iron-sulfur (Fe-S) cluster assembly factor involved in iron-sulfur cluster biogenesis. Iron-sulfur clusters are necessary for electron transport through oxidative phosphorylation (OXPHOS) as well for other cellular proteins, including for normal maturation of lipoate-containing enzymes and for assembly of OXPHOS complexes.

The BOLA3 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID: 21944046). While various names have been given to the constellation of features seen in those with BOLA3-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the BOLA3 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants from five individuals from three publications (PMIDs: 21944046, 22562699, 24334290). More cases are reported in the medical literature (PMIDs: 26741492, 30302924, 29353736, 29654549, 32742935, 35803560) but not included in this curation as the maximum case level score was reached. Affected individuals are variably affected although onset tends to be infantile and early death may occur. Most reported individuals have leukodystrophy and seizures, but additional clinical features include neurodegeneration, spasticity, contractures, lethargy, myoclonus, ataxia, choreoathetoid movements, irritability, intellectual disability, developmental delay, developmental regression, hypertrophic or dilated cardiomyopathy, feeding difficulty, failure to thrive, vomiting, diarrhea, hepatomegaly, respiratory insufficiency, and optic atrophy. Brain imaging has shown changes in white matter, midbrain, cerebral/cerebellar atrophy, and cervical spine. Lab abnormalities include lactic acidosis, elevated glucose, elevated plasma glycine, elevated tricarboxylic acid (TCA) cycle metabolites on urine organic acids, and decreased activity of 2-oxoacid dehydrogenases and the glycine cleavage enzyme. Muscle biopsies have shown variable decreased activities of OXPHOS complexes I, II, II + III, and IV (also decreased in fibroblasts) and decreased pyruvate dehydrogenase complex activity. Some individuals have normal OXPHOS complex activities. Variants reported include nonsense, missense, and frameshift.

Loss of function is the mechanism of disease. This gene-disease association is also supported by known biochemical function (PMID: 33340416).

In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. 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 July 24, 2023 (SOP Version 9).