Submission Details

The relationship between ABCB7 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 28, 2023. ABCB7 encodes ATP-binding cassette, subfamily B, member 7. This protein is involved in the transport of iron between mitochondria and the cytosol (transport of iron-sulfur (Fe-S) clusters from the lumen of mitochondria to the cytosol), and pathogenic variants result in mitochondrial iron accumulation (since iron cannot be transferred to cytosol) that then causes oxidative stress. Furthermore, impaired iron homeostasis disrupts the heme synthesis pathway as Fe-S cluster assembly is essential for heme production.

ABCB7 was first reported in relation to X-linked primary mitochondrial disease in 1999 (PMID: 10196363, although these individuals were from a family first reported in 1985, PMID: 4045952) with four males affected by developmental delay, ataxia, dysmetria, dysarthria, and anemia. While various names have been given to the constellation of features seen in those with ABCB7-related disease including with X-linked sideroblastic anemia with ataxia (XLSA/A), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the ABCB7 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 six unique missense variants identified in six kindreds (PMIDs: 10196363, 11050011, 11843825, 22398176, 26242992, 34354969). There were several affected males across these six kindreds. Some female carriers had mild hematologic changes but no neurologic features. Affected males had ataxia (non-progressive, typically noted early in life), sideroblastic anemia (typically mild, sometimes absent), and variable growth impairment. Other features seen include developmental delay, dysmetria, dysarthria, tremor, variable reflexes (brisk, diminished), spasticity, nystagmus, ophthalmoplegia, intellectual disability (in one individual), schizophrenia (in one individual), and seizures (in one individual). Some individuals were noted to have cerebellar hypoplasia on brain imaging while this was normal in others. Muscle biopsies and metabolic screening labs were not routinely reported in these cases.

This gene-disease association is also supported by its known biochemical function (PMID: 33340416), model organisms including a medaka fish (PMID: 19046159), mouse (PMID: 16467350), and Caenorhabditis elegans (PMID: 21464130).

In summary, there is moderate evidence to support the relationship between ABCB7 and primary mitochondrial disease. 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 September 28, 2023 (SOP Version 9).