The relationship between IBA57 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. IBA57 encodes an iron-sulfur cluster assembly protein that acts late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins.
IBA57 was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23462291), in a neonate with intrauterine growth restriction, brain malformations detected in utero, hypotonia, microcephaly, and hyperglycinemia who died perinatally. While various names have been given to the constellation of features seen in those with IBA57-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the IBA57 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 variants (three missense, two nonsense, and one predicted missense variant resulting in splicing abnormalities), in five probands across four publications (PMIDs: 23462291, 25971455, 25609768, 28913435). Compelling familial segregation data was also included in scoring (PMID: 25609768). There are at least 50 cases reported in the literature through 2022 (PMID: 36360281). Two general clinical phenotypes have been reported. One is an infantile onset, sometimes fatal, microcephaly and cavitating leukodystrophy with or without other brain malformations with metabolic acidosis and hyperglycinemia. The other is childhood/adolescent onset spastic paraplegia with or without optic atrophy. Notably, this second phenotype is reported in relation to a variant impacting splicing. Affected individuals show reduction in activities and amounts of lipoate containing enzymes (PMIDs: 23462291, 25971455, 25609768, 28913435).
This gene-disease association is also supported by functional implication given protein interaction with other proteins of the Fe-S cluster biosynthesis and assembly machinery and the lipoylation pathway, as well as functional alteration in patient cells (PMIDs: 33007329, 27785568).
In summary, there is definitive evidence to support the relationship between IBA57 and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 11, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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