The relationship between ISCA2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2023. ISCA2 encodes the protein iron-sulfur cluster assembly 2 that, along with ISCA1 and IBA57, is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria functioning late (maturation) in the biosynthetic pathway of mitochondrial 4Fe-4S proteins.
ISCA2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID: 25539947), in several individuals with infantile-onset neurodegeneration and severe leukodystrophy. While various names have been given to the constellation of features seen in those with ISCA2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the ISCA2 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 eight unique variants (seven missense, one frameshift) identified in twenty-one probands from eight publications (PMIDs: 25539947, 25558065, 28803783, 29297947, 29122497, 29359243, 31279336, 32424628). One of the seven missense variants was a founder variant, c.229G>A (p.Gly77Ser; NM_194279.4) that was seen in the homozygous state in 16 probands of Saudi Arabian descent. Affected individuals commonly present in the infantile period with regression, nystagmus/optic atrophy, and white matter involvement, and most reported individuals died in early childhood. There is one report of a more mildly affected individual with spastic paraplegia (PMID: 28803783). Muscle biopsies in affected individuals were variable, including variable mitochondrial respiratory chain enzyme activities. Brain imaging generally showed diffuse bilateral symmetric signal abnormality in cerebral white matter with variable involvement of other parts of the brain. Metabolic labs showed variable elevated blood and cerebrospinal fluid lactate and glycine.
This gene-disease association is also supported by its known biochemical function (PMID: 33340416) and functional alteration in non-patient cells (PMIDs: 29297947, 22323289).
In summary, there is definitive evidence to support the relationship between ISCA2 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 August 21, 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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