The relationship between IARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2019. The IARS2 gene encodes mitochondrial isoleucyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits.
The IARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 25130867). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
This curation included four unique variants identified in two cases from two publications (PMIDs: 25130867, 30041933). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in a syndrome known by the acronym CAGSSS (cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia) which is a distinct clinical entity from the Leigh syndrome spectrum. This gene-disease association is also supported by known biochemical function and expression (PMIDs: 29980628, 25613900).
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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel November 20, 2019 (SOP Version 7).
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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