The relationship between FARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. The FARS2 gene encodes mitochondrial phenylalanyl-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 FARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22499341). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in four cases from three publications (PMIDs: 22499341, 27549011, 29126765). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in Alpers syndrome and other mitochondrial diseases which will be assessed separately. This gene-disease association is also supported by expression data, biochemical function data, and functional alterations in patient cells (PMIDs: 27977873, 26553276, 29126765).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 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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