The relationship between ECHS1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 9, 2019. The ECHS1 gene encodes the mitochondrial short-chain enoyl-CoA hydratase (SCEH), which functions in the beta-oxidation of short chain fats, the isoleucine catabolic pathway, and the valine catabolic pathway. In the valine catabolic pathway, SCEH acts upstream of HIBCH and converts methacrylyl-CoA to (S)-3-hydroxyisobutyryl-CoA and acryloyl-CoA to 3-hydroxypropionyl-CoA. The exact disease mechanism has not been fully elucidated, but elevated levels of the SCEH substrate methacrylyl-CoA are toxic and impair functioning of the pyruvate dehydrogenase complex and the oxidative phosphorylation complexes (PMID: 25125611).
The ECHS1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID 25125611). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 16 variants in 12 cases from 7 publications (PMIDs: 26000322, 25393721, 25125611, 28409271, 29575569, 28755360, 26099313). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, functional alterations in patient cells, and rescue experiments (PMIDs: 27977873, 25613900, 26251176, 25125611, 26000322).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 9, 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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