The relationship between SERAC1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The SERAC1 gene encodes serine active site-containing protein 1 which has a critical role in phosphatidylglycerol remodeling essential for both mitochondrial function and intracellular cholesterol trafficking.
The SERAC1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22683713). Of note, the clinical features associated with SERAC1-related disease have been termed ‘MEGDEL’ which is an acronym for ‘3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome’, and is also sometimes referred to as MEGD(H)EL syndrome, to include hepatic dysfunction, which is a frequent manifestation in the first year of life. Evidence supporting the gene-disease relationship between SERAC1 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included six unique variants identified in six cases from four publications (PMIDs: 29205472, 23918762, 23707711, 22683713). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression data, functional alteration in patient cells, and rescue in patient cells (PMID: 22683713).
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 gene-disease association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 8, 2020 (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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