Submission Details

The relationship between ETHE1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 10, 2018. 34 articles were reviewed. ETHE1 was first reported in association with ethylmalonic encephalopathy in 2004 (Tiranti et al., PMID 14732903) and first associated Leigh syndrome spectrum in 2006 (Herberle et al., PMID 16376514). At least 39 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands with Leigh syndrome spectrum in 7 publications (PMID: 18593870, 20978941, 20528888, 27830356, 26917598, 16376514). This gene-disease association is supported by expression, animal model, and rescue experiments. As previously stated, this gene has been primarily associated with ethylmalonic encephalopathy (progressive disorder characterized by mutisystem involvement including chronic diarrhea, developmental delay, petechiae, and acrocyanosis). This phenotype will be assessed separately. In summary, there is definitive evidence to support the relationship between ETHE1 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 10, 2018 (SOP Version 6).