The relationship between EHHADH and Fanconi renotubular syndrome 3, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of March, 2023. EHHADH encodes enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase, a bifunctional enzyme (a.k.a L-bifunctional protein) and is one of the four enzymes of the peroxisomal beta-oxidation pathway. A single heterozygous missense variant in this gene has been reported in the literature to cause Fanconi renotubular syndrome 3.
EHHADH was first reported in relation to autosomal dominant Fanconi renotubular syndrome 3 in 2014. (Klootwijk et al, PMID: 24401050). To the best of our knowledge, this is the only report of a genetic defect in EHHADH identified in a family with the disease.
Summary of Case Level Data (2.5 points): A heterozygous missense variant has been reported in 1 family with nine affected individuals in 2 publications (PMIDs: 24401050, 1627757). Functional evidence shows that this primarily peroxisomal protein is mistargeted to the mitochondria as the variant, Glu3Lys, creates a mitochondrial-targeting signal and interferes with mitochondrial function by interacting with the mitochondrial trifunctional protein (PMID: 24401050, 27160910). The mechanism for disease is expected to be dominant negative.
Summary of experimental data (1 point): This gene-disease association is supported by limited experimental evidence. The EHHADH protein is shown to be expressed in the renal proximal tubules, which are tissues relevant to the disease (PMIDs: 24401050, 10336479). In addition, experiments with the variant expressed in proximal tubular cells show functional impairment and confirm mistargeting of the protein to the mitochondria (PMIDs: 24401050, 10336479).
In summary, there is limited evidence to support the gene-disease relationship of EHHADH and Fanconi renotubular syndrome 3. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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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