Submission Details

DHTKD1 was first reported in relation to autosomal recessive 2-aminoadipic 2-oxoadipic aciduria in 2012 (Danhauser et al., PMID:23141293). DHTKD1 encodes a a thiamine diphosphate-dependent 2-oxo acid dehydrogenase which is part of the lysine degrative pathway specifically catalyzing the reaction of 2-oxoadipate to Glutaryl-CoA in the mitochondria. At least 13 variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eleven probands in three publications (PMIDs: 26141459, 25860818, 23141293). Although many of the probands with variants in this gene display phenoypes other than the 2-aminoadipic 2-oxoadipic aciduria itself such as developmental delay, motor defecits, speech delay, or ADHD, the association of DHTKD1 with these phenotypes has not yet been experimentally confirmed and is therefore classified as a biochemical abnormality. The mechanism for disease is homozygous loss of function, with defecits in viable protein levels preventing the lysine degredation pathway from proceeding normally causing a buildup of metabolites in the tissues, blood, and urine. (Danhauser et al.) Of note, this gene has also been implicated in Autosomal Dominant Charcot-Marie-Tooth Disease Type 2Q in a single family (Xu et al., PMID: 23141294). This assertion has been split and will be assessed separately. This gene-disease association is supported by two animal models, a rescue in patient fibroblasts, in vitro functional assays, and the function of the protein. Two DHTKD1 KO mouse models, created via different methods, displayed significantly elevated 2-aminoadipic and 2-oxoadipic acid levels in tissues and urine. A rescue using wild-type DHTKD1 cDNA in patient fibroblasts was also performed which rescued the increased acid levels around the cells. Finally, investigation into DHTKD1's function displayed that it is essential for mitochondrial function, biogenesis, and energy metabolism and that knockdown can lead to impaired function. In summary, DHTKD1 is definitively associated with autosomal recessive 2-aminoadipic 2-oxoadipic aciduria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 02/27/2020. (SOP Version 7)