HGD was first reported in relation to autosomal recessive inheritance of alkaptonuria in 1996 (Fernández-Cañón JM, et al., 1996, PMID: 8782815). At least 115 unique variants (including many missense and nonsense, several splicing, and some frameshift, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 8782815, 9529363, 9154114, 9674916). Variants in this gene segregated with disease in 18 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by the biochemical function of HGD, its expression in the liver, and a mouse model which displays high levels of urinary homogentisic acid, as observed in humans (PMIDs: 13271328, 8782815, 8188247). HGD functions in phenylalanine and tyrosine metabolism to convert homogentisate to maleylacetoacetate; in the absence of HGD activity accumulation of homogentisate results in alkaptonuria. In summary, HGD is definitively associated with autosomal recessive inheritance of alkaptonuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.