Submission Details

The UROD gene was first reported in relation to inherited porphyria with the 1986 publication of an affected patient harboring a variant in the homozygous state (PMID: 3775362). Affected individuals harboring biallelic variants are typically diagnosed with hepatoerythropoietic porphyria, and generally present in infancy or childhood with cutaneous photosensitivity, blistering and hyperpigmentation of sun-exposed skin, severe uroporphyrinuria, erythrocyte deficiency of UROD enzymatic activity, and sometimes liver damage. Inherited porphyria has been reported in association with UROD variants in the heterozygous state as well, starting with the 1989 publication of a patient with familial porphyria cutanea tarda (PMID: 2920211). Cases with this diagnosis generally exhibit similar but less severe presentation, incomplete penetrance, and adult onset induced by triggers such as iron overload, use of alcohol or estrogens, or viral infections such as hepatitis C. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (UROD loss-of-function) has been found to be consistent between the hepatoerythropoietic porphyria cases with biallelic variants and the familial porphyria cutanea tarda cases with monoallelic variants. In addition, the phenotypic differences between the biallelic and monoallelic cases appear to represent a single spectrum of disease. Therefore, cases caused by inherited UROD variants have been lumped into a single disease entity referred to as UROD-related inherited porphyria (MONDO:0100498, MIM #176100), with a semidominant mode of inheritance.

Eleven suspected pathogenic variants have been scored as part of this curation (six missense, two nonsense, one frameshift, one disrupting the start codon, and one triggering splicing defects), which have been collectively reported in eleven probands in six publications (PMID: 2243121, PMID: 2920211, PMID: 3775362, PMID: 8644733, PMID: 19419417, PMID: 34367815). The mechanism of pathogenicity appears to be monoallelic or biallelic loss of UROD function conferred by null and/or hypomorphic variants. Monoallelic cases have approximately 50% of normal UROD enzymatic function at the cellular level (PMID: 7062951) but exhibit less than 10% penetrance due to the requirement for a trigger to further depress UROD enzymatic levels to approximately 20% of normal. Iron overload appears act as a trigger by inhibiting cytochrome P450 enzymes, resulting in the production of reactive oxygen species that react with the uroporphyrinogen substrates to generate UROD inhibitors (PMID: 9763408). Biallelic cases appear to retain between 5% and 14% of normal UROD enzymatic function, depending on the tissue examined (PMID: 8644733). Nine out of eleven probands included in this curation were heterozygous for their respective variants, while two probands were homozygous. Segregation evidence was available in one of these publications (PMID: 2243121) and has contributed to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but has not been included in this curation as the maximum score for this category of evidence has already been reached.

This gene-disease association is also supported experimental evidence demonstrating that UROD encodes the human enzyme responsible for catalyzing coproporphyrinogen III synthesis from uroporphyrinogen III (PMID: 6370830). This represents a critical step in the heme biosynthesis pathway and is consistent with the very high levels of uroporphyrin and heptacarboxylporphyrin in the urine of affected patients. Genetically engineered mouse and naturally occurring zebrafish models have shown that either monoallelic (PMID: 11134514) or biallelic (PMID: 9806541) UROD loss-of-function can recapitulate many of the molecular and systemic phenotypes observed in human patients, including urinary accumulation of uroporphyrin and heptacarboxylporphyrin, hepatic accumulation of iron, photosensitivity, and hematological defects, which in some cases can be rescued by expression of a wild-type transgene (PMID: 9806541).

In summary, UROD is definitively associated with UROD-related inherited porphyria. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on August 12th, 2022 (SOP Version 9).