Submission Details

The CPOX gene was first reported in relation to hereditary coporphyria in 1994, with the publication of a family with an affected proband showing autosomal recessive inheritance (PMID: 2563167). A more diverse range of affected individuals have since emerged harboring either biallelic or monoallelic variants in CPOX. Cases with monoallelic variants are generally diagnosed with hereditary coporphyria and exhibit incomplete penetrance, with the majority of carriers likely remaining unaffected throughout their lifetimes. Affected individuals generally present with an acute attack of abdominal pain with nausea and vomiting, sometimes accompanied by other gastrointestinal, neurological, and/or psychiatric symptoms (PMID: 12227458). Onset of such an attack typically occurs during adolescence or later, and can be triggered by barbiturate or sulfonamide drugs known to activate heme synthesis or by low caloric intake, infection, alcohol consumption, or hormones. These monoallelic cases are distinguished from other forms of porphyria at the metabolic level, where symptomatic patients not only exhibit elevated urinary levels of delta-aminolevulinic acid, porphobilinogen, and/or related porphyrin metabolites, but also increased accumulation of coproporphyrin III, particularly in feces. While lymphocytes from monoallelic patients generally show a reduction in the activity of the CPOX enzyme to 50-70% of wild-type levels (PMID: 8990017, PMID: 9454777), those from biallelic patients retain 2-22% of wild-type CPOX activity (PMID: 8159699, PMID: 10505225, PMID: 9454777). Cases harboring biallelic CPOX variants are rare and fully penetrant, with neonatal or early childhood onset of a more severe set of phenotypes including jaundice, hemolytic anemia, hepatosplenomegaly, iron accumulation in liver cells, erythrodontia, red urine, fragile skin, and/or cutaneous photosensitivity leading to scarring of sun-exposed skin. While biallelic cases are metabolically similar to monoallelic cases in that they exhibit high levels of coproporphyrin in urine and especially in feces, a subset of biallelic cases show specific fecal accumulation of an intermediate product of the CPOX enzyme, harderoporphyrin, resulting in an alternative diagnosis of harderoporphyria (PMID: 7757079). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (CPOX loss-of-function) was found to be consistent between the hereditary coporphyria cases with either monoallelic or biallelic variants and the harderoporphyria cases with biallelic variants. In addition, the metabolic and phenotypic differences between the diverse cases (especially at the metabolic level) appeared to represent a single spectrum of disease. Therefore, cases caused by inherited CPOX variants have been lumped into a single disease entity referred to as CPOX-related hereditary coproporphyria (MONDO:0800180), with a semidominant mode of inheritance.

Fourteen suspected pathogenic variants have been scored as part of this curation (six missense, one single codon deletion, and four triggering splicing defects), which have been collectively reported in thirteen probands in nine publications (PMID: 8012360, PMID: 8990017, PMID: 10505225, PMID: 9454777, PMID: 7757079, PMID: 11309681, PMID: 9888388, PMID: 27507172, PMID: 35669728). The mechanism of pathogenicity appears to be monoallelic or biallelic loss of CPOX function conferred by null and/or hypomorphic variants. Seven out of eleven probands were heterozygous for their respective variants, harboring either a predicted null or a hypomorphic variant, while none of the published biallelic cases harbored two alleles predicted to result in complete loss of function (PMID: 8012360, PMID: 10505225, PMID: 9454777, PMID: 7757079). Segregation evidence was available in one of these publications (PMID: 7757079) but was not sufficient to contribute to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but was not included in this curation as the maximum score for this category of evidence had already been reached.

This gene-disease association is also supported by experimental evidence demonstrating that CPOX encodes the human coproporphyrinogen oxidase enzyme responsible for catalyzing protoporphyrinogen IX synthesis from coproporphyrinogen III (PMID: 8407975). This represents the sixth step in the heme biosynthesis pathway and is consistent with the accumulation of coproporphyrin III in the feces and urine of affected patients. Porphyria-causing variants are also found in the HMBS gene encoding the porphyrinogen deaminase enzyme (PMID: 6975621) and the UROD gene encoding the uroporphyrinogen decarboxylase enzyme (PMID: 6370830), which respectively catalyze the third and fifth steps in the heme biosynthesis pathway. CPOX silencing in a lymphoblast cell line decreases heme synthesis (PMID: 11248690). Mutagenized mouse models have shown that monoallelic Cpox loss-of-function can recapitulate some of the metabolic defects observed in heterozygous human patients, including phenobarbital-induced elevation of urinary and fecal porphyrins (especially the ratio of coproporphyrinogen III to coproporphyrinogen I), and also exhibit microcytic anemia (PMID: 28600349, PMID: 35527013).

In summary, CPOX is definitively associated with CPOX-related hereditary coproporphyria. 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 December 9th, 2022 (SOP Version 9).