Non-acute porphyrias

Gene: CPOX

Green List (high evidence)

Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).

Created: 20 Oct 2025, 2:08 p.m. | Last Modified: 4 Nov 2025, 1:42 p.m.

Panel Version: 1.29

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892

Publications

• 6886003
• 7757079
• 8012360
• 9454777
• 10505225
• 11309681
• 11074238
• 16159891
• 21103937
• 23236641
• 30828546
• 33008663
• 40296768

Green List (high evidence)

Relevant metabolic investigation: Plasma porphyrin fluorescence emission, faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 11309681 Lamoril reports that hereditary coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.
PMID: 23236641 Wang reports that HCP is classified as both an acute (hepatic) porphyria (with abdominal, cardiovascular and neurologic symptoms) and a chronic (cutaneous) porphyria with long-standing photosensitivity. Clinical penetrance is low, and symptoms are very rare before puberty. The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP).
PMID: 11074238 Kuhnel reports that bullae and fragility of light-exposed skin occurred in only 14% of 46 patients with HCP (current or past).
PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of HCP one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.
There have been 12 patients from 9 families published with clinical details and biallelic pathogenic variants (PMID: 40296768 Kelestemur, 33008663 Fukui, 30828546 Moghe, 21103937 Hasanoglu, 16159891 Schmitt, 10505225 Doss, 9454777 Lamoril, 7757079 Lamoril, 8012360 Martasek). 10 of these 12 individuals had cutaneous symptoms. The most common manifestation was pigmentation (5 patients, 2 of these had adrenal insufficiency) followed by blisters (3), skin fragility (3) and erythema (2), other symptoms, scarring, papules, milia and hypertrichosis, were reported in single patients. Two patients had severe cutaneous photosensitivity following phototherapy (PMID: 6886003 Nordmann, 21103937 Hasanoglu).
Eight patients (from five families) with biallelic pathogenic variants had neonatal jaundice, haemolytic anaemia and hepatosplenomegaly. Of this eight, 5 patients (from 3 families) had at least one pathogenic variant located in the presumed CPOX active site (Asp400–Lys404) and harderoporprhyrin in their faecal samples leading to a diagnosis of harderoporphyria (PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril). In three patients (two families) the variants were outside this region. These homozygous hereditary coproporphyria patients were not tested for faecal harderoporphyrin (40296768 Kelestemur, 21103937 Hasanoglu).
PMID: 16159891 Schmitt reported one patient with homozygous variant p.(Lys404Glu) and harderoporphyria who was diagnosed at 39 years of age due to cutaneous symptoms with mild anaemia.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).

Created: 11 Sep 2025, 9:46 a.m. | Last Modified: 11 Sep 2025, 9:46 a.m.

Panel Version: 1.26

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
121300; 618892

Publications

• 11309681
• 23236641
• 11074238
• 16159891
• 40296768
• 33008663
• 30828546
• 21103937
• 16159891
• 10505225
• 9454777
• 7757079
• 8012360
• 6886003

Green List (high evidence)

Comment when marking as ready: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 24 Jan 2019, 4:21 p.m.

Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: CPOX; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 7 Jan 2019, 3:53 p.m.

Green List (high evidence)

More than 3 unrelated cases reported. One homozygous patient repored, therefore mode of inheritance selected was 'both' to cover this. The 'treatable tag was added due to information from PMID: 12227458 in which the patient was treated with heme arginate.

Created: 23 Feb 2017, 5:13 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Coproporphyria 121300; Harderoporphyria 121300

Publications

• 27604308
• 12227458
• 8159699
• 7987309
• 8990017