Non-acute porphyrias

Gene: PPOX

Green List (high evidence)

Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood (PMIDs: 19460837, 38940544). Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms.
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on available evidence, the mode of inheritance for Non-acute porphyrias should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Created: 13 Oct 2025, 2:48 p.m. | Last Modified: 14 Oct 2025, 9:41 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
Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297

Publications

• 9811936
• 10486317
• 19460837
• 33159949
• 35584894
• 37879139
• 38940544
• 40114189

Green List (high evidence)

Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed based on biochemical testing including analysis of plasma porphyrin fluorescence emission as the clinical penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.

Created: 8 Sep 2025, 9:53 a.m. | Last Modified: 8 Sep 2025, 9:53 a.m.

Panel Version: 1.26

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
176200; 620483

Publications

• 35584894
• 10486317
• 38940544
• 37879139

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: PPOX; 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)

Associated with variegate porphyria in many cases (PMID: 19460837). Homozygous for has more severe phenotype

Created: 23 Feb 2017, 5:15 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Porphyria variegata 176200

Publications

• 19460837
• 9811936