Intellectual disability
Gene: PPOX

PPOX (protoporphyrinogen oxidase)
EnsemblGeneIds (GRCh38): ENSG00000143224
EnsemblGeneIds (GRCh37): ENSG00000143224
OMIM: 600923, Gene2Phenotype
PPOX is in 14 panels

5 reviews

Ida Ertmanska (Genomics England Curator)

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. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Intellectual disability.
Created: 7 Oct 2025, 3:45 p.m. | Last Modified: 7 Oct 2025, 4:14 p.m.

Panel Version: 9.117

Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with severe developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Created: 7 Oct 2025, 3:26 p.m. | Last Modified: 7 Oct 2025, 3:48 p.m.

Panel Version: 9.116

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Variegate porphyria, childhood-onset, 620483; variegate porphyria, MONDO:0008297

Publications

Created: 7 Oct 2025, 3:26 p.m.
Last Modified: 7 Oct 2025, 4:14 p.m.
Panel version: 9.117

Sharon Whatley (International Porphyria Network)

Green List (high evidence)

Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 37879139 Assaleh reports that biallelic variegate porphyria (VP) is rare. To the best of our knowledge there are 25 patients (in 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. At least 12 of these patients from 8 families (PMID:40114189 Kaiser, 37879139 Assaleh, 35164799 Vafaee-Shahi, 9811936 Roberts, 8290408 Hift, 2004012 D’Alessandro Gandolfo, 6143163 Korda) had intellectual disability.
PMID: 40114189 Kaiser reports 2 siblings with biallelic VP characterised by skin lesions, nystagmus, brachydactyly, seizures, developmental delay with intellectual disability and short stature. Magnetic resonance imaging of the brain revealed a severe myelin deficit suggesting hypomyelination in both children. The homozygous variant identified in the PPOX gene was c.164A > C, p.(Glu55Ala).
PMID: 37879139 Assaleh describes three children from a consanguineous family who presented with nystagmus, developmental delay and ataxia, photosensitive skin manifestations, and adrenal insufficiency. Neuroimaging revealed diffuse severe hypomyelination associated with progressive brain atrophy and severe intellectual disability. Analysis of porphyrins in plasma, urine, and stool together with a genetic study of the PPOX gene which contained a homozygous variant, c.1108_1119del, p.(Gly370_Trp373del) confirmed the diagnosis of homozygous variegate porphyria.
PMID: 35164799 Vafaee-Shahi reported a child who developed skin lesions at 2 years old. He presented at 6 years of age with lesions, hyperpigmentation, fragility, and blistering of sun‑exposed skin. He had three episodes of generalized tonic‑clonic seizure. Weakness of limbs and brachydactyly were observed. He had aggressive behaviour, learning disability and abdominal pain. Genetic analysis showed him to be homozygous for the variant c.1072G > A, p.(Gly358Arg) in the PPOX gene.
PMID: 9811936 Roberts summarises 3 previously reported, unrelated, homozygous VP patients with intellectual disability. The onset of skin lesions was between birth and 18 months with clinodactyly. Two had nystagmus and growth retardation. None had a history of acute attacks of porphyria. Genetic analysis of the PPOX gene showed patient 1 to be homozygous for c.1297G>C, p.(Ala433Pro), patient 2 c.506G>A, p.(Gly169Glu) and c.1072G>A, p.(Gly358Arg) and patient 4: c.1072G>A, p.(Gly358Arg) and c.807+1_807+18del18 that caused a deletion of exon 7.
PMID: 8290408 Hift reports a male infant with biochemical evidence of homozygous VP, born to consanguineous parents. He developed epilepsy at 5 months and showed developmental delay with intellectual disability, nystagmus and clinodactyly. Skin manifestations were noted from the age of 6 months with hypertrichosis, hyperpigmentation, scarring and milia.
PMID: 2004012 D’Alessandro Gandolfo reported a child with a biochemical diagnosis of homozygous variegate porphyria with vesicles and blisters in sun exposed areas of skin in the first few months of life. He had convulsive attacks and there was delay in his speech and motor development with intellectual disability. He had defects in the distal phalanges of both hands.
PMID: 6143163 Korda reports on the sibling of a child subsequently described by Roberts (PMID: 9811936). Onset of serious photodematosis occurred in the first days of life accompanied by severe neurological symptoms. She had mild ocular nystagmus and intellectual disability. At age 6 months bone marrow examination revealed dyserythropoietic anaemia.
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 (~1%).
Created: 8 Sep 2025, 11:35 a.m. | Last Modified: 8 Sep 2025, 11:35 a.m.

Panel Version: 9.72

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
620483

Publications

Created: 8 Sep 2025, 11:35 a.m.
Last Modified: 8 Sep 2025, 11:35 a.m.
Panel version: 9.72

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

There is currently no evidence to suggest there is an association of this gene with intellectual disability.
Created: 18 Dec 2017, 3:39 p.m.

Created: 18 Dec 2017, 3:39 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.40

Caroline Wright (Sanger)

Red List (low evidence)

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:30 a.m.

Panel version: 0.306

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Victorian Clinical Genetics Services
Radboud University Medical Center, Nijmegen

Phenotypes

Variegate porphyria, childhood-onset, OMIM:620483
variegate porphyria, MONDO:0008297

Tags

Q3_25_promote_green

OMIM

600923

Clinvar variants

Variants in PPOX

Penetrance

Complete

Publications

Panels with this gene