Congenital Erythropoietic Porphyria via the UROS Gene

Congenital Erythropoietic Porphyria (CEP), also known as Günther’s disease, is a metabolic disorder due to impairment of the fourth enzyme, uroporphyrinogen III synthase (UROS), in the heme biosynthetic pathway. Symptom onset is variable and corollary to the degree of UROS activity and amount of sun exposure. In severe cases, infants present at birth with skin blistering, hydrops fetalis, and are prone to secondary dermal infections which can lead to scarring. Other symptoms include corneal ulcers, reddish-brown coloring of teeth, mild bone loss, hemolytic anemia and bone marrow expansion. Milder cases of CEP present in adulthood with cutaneous photosensitivity (Katugampola et al. 2012). Vitamin D deficiency can be a secondary effect of CEP due to avoidance of sun exposure. Treatments for CEP include avoidance of sun exposure, vitamin D supplementation, and transfusions if hemolytic anemia is severe. Bone marrow transplantation is currently the only curative therapy. Genetic testing is helpful in the differential diagnosis of CEP from other types of porphyria, epidermolysis bullosa, and myelodysplastic syndrome (Erwin et al. 2013; Karim et al. 2015).

CEP is inherited in an autosomal recessive manner through pathogenic variants in the UROS gene. Clinical phenotype is related to the degree of UROS activity with severe individuals having undetectable enzymatic levels. Biallelic pathogenic variants in the UROS gene are fully penetrant with the majority of cases presenting during infancy. Missense pathogenic variants occur in the majority of cases and have been reported throughout the coding region. The c.217T>C (p.Cys73Arg) variant is present in about a third of cases and is the most commonly found pathogenic variant in the UROS gene (Fortian et al. 2009; Erwin et al. 2013; Warner et al. 2002). Splice site alterations, small insertions/deletions, and promoter variants have also been reported in a minority of cases of CEP (Solis et al. 2001; Xu et al. 1995). Gross deletions encompassing one or more exons have only been reported in one case (Katugampola et al. 2012). The UROS gene encodes the uroporphyrinogen III synthase with catalyzes hydroxymethylbilane to uroporphyrinogen III in the heme biosynthetic pathway. Deposition of porphyrin isomers in tissues become photo-activated leading to oxygen radical formation and damage (Karim et al. 2015).

In a series of unrelated patients with CEP, pathogenic variants in the UROS gene were identified in 24 of 27 cases (Katugampola et al. 2012). Analytical sensitivity should be high as nearly all reported variants are detectable by sequencing. Only one case of a gross deletion encompassing exons 2-3 has been reported and is not detectable by sequencing (Katugampola et al. 2012).

This test provides full coverage of all coding exons of the UROS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).