Chronic/Cutaneous Porphyria Panel

Porphyrias are a group of metabolic disorders caused by impairment of heme biosynthesis pathway. There are two different forms of porphyria: acute/neurovisceral and chronic/cutaneous. Symptom onset typically occurs in late childhood to adulthood. Chronic porphyrias include congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), hereditary coproporphyria (HCP) variegate porphyria (VP), erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). In these patients, either blistering or non-blistering cutaneous lesions occur at sites 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 (Karim et al. 2015).

PCT is the most common form of porphyria with an occurrence of 1 in 10,000 in Europeans. Genetic testing is helpful in confirming diagnosis of chronic/cutaneous porphyria subtypes and from other cutaneous blistering conditions. Standard treatments typically involve monitoring of urinary porphyrin levels and phlebotomies to reduce iron stores. Avoidance of susceptibility factors and increased surveillance for hepatocellular carcinoma are also common for patients, especially with PCT (Liu et al. 1993). Vitamin D deficiency can be a secondary effect of chronic/cutaneous porphyria due to avoidance of sun exposure. Patients with VP and HEP also may present with acute/neurovisceral symptoms (Karim et al. 2015).

There are currently six different forms of chronic/cutaneous porphyria caused by specific pathogenic variants in genes involved in heme biosynthesis: hereditary coproporphyria (CPOX), variegate porphyria (PPOX), porphyria cutanea tarda/hepatoerythropoietic porphyria (UROD), congenital erythropoietic protoporphyria (UROS), erythropoietic protoporphyria (FECH), and X-linked protoporphyria (ALAS2). PCT, VP, and HCP inherited in an autosomal dominant manner whereas HEP, EPP, CEP are inherited in an autosomal recessive manner. Pathogenic variants in the ALAS2 gene are associated with an X-linked recessive form of porphyria (Karim et al. 2015; Besur et al. 2014).

See individual gene test descriptions for information on molecular biology of gene products.

Detection of Pathogenic variants in the FECH gene was found in 140 of 151 patients with protoporphyia with the remaining 11 demonstrating X-linked forms through pathogenic variants in the ALAS2 gene (Balwani et al. 2012). Analytical sensitivity is ~90% as gross deletions cannot be detected by this method and are responsible for ~10% of cases (Whatley et al. 2007; Gouya et al. 2006).

In a series of 103 patients where variegate porphyria diagnosis was established by elevated fecal porphyrin measurement, decreased PPOX activity, and elevated plasma porphyrin fluorescence, pathogenic variants were identified in 96% of cases (Whatley et al. 1999). Analytical sensitivity is >95% for detection of pathogenic variants in the PPOX gene (Singal and Anderson 1993).

In two studies with individuals having a clinical and biochemical diagnosis of hereditary coproporphyria, pathogenic variants in the CPOX gene were identified in 29 of 31 and 32 of 32 patients respectively (Whatley et al. 2009; Rosipal et al. 1999). Analytical sensitivity is >95% as gross deletions in the CPOX gene have only been reported in rare cases (Whatley et al. 2009).

In a series of unrelated patients with congenital erythropoietic protoporphyria, pathogenic variants in the UROS gene were identified in 24 of 27 cases (Katugampola et al. 2012). Analytical sensitivity is >99% as all reported variants are detectable by this method. Only one case of a gross deletion encompassing exons 2-3 in the UROS gene has been reported (Katugampola et al. 2012).

In a patient cohort containing both sporadic and familial porphyria cutanea tarda, pathogenic variants in the UROD gene were identified in 131 of 248 patients (Aarsand et al. 2009). Analytical sensitivity is >95% as large deletions cannot be detected by this method and have been reported in a few cases (Mendez et al. 1998; Liu et al. 2013).

Gross deletions have been reported in <10% of erythropoietic protoporphyria cases (FECH gene), <5% of variegate porphyria cases (PPOX gene), <5% of hereditary coproporphyria cases (CPOX gene), <2% of congenital erythropoietic porphyria cases (UROS gene), and <5% of porphyria cutanea tarda cases (UROD gene). To date, gross deletions/duplications have not been reported in the ALAS2 gene.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).