Porphyria Panel

Porphyrias are a group of metabolic disorders caused by impairment of the heme biosynthesis pathway. There are two different forms of porphyria: acute/neurovisceral and chronic/cutaneous. Symptom onset typically occurs in late childhood to adulthood. Acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), ALA dehydratase prophyria (ADP) and hereditary coproporphyria (HCP). These disorders involve episodic nervous system attacks often resulting in abdominal pain, and psychiatric and neurologic effects. In severe cases attacks can be life threatening resulting in peripheral motor neuropathy, seizures, coma, or bulbar paralysis.

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.

PCT is the most common form of porphyria with an occurrence of 1 in 10,000 in Europeans. AIP and EPP are found in 1 in 20,000 and 1 in 50,000 Europeans respectively (Karim et al. 2015; Besur et al. 2014). Acute and chronic specific porphyria panels as well as individual porphyria gene testing are also available.

There are currently eight different forms of porphyria caused by specific pathogenic variants in genes involved in heme biosynthesis: ALA dehydratase porphyria (ALAD), acute intermittent porphyria (HMBS), hereditary coproporphyria (CPOX), variegate porphyria (PPOX), porphyria cutanea tarda/hepatoerythropoietic porphyria (UROD), congenital erythropoietic protoporphyria (UROS), erythropoietic protoporphyria (FECH), and X-linked protoporphyria (ALAS2).

Autosomal dominant forms of porphyria include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria cutanea tarda. Autosomal recessive forms include ALA dehydratase porphyria, hepatoerythropoietic porphyria, congenital erythropoietic protoporphyria and erythropoietic protoporphyria. Only pathogenic variants in the ALAS2 gene are involved in 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. 2013). 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 porphyria, 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 only been reported in a few cases (Mendez et al. 1998; Liu et al. 2013).

In patients with decreased PBG activity indicative of acute intermittent porphyria, underlying pathogenic variants in the HMBS gene were detected in 240 of 252 individuals (Puy et al. 1997). Analytical sensitivity for detection of causative variants in the HMBS gene is >95% as large deletions are present in only a few cases (Whatley et al. 2009).

Analytical sensitivity for the ALAD gene should be high as all pathogenic variants reported are detectable by sequencing. Clinical sensitivity cannot be estimated because of the small number of patients reported to date.

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), <5% of porphyria cutanea tarda cases (UROD gene), and <5% of acute intermittent porphyria cases (HMBS gene). To date, gross deletions/duplications have not been reported in the ALAD or ALAS2 genes.

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).