Erythropoietic Protoporphyria via the FECH Gene

Erythropoietic protoprophyria (EPP) is an inborn error of heme biosynthesis resulting in cutaneous photosensitivity. Symptoms include acute painful photosensitivity with stinging and burning sensations upon sunlight exposure but without blistering. Chronic permanent skin lesions, anemia, iron deficiency, cholelithiasis, chronic liver disease are potentially life threatening secondary symptoms of EPP (Lecha et al. 2009). EPP onset is during the first year of life, but mean diagnosis age is 22 underlying the difficulties in accurately diagnosing EPP (Wahlin et al. 2010). Genetic testing can be helpful in the differential diagnosis of EPP from phototoxic drug reactions, hydroa vacciniforme, solar urticarial, contact dermatitis, angioedema and other forms of porphyria. Standard treatments include avoidance of sun exposure and beta carotene therapy.

EPP is inherited in an autosomal recessive manner through mutations in the FECH gene. In greater than 90% of cases, a pathogenic variant is co-inherited in trans with the hypomorphic variant c.315-48T>C (IVS3-48C) (Balwani et al. 2012). Patients homozygous for the c.315-48C>T variant have been reported to have EPP in rare cases (Whatley et al. 2004), but the penetrance is low. The c.315-48C>T variant, which reduces FECH transcript levels through generation of a cryptic acceptor splice site, leads to nonsense mediated decay and lower FECH protein levels (Gouya et al. 2006; Gouya et al. 2002). Pathogenic variants reported in trans to the c.315-48C>T variant are missense, splice site alterations, small insertion/deletions, and nonsense mutations making up 32%, 22%, 19%, and 14% of EPP mutations (Gouya et al. 2006). The minor allele frequency for the c.315-48C>T variant is 43%, 31%, 11%, 2.7%, and <1% in Japanese, southeast Asian, White French, North African, and African American populations with EPP being nearly absent in the later ethic cohorts. Gross deletions in the FECH gene have been identified in ~10% of cases of EPP (Whatley et al. 2007). An X-linked form of protoporphyria representing ~2% of cases has been reported to occur through gain of function mutations in the ALAS2 gene (Balwani et al. 2013). Somatic mutations have been reported in the FECH gene in patients with myelodysplasia (Aplin et al. 2001). The FECH protein catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. When protoporphyrin accumulates in tissues it becomes photo-activated resulting in excess energy to be transferred to oxygen. This leads to heightened reactive oxygen species causing cellular damage and disease (Lecha et al. 2009).

Causative mutations in the FECH gene were found in 140 of 151 patients with protoporphyia with the remaining 11 demonstrating X-linked forms through mutation in the ALAS2 gene (Balwani et al. 2013). Analytical sensitivity for detection of FECH mutations is ~90% as gross deletions cannot be detected by this method and are responsible for ~10% of EPP cases (Whatley et al. 2007; Gouya et al. 2006).

This test provides full coverage of all coding exons of the FECH 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).

This test also includes coverage of the following pathogenic variants: c.-252_-251delAG, c.-252A>G, c.-251G>C, c.315-67G>A and c.315-48T>C.

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).