Variegate Porphyria via the PPOX Gene

Variegate Porphyria (VP) is a metabolic disorder due to impairment of the seventh enzyme, protoporphyrinogen oxidase (PPOX), in the heme biosynthesis pathway. VP prevalence is highest in South African populations with 3 in 1,000 individuals compared to Europeans where 1 in 100,000 are affected. Onset primarily occurs after puberty with patients presenting with cutaneous and/or neurovisceral symptoms. Cutaneous symptoms are most common with VP patients and mirror patients with porphyria cutanea tarda (PCT) and hereditary coproporphyria (HCP). Chronic blistering occurs at sun exposed skin areas and can lead to scarring, thickening, abnormal pigmentation, and milia (Whatley et al. 1999; Singal and Anderson 2013). Neurovisceral symptoms mimic patients with acute intermittent porphyria (AIP) and include acute attacks leading to abdominal pain, nausea, vomiting, tachycardia, and hypertension. Attacks may be provoked by certain drugs, stress, caloric restriction, or steroid hormones. VP penetrance is low with the majority of patients being asymptomatic throughout life. Biochemical analysis showing elevated porphobilinogen (PBG) and aminolevulinic acid (ALA) in urine are primary indicators for VP, but may appear normal during asymptomatic phases (Whatley et al. 1999; Singal and Anderson 2013). Genetic testing is often helpful for differential diagnosis of VP from other forms of porphyria and for establishing diagnosis during asymptomatic phases. Diagnosis of VP in asymptomatic individuals allows management of acute attacks through avoidance of symptomatic triggers mentioned above (Whatley et al. 2009).

VP is inherited in an autosomal dominant manner through pathogenic variants in the PPOX gene. In rare cases, autosomal recessive forms have been reported with one mutated allele possessing some enzymatic activity. These patients presented with VP in childhood and intellectual disability (Frank et al. 1998). A founder mutation, c.175C>T (p.Arg59Trp), impairs PPOX enzymatic activity and is estimated to be present in 3 per 1,000 individuals in South African populations and account for 95% of these cases (Messnier et al. 1996). In a study of western European individuals with VP, missense (38%), small insertions/deletions (36%), splice site (14%), and nonsense (11%) changes were reported (Whatley et al. 1999). Gross deletions have been reported in rare cases and occur within exons 5 through 9 (Barbaro et al. 2013). Penetrance for VP is low with the majority of individuals heterozygous for a pathogenic variant in the PPOX gene being asymptomatic (Singal and Anderson 2013). The PPOX gene encodes the protoporphyrinogen oxidase enzyme which is involved in heme synthesis and catalyzes the oxidation of protoporphyrinogen to protoporphyrin. This enzymatic reaction is the seventh step in heme synthesis (Singal and Anderson 2013).

In a series of 103 patients where VP diagnosis was established by elevated fecal porphyrin, 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 by this method (Singal and Anderson 2013).

Two gross deletions, encompassing exons 5-6 and 5-9, have been reported to date. The clinical sensitivity is difficult to estimate due to the limited number of cases, but appears to be relatively low.

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