Submission Details

The gene FECH which codes for the enzyme ferrochelatase has been definitively associated with the autosomal recessive condition, erythropoietic protoporphyria (EPP). Ferrochelatase catalyzes the eighth and final step in heme biosynthesis incorporating iron into the protoporphyrin ring. The disease was initially mischaracterized with an autosomal dominant inheritance pattern (PMID: 1755842). This is because the classical clinical presentation is a loss-of-function mutation in trans with an intronic hypomorphic allele IVS3-48T>C (this variant has a frequency as high as 34% in the Latino/admixed American populations). This intronic variant was initially ignored because it was common resulting in the disease being mischaracterized with an autosomal dominant inheritance pattern. However, this common allele should not be overlooked as it causes aberrant splicing of exon 3 resulting in an additional 63 base pairs to exon 3 which causes nonsense mediated decay of the transcript. Combined with a null allele in trans, the common IVS3-48T>C variant causes enzyme levels to drop below 35%. Below this level, clinical symptoms of acute cutaneous photosensitivity to sunlight begin to appear. The lower the functional enzyme concentration, typically the more severe disease (cases with two LOF alleles in trans report severe disease often with liver complications). Symptoms of phototoxicity and hepatoxicity are caused by protoporphyrin accumulation in the plasma, skin, feces, and liver. Hundreds of cases have been studied and the results for this gene-disease relationship have held over time. Of note, EPP cases have been reported in Americans, Europeans and Japanese. No cases have been reported in black Africans.

Summary of Case Level Data (10.45 points): 10 probands were scored with 15 unique variants (one nonsense, one frameshift, eight missense, five splicing defects). We opted not to score autosomal dominant reported cases prior to the early 2000’s that lacked genotype information for the common hypomorphic IVS3-48T>C position. We increased the score for the common IVS3-48T>C defect from (.1) to (.5) since there was functional data demonstrating aberrant splicing and nonsense mediated decay.

Summary of Experimental Evidence (3 points): This gene-disease relationship is also supported by experimental evidence including three mouse models (PMID:28093505, PMID: 8325637, PMID: 9989256), multiple crystal structures (PMID: 17884090, PMID: 24043703, PMID: 17261801), and the FECH enzyme activity assay (PMID:16385445). In summary, FECH has been definitively associated with the autosomal recessive condition, erythropoietic protoporphyria (EPP). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.