Undiagnosed metabolic disorders

Gene: FECH

Green List (high evidence)

Relevant metabolic investigation: Erythrocyte metal free protoporphyrin

PMID: 7857832 Todd reports that erythropoietic protoporphyria (EPP) is a rare disorder caused by the partial deficiency of ferrochelatase, the terminal enzyme of haem biosynthesis that is coded by the FECH gene. Affected patients usually present with episodes of severe phototoxic pain in skin exposed to visible light caused by the accumulation of photoreactive protoporphyrin IX.

PMID: 16911284 Holme found the median age of presentation to be less than one year of age although diagnosis was delayed until a median age of 12 years. Infants are extremely sensitive to sunlight, experiencing pain, burning, and swelling of the skin and may present with crying or screaming after being exposed. This acute photosensitivity of sun exposed areas is lifelong.

PMID: 39969427 Levy reported that the accumulation of protoporphyrin in the liver caused cholestatic liver injury in 3.4% of 322 patients with EPP and progressed to severe liver failure in 2.5%.

PMID: 32873934 Dickey reports the EPP prevalence to be 0.0059% (~1 in 17,000) from the UK biobank and suggests that the disorder is underreported. Among more than 155 family cohorts of EPP patients that have been published in the literature, no occurrence of a nonpenetrant disease-associated genotype has been reported. It is therefore assumed that EPP is fully penetrant.

PMID: 38940544 Aarsand reports that the genetics of EPP is complex with ~5% of cases of unknown genomic pathology. There are several different known genetic mechanisms that cause the EPP phenotype including defects in other genes such as ALAS2 found in 2-10% of EPP patients and ALAS2 together with CLPX identified in one patient. Rarely EPP can develop in later life due to genomic instability in myelodysplastic syndromes affecting the FECH gene. Approximately 4% of EPP patients have biallelic pathogenic variants in the FECH gene while most EPP cases are due to a pathogenic FECH variant trans to an intronic variant that causes low expression of that allele.

PMID: 11753383 Gouya discovered an intronic single nucleotide change c.315-48T>C in intron 3 of the FECH gene that modulates the use of an aberrant splice acceptor site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased level of mRNA. This in trans to a pathogenic variant was found to cause phenotypic expression of EPP.

PMID: 16385445 Gouya reports that this intronic variant is present in >90% of EPP patients.

The FECH low-expression variant c.315-48T>C has a total allele frequency of 0.06713 and an allele frequency of 0.3803 in those of East Asian ancestry with ~7% of these being homozygotes (GnomAD v4.10). However clinical detection of EPP remains low. Even taking into account underreporting, this suggests that the low expression variant in the homozygous form causes a reduction in the ferrochelatase enzyme activity but not to a level that causes disease, otherwise EPP would be much more common.

It is essential that any genetic sequencing includes the region of intron 3 (c.315-48T>C) that harbours the low expression variant.

Created: 28 Aug 2025, 4:01 p.m. | Last Modified: 28 Aug 2025, 4:01 p.m.

Panel Version: 1.630

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
177000

Publications

• 7857832
• 16911284
• 39969427
• 32873934
• 38940544
• 11753383
• 16385445

Comment on phenotypes: Erythropoietic protoporphyria (Porphyrias with acute painful photosensitivity);Erythropoietic protoporphyria, mild variant

Created: 19 Sep 2019, 3 p.m. | Last Modified: 19 Sep 2019, 3 p.m.

Panel Version: 1.299

Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 16 variants identified in unrelated cases.

Created: 19 Sep 2019, 2:59 p.m. | Last Modified: 19 Sep 2019, 2:59 p.m.

Panel Version: 1.298

Amber review assigned as this gene is Green on the V1 panel(s) named as a phenotype(s)

Created: 6 Jan 2017, 1:58 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Erythropoietic protoporphyria, mild variant