Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria

Genet Med. 2021 Jan;23(1):140-148. doi: 10.1038/s41436-020-00951-8. Epub 2020 Sep 2.


Purpose: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets.

Methods: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed.

Results: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin.

Conclusion: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.

Keywords: anemia; erythropoietic protoporphyria (EPP); ferrochelatase (FECH); mean corpuscular volume (MCV); prevalence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Europe
  • Ferrochelatase / genetics
  • Humans
  • Mutation
  • Protoporphyria, Erythropoietic* / diagnosis
  • Protoporphyria, Erythropoietic* / epidemiology
  • Protoporphyria, Erythropoietic* / genetics
  • United Kingdom / epidemiology


  • Ferrochelatase