Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria

Amy K. Dickey, Corbin Quick, Sarah Ducamp, Zhaozhong Zhu, Yen Chen A. Feng, Hetanshi Naik, Manisha Balwani, Karl E. Anderson, Xihong Lin, John E. Phillips, Lina Rebeiz, Herbert L. Bonkovsky, Brendan M. McGuire, Bruce Wang, Daniel I. Chasman, Jordan W. Smoller, Mark D. Fleming, David C. Christiani

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)140-148
Number of pages9
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 2021


  • anemia
  • erythropoietic protoporphyria (EPP)
  • ferrochelatase (FECH)
  • mean corpuscular volume (MCV)
  • prevalence

ASJC Scopus subject areas

  • Genetics(clinical)


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