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Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

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


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.


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.


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.


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.

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