| Title: | Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria |
| Journal: | Genetics in Medicine |
| Published: | 2 Sep 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32873934/ |
| DOI: | https://doi.org/10.1038/s41436-020-00951-8 |
| URL: | http://www.gimjournal.org/article/S1098360021025090/pdf |
Publication 4814
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Abstract
PurposeErythropoietic 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.MethodsDisease-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.ResultsAnalysis 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.ConclusionThe 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.</p>
18 Authors
- 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
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