@article{350b29ab0e884e5fa790880554011621,
title = "Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria",
abstract = "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",
author = "Dickey, {Amy K.} and Corbin Quick and Sarah Ducamp and Zhaozhong Zhu and Feng, {Yen Chen A.} and Hetanshi Naik and Manisha Balwani and Anderson, {Karl E.} and Xihong Lin and Phillips, {John E.} and Lina Rebeiz and Bonkovsky, {Herbert L.} and McGuire, {Brendan M.} and Bruce Wang and Chasman, {Daniel I.} and Smoller, {Jordan W.} and Fleming, {Mark D.} and Christiani, {David C.}",
note = "Funding Information: The authors thank Heidi Rehm for her assistance with FECH variant interpretation and Meg Min-Jung Wang for her assistance with accessing the UK Biobank. This research has been conducted using the UK Biobank Resource under application number 47222.16 A.K.D. is supported in part by Massachusetts General Hospital{\textquoteright}s Healthcare Transformation Laboratory. The Porphyrias Consortium (U54 DK083909) is a part of the National Center for Advancing Translational Sciences Rare Diseases Clinical Research Network (NCATS RDCRN), which is funded through a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The WGHS is supported by the National Heart, Lung, and Blood Institute (NHLBI) (HL043851 and HL080467) and the National Cancer Institute (NCI) (CA047988 and UM1CA182913), with funding for genotyping provided by Amgen. Funding Information: A.K.D. and L.R. report serving as consultants for Alnylam Pharmaceuticals. K.E.A. reports grants and personal fees from Alnylam, Recordati Rare Diseases, and Mitsubishi-Tanabe Pharma. H.L.B. reports serving as a consultant for Alnylam, Recordati Rare Diseases, Mitsubishi-Tanabe North America, and Clinuvel and receiving grant support from Anlylam, Gilead Sciences, and Mitsubishi-Tanabe Pharma. J.E.P. reports serving as a consultant for Alnylam, Recordati, Mitsubishi-Tanabe Pharma, and Agios. M.D.F. is on the Scientific Advisory Board of Disc Medicine. All of the competing interests listed above are outside/unrelated to this work. The other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",
year = "2021",
month = jan,
doi = "10.1038/s41436-020-00951-8",
language = "English",
volume = "23",
pages = "140--148",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Elsevier BV",
number = "1",
}