Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.,Genetics in Medicine

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Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-09-02 , DOI: 10.1038/s41436-020-00951-8
Amy K Dickey _{1,

2} , Corbin Quick ₃ , Sarah Ducamp _{2,

4} , Zhaozhong Zhu ₅ , Yen-Chen A Feng _{5,

6,

7} , Hetanshi Naik ₈ , Manisha Balwani ₈ , Karl E Anderson ₉ , Xihong Lin ₅ , John E Phillips ₁₀ , Lina Rebeiz _{1,

11} , Herbert L Bonkovsky ₁₂ , Brendan M McGuire ₁₃ , Bruce Wang ₁₄ , Daniel I Chasman _{2,

11} , Jordan W Smoller _{2,

5,

6,

7} , Mark D Fleming _{2,

4} , David C Christiani _{1,

2,

5}

Affiliation

Deparment of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Genetics and Genomic Sciences, Mount Sinai Hospital, New York City, NY, USA.
Division of Gastroenterology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Hematology Department, University of Utah School of Medicine, Salt Lake City, UT, USA.
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Medicine, Section on Gastroenterology & Hepatology, Wake Forest Baptist Health, Winston-Salem, NC, USA.
Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, CA, USA.

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.

中文翻译：

英国生物库中红细胞生成性原卟啉症诊断不足的证据。

目的

红细胞生成性原卟啉症 (EPP) 以疼痛的皮肤光敏性为特征，由铁螯合酶 ( FECH ) 的致病变异引起。对于 96% 的患者，EPP 是由于共同遗传了一个罕见的反式致病性变异，即常见的亚型变异 c.315-48T>C（次要等位基因频率为 0.05）。从欧洲确诊人数得出的 EPP 患病率估计为 0.00092%，但由于诊断不足，这可能是保守的。没有研究使用大型遗传数据集估计 EPP 流行率。

方法

在 UK Biobank中发现了与疾病相关的FECH变体，这是一个包含 500,953 个个体的数据集，包括 49,960 个外显子组序列。然后估计 EPP 流行率。评估了FECH变体与 EPP 相关性状的关联。

结果

对英国生物库中致病性FECH变异的分析提供的证据表明，EPP 的患病率为 0.0059%（95% 置信区间 [CI]：0.0042–0.0076%），是英国之前认为的 1.7–3.0 倍。在常见的 c.315-48T>C FECH变体的纯合子中，红细胞平均红细胞体积 (MCV) 和血红蛋白都有新的减少。