|
SCI 11 May 2019 Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population
IMPORTANCE 重要性 Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations. 基因组测序在疾病诊断中的广泛应用引起了人们对基因型与表型相关性程度的关注。 OBJECTIVE 目的 To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease. 将疾病相关的等位基因频率与临床疾病的预期和报道的患病率相联系。 DESIGN, SETTING, AND PARTICIPANTS 设计，设置及参与者 Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1,2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. 本研究以隐性基因型,有癌症倾向的着色性干皮病(XP)为模型。从2017年1月1日到2018年5月4日，对美国国立卫生研究院(National Institutes of Health)的人类基因突变数据库和一组患者进行了检索和筛选，以找出与XP相关的已知突变。这些患者的临床表型从文献报道和美国国立卫生研究院的医疗记录中获得。 The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population. 根据已知致病突变频率而从基因上预测患病率与以临床表现而诊断XP的患者的患病率进行比较。利用基因组突变频率数据库、美国国家癌症研究所癌症流行病学和遗传学健康对照数据库以及Inova医院研究数据库对20多万个等位基因的外显子组进行测序，以研究这些突变在普通人群中的频率。 MAIN OUTCOMES AND MEASURES 主要结果及措施 Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations. 列出所有与XP相关的已知突变，它们在3个大型的外显子组序列数据库中的频率，使用建模方程确定美国XP患者的数量，并比较观察到的和报道的具有特定突变的XP患者的数量。 RESULTS 结果 A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. 美国国立卫生研究院和人类基因突变数据库共筛选出156个与XP相关的致病性错义和无义突变。基因组突变频率数据库提供了其中65个突变的频率数据，总频率为1.13%。XPF (ERCC4)突变（p.P379S）的等位基因频率为0.4%，XPC基因突变（p.P334H）的等位基因频率为0.3%。 With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation. 根据Hardy-Weinberg方程，我们获知在美国应该有8000多名纯合子的基因突变患者。相比之下，只有3例XP患者报告有XPF突变，1例报告有XPC突变。 CONCLUSIONS AND RELEVANCE 结论及意义 The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population. 这项研究的结果表明，临床医生在尝试将遗传变异的临床意义与疾病风险的患病率相联系时，应谨慎使用大型基因组数据库。已知的易患皮肤癌的基因的突变可能是导致普通人群中某些皮肤癌高发的原因。 喜欢SCI天天读的理由 陪您一起学习SCI医学论文 每天5分钟，让自己的英语牛逼起来 特殊福利让您惊喜连连 |
|
|
