Maniam Pavithran, Zhou Kaixin, Lonergan Mike, Berg Jonathan N, Goudie David R, Newey Paul J
Division of Molecular & Clinical Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland.
Clinical Genetics, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland.
J Endocr Soc. 2018 Jun 18;2(7):806-816. doi: 10.1210/js.2018-00120. eCollection 2018 Jul 1.
Germline mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.
在少数嗜铬细胞瘤/副神经节瘤（PPGL）病例中报告了种系突变，但这些突变与恶性肿瘤风险增加相关，这使得一些人主张对“高危”一级亲属进行级联基因检测和监测筛查。然而，此类方法依赖于对变异致病性和疾病外显率的准确估计，而这些估计可能受到确诊和报告偏倚的影响，尽管最近提供的基于大量人群的DNA序列数据集可能为辅助变异解读提供一个潜在无偏倚的资源。因此，本研究的目的是通过将基于文献的PPGL病例中报告的变异频率与基因组聚合数据库（GnomAD）数据集中出现的频率进行比较，来评估这些变异的致病性和外显率，该数据集提供了138,632个人的高质量DNA序列数据。在总共95例PPGL索引病例中，共鉴定出39种不同的错义或功能丧失（LOF）变异。值得注意的是，许多与PPGL相关的等位基因在GnomAD队列中的出现频率出乎意料地高，背景人群中分别约有1%和0.1%携带罕见的错义或LOF变异。尽管相对于GnomAD对照，PPGL病例中几种等位基因的致病性得到了显著富集的支持，但根据各自队列中等位基因频率计算的疾病外显率估计值远低于先前报道，范围为0.1%至4.9%。因此，尽管本研究为[变异]在PPGL形成中的病因学作用提供了支持，但它表明大多数变异携带者不会表现出PPGL，也不太可能从定期监测筛查中受益。
