PURPOSE Autosomal dominant polycystic kidney disease (ADPKD) is a common adult-onset monogenic disorder, with prevalence of 1/1000. Population databases including ExAC have improved pathogenic variant prioritization in many diseases. Due to pseudogene homology of PKD1, the predominant ADPKD disease gene, and the variable disease severity and age of onset, we aimed to investigate the utility of ExAC for variant assessment in ADPKD. METHODS We assessed coverage and variant quality in the ExAC cohort and combined allele frequency and age data from the ExAC database (n = 60,706) with curated variants from 2000 ADPKD pedigrees (ADPKD Mutation Database). RESULTS Seventy-six percent of PKD1 and PKD2 were sequenced adequately for variant discovery and variant quality was high in ExAC. In ExAC, we identified 25 truncating and 393 previously reported disease-causing variants in PKD1 and PKD2, 6.9-fold higher than expected. Fifty-four different variants, previously classified as disease-causing, were observed in ≥5 participants in ExAC. CONCLUSION Our study demonstrates that many previously implicated disease-causing variants are too common, challenging their pathogenicity, or penetrance. The presence of protein-truncating variants in older participants in ExAC demonstrates the complexity of variant classification and highlights need for further study of prevalence and penetrance of this common monogenic disease.

中文翻译：

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人群数据改善了常染色体显性多囊肾病的变异解释。

目的 常染色体显性遗传多囊肾病 (ADPKD) 是一种常见的成人发病单基因疾病，患病率为 1/1000。包括 ExAC 在内的人群数据库提高了许多疾病的致病性变异优先级。由于 PKD1（主要的 ADPKD 疾病基因）的假基因同源性，以及可变的疾病严重程度和发病年龄，我们旨在研究 ExAC 在 ADPKD 变异评估中的效用。方法 我们评估了 ExAC 队列的覆盖率和变异质量，并将来自 ExAC 数据库（n = 60,706）的等位基因频率和年龄数据与来自 2000 个 ADPKD 谱系（ADPKD 突变数据库）的精选变异相结合。结果 76% 的 PKD1 和 PKD2 被充分测序以发现变异，并且 ExAC 中的变异质量很高。在 ExAC 中，我们在 PKD1 和 PKD2 中鉴定了 25 个截断和 393 个先前报道的致病变异，比预期高 6.9 倍。在 ExAC 的 ≥5 名参与者中观察到 54 种不同的变异，以前被归类为致病。结论 我们的研究表明，许多先前涉及的致病变异太常见，挑战了它们的致病性或外显率。ExAC 的老年参与者中存在蛋白质截短变异证明了变异分类的复杂性，并强调需要进一步研究这种常见单基因疾病的患病率和外显率。结论 我们的研究表明，许多先前涉及的致病变异太常见，挑战了它们的致病性或外显率。ExAC 老年参与者中存在蛋白质截短变异表明变异分类的复杂性，并强调需要进一步研究这种常见单基因疾病的患病率和外显率。结论 我们的研究表明，许多先前涉及的致病变异太常见，挑战了它们的致病性或外显率。ExAC 老年参与者中存在蛋白质截短变异表明变异分类的复杂性，并强调需要进一步研究这种常见单基因疾病的患病率和外显率。