Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes
Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes
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DOI：
10.1038/s41436-020-0816-3
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发表时间：
2020-05-13
影响因子：
8.8
通讯作者：
Halbritter, Jan
中科院分区：
文献类型：
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作者：
Schoenauer, Ria;Baatz, Sebastian;Halbritter, Jan
目的 常染色体显性多囊肾病 (ADPKD) 是最常见的遗传性肾病。尽管越来越多的证据表明遗传异质性，ADPKD 诊断仍然主要基于发现其他 PKD 基因之前制定的临床影像标准。本研究旨在评估基因验证在临床 ADPKD 中的诊断价值。方法 在这项前瞻性诊断试验中，通过 PKD 基因组和多重连接依赖性探针扩增 (MLPA) 对 100 个临床诊断为 ADPKD 的家庭进行了分析；在面板/MLPA 阴性家族中进行外显子组测序 (ES)。结果 在 81 个家族 (81%) 中鉴定出诊断性 PKD1/2 变异，其中 70 个在 PKD1 中，11 个在 PKD2 中。在另外 9 个家族 (9%) 中检测到意义不明的 PKD1 变异。与未截断和 PKD2 改变相比，PKD1 截断后的肾存活率明显更差。该队列中有 10% 的人 PKD1/2 阴性，揭示了其他遗传诊断，例如常染色体隐性 PKD、Birt-Hogg-Dube 综合征和 ALG9 相关 PKD。此外，在未解决的案例中，ES 产生了潜在的新型 PKD 候选者。结论 通过说明巨大的遗传异质性，本研究通过诊断验证、伪造和疾病预测证明了基因检测在现实世界 PKD 队列中的价值。在快速进展型 ADPKD 特异性治疗时代，基因确认应成为个性化患者护理的基础。
Purpose Autosomal dominant polycystic kidney disease (ADPKD) represents the most common hereditary nephropathy. Despite growing evidence for genetic heterogeneity, ADPKD diagnosis is still primarily based upon clinical imaging criteria established before discovery of additional PKD genes. This study aimed at assessing the diagnostic value of genetic verification in clinical ADPKD. Methods In this prospective, diagnostic trial, 100 families with clinically diagnosed ADPKD were analyzed by PKD gene panel and multiplex ligation-dependent probe amplification (MLPA); exome sequencing (ES) was performed in panel/MLPA-negative families. Results Diagnostic PKD1/2 variants were identified in 81 families (81%), 70 of which in PKD1 and 11 in PKD2. PKD1 variants of unknown significance were detected in another 9 families (9%). Renal survival was significantly worse upon PKD1 truncation versus nontruncation and PKD2 alteration. Ten percent of the cohort were PKD1/2-negative, revealing alternative genetic diagnoses such as autosomal recessive PKD, Birt-Hogg-Dube syndrome, and ALG9-associated PKD. In addition, among unsolved cases, ES yielded potential novel PKD candidates. Conclusion By illustrating vast genetic heterogeneity, this study demonstrates the value of genetic testing in a real-world PKD cohort by diagnostic verification, falsification, and disease prediction. In the era of specific treatment for fast progressive ADPKD, genetic confirmation should form the basis of personalized patient care.