美国宾西法尼亚州肾脏健康研究中心Tooraj Mirshahi团队研究了常染色体显性多囊肾病临床人群的外显子组测序。该项研究成果发表在2022年12月27日出版的《美国医学会杂志》上。

大多数常染色体显性多囊肾病（ADPKD）遗传学研究都采用了肾脏专科队列，重点关注PKD1和PKD2。这些可能导致对ADPKD相关基因变体及其表型表达的人群流行率的偏差估计。

为了在一个未经选择的大队列中确定ADPKD的患病率以及PKD1、PKD2和其他与囊性肾病相关的基因的贡献，研究组进行了一项回顾性观察性研究，使用宾夕法尼亚州中部和东北部一个未经选择的基于卫生系统的队列，其中包括外显子组测序（2004年至2020年登记）和电子健康记录数据（截至2021年10月）。基因型优先方法包括整个队列，表型优先方法侧重于ADPKD诊断代码患者，通过图表和影像学检查予以证实。

暴露因素为PKD1、PKD2和其他与囊性肾病相关的基因（即ALG8、ALG9、DNAJB11、GANAB、HNF1B、IFT140、SEC61B、PKHD1、PRKCSH、SEC63）中的功能缺失（LOF）变体；PKD1和PKD2中可能的致病性错义变体。基因型初步分析：ADPKD诊断码（Q61.2、Q61.3、753.13、753.12）；表型优先分析：PKD1、PKD2或其他与囊性肾病相关的基因中存在罕见变异。

174172名患者（中位年龄60岁；60.6%为女性；93%为欧洲血统）中，303名患者具有ADPKD诊断代码，其中235名患者具有足够的图表审查数据以供确认。除了PKD1和PKD2外，IFT140、GANAB和HNF1B中的LOF变体在校正多次比较后与ADPKD诊断相关。在PKD1中有LOF变体的患者中，68人中有66人（97%）患有ADPKD；43例PKD2中LOF变体患者中有43例（100%）患有ADPKD。

相比之下，77名PKD1错义变体患者中只有24名（31.2%）患有ADPKD，这表明分类错误或外显率可变。在图表审查确认的ADPKD患者中，235名患者中有180名（76.6%）有潜在的遗传原因，其中大多数是PKD1（127名患者）或PKD2（34名患者）的罕见变异；235例中有19例（8.1%）在与囊性肾病相关的其他基因中存在变异。

在这235名确诊ADPKD患者中，150名（63.8%）有ADPKD家族史。有ADPKD家族史者与无家族史者相比，ADPKD遗传决定因素的产率更高（91.3%与50.6%；差异为40.7%）。以前未报道的PKD1、PKD2和GANAB变异体通过表明致病性的谱系数据进行了鉴定，以前报道的几种可能致病的PKD1错义变异体似乎是良性的。

这项研究表明，在美国的一个地区卫生系统中，ADPKD患者的遗传和表型差异很大。

附：英文原文

Title: Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease

Author: Alexander R. Chang, Bryn S. Moore, Jonathan Z. Luo, Gino Sartori, Brian Fang, Steven Jacobs, Yoosif Abdalla, Mohammed Taher, David J. Carey, William J. Triffo, Gurmukteshwar Singh, Tooraj Mirshahi

Issue&Volume: 2022/12/27

Abstract:

Importance  Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression.

Objective  To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort.

Design, Setting, and Participants  This retrospective observational study used an unselected health system–based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review.

Exposures  Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2.

Main Outcomes and Measures  Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease.

Results  Of 174172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as “likely pathogenic” had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P<.001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign.

Conclusions and Relevance  This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.

DOI: 10.1001/jama.2022.22847

Source: https://jamanetwork.com/journals/jama/article-abstract/2799908