Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Swiss National Centre of Competence in Research Kidney.CH, University of Zürich, Zürich, Switzerland.
Nephrol Dial Transplant. 2024 Aug 30;39(9):1426-1441. doi: 10.1093/ndt/gfae074.
Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies have shown a high heritability of nephrolithiasis, but data on the prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.
We performed whole exome sequencing in 787 participants in the Bern Kidney Stone Registry, an unselected cohort of adults with one or more past kidney stone episodes [kidney stone formers (KSFs)] and 114 non-kidney stone formers (NKSFs). An exome-based panel of 34 established nephrolithiasis genes was analysed and variants assessed according to American College of Medical Genetics and Genomics criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.
The mean age of KSFs was 47 ± 15 years and 18% were first-time KSFs. A Mendelian kidney stone disease was present in 2.9% (23/787) of KSFs. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). Of the KSFs, 8.1% (64/787) were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSFs with Mendelian disease had a lower age at the first stone event (30 ± 14 versus 36 ± 14 years; P = .003), were more likely to have cystine stones (23.4% versus 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% versus 52.5%) compared with KSFs without a genetic diagnosis. The phenotype of KSFs with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSFs without diagnostic variants. In NKSFs, no Mendelian disease was detected and LP/P variants were significantly less prevalent compared with KSFs (1.8% versus 8.1%).
Mendelian disease is uncommon in unselected adult KSFs, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSFs.
大多数患者的肾结石形成的分子机制仍不清楚。先前的研究表明肾结石病具有很高的遗传性，但缺乏对未经选择的肾结石成人中遗传疾病的患病率和特征的数据。本研究旨在填补这一重要的知识空白。
我们对伯尔尼肾结石登记处的 787 名参与者进行了全外显子组测序，这是一个未经选择的成年肾结石患者（肾结石形成者[KSF]）和 114 名非肾结石形成者（非 KSF）的队列。分析了一个基于外显子的 34 个已确立的肾结石基因的小组，并根据美国医学遗传学和基因组学学院的标准评估了变体。致病性（P）或可能致病性（LP）变体被认为是诊断性的。
KSF 的平均年龄为 47±15 岁，18%为首次 KSF。2.9%（23/787）的 KSF 存在孟德尔肾结石病。最常见的遗传诊断为胱氨酸尿症（SLC3A1、SLC7A9；n=13）、维生素 D-24 羟化酶缺乏症（CYP24A1；n=5）和原发性高草酸尿症（AGXT、GRHPR、HOGA1；n=3）。KSF 中，8.1%（64/787）为 LP/P 变体单等位基因易患肾结石，最常见于 SLC34A1/A3 或 SLC9A3R1（n=37）、CLDN16（n=8）和 CYP24A1（n=8）。患有孟德尔疾病的 KSF 首次肾结石事件的年龄较低（30±14 岁与 36±14 岁；P=0.003），更有可能患有胱氨酸结石（23.4%与 1.4%），而不太可能患有草酸钙一水合物结石（31.9%与 52.5%）。与没有遗传诊断的 KSF 相比，具有致肾结石变异的 KSF 的表型较微妙，且与没有诊断变异的 KSF 有明显重叠。在 NKSF 中，未发现孟德尔疾病，LP/P 变体的患病率明显低于 KSF（1.8%与 8.1%）。
在未经选择的成年 KSF 中，孟德尔疾病并不常见，但易患肾结石的变体在成年 KSF 中明显富集。
