Prevalence and characteristics of genetic disease in adult kidney stone formers

Manuel A Anderegg; Eric G Olinger; Matteo Bargagli; Rob Geraghty; Lea Taylor; Alexander Nater; Rémy Bruggmann; John A Sayer; Bruno Vogt; André Schaller; Daniel G Fuster

doi:10.1093/ndt/gfae074

Prevalence and characteristics of genetic disease in adult kidney stone formers

Nephrol Dial Transplant. 2024 Mar 27:gfae074. doi: 10.1093/ndt/gfae074. Online ahead of print.

Authors

Manuel A Anderegg^{1

2}, Eric G Olinger^{1

2

3

4}, Matteo Bargagli^{1

2}, Rob Geraghty³, Lea Taylor⁵, Alexander Nater⁵, Rémy Bruggmann⁵, John A Sayer^{3

6

7}, Bruno Vogt¹, André Schaller⁸, Daniel G Fuster^{1

2}

Affiliations

¹ Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Switzerland.
² Swiss National Centre of Competence in Research (NCCR) Kidney.CH.
³ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁴ Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
⁵ Interfaculty Bioinformatics Unit, University of Bern and Swiss Institute of Bioinformatics (SIB), Switzerland.
⁶ Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁷ National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle Upon Tyne, NE4 5PL UK.
⁸ Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Switzerland.

PMID: 38544324
DOI: 10.1093/ndt/gfae074

Abstract

Background: Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high a heritability of nephrolithiasis, but data on prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.

Methods: We performed whole exome sequencing in 787 participants of the Bern Kidney Stone Registry, an unselected cohort of adults with ≥ 1 past kidney stone episode (KSF), and 114 non-stone-forming individuals (NKSF). An exome-based panel of 34 established nephrolithiasis genes was analyzed and variants assessed according to ACMG criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.

Results: Mean age of KSF was 47±15 years, and 18% were first time KSF. A Mendelian kidney stone disease was present in 2.9% (23 of 787) of KSF. 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). 8.1% (64 of 787) of KSF 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). KSF with Mendelian disease had a lower age at the first stone event (30±14 years vs. 36±14 years, p=0.003), were more likely to have cystine stones (23.4% vs. 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% vs. 52.5%) compared to KSF without genetic diagnosis. The phenotype of KSF with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSF without diagnostic variants. In NKSF, no Mendelian disease was detected, and LP/P variants were significantly less prevalent compared to KSF (1.8% vs. 8.1%).

Conclusion: Mendelian disease is uncommon in unselected adult KSF, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSF.

Keywords: kidney stones; mendelian; monogenic; nephrolithiasis; whole exome sequencing.