Prevalence and characteristics of genetic disease in adult kidney stone formers

Abstract

Background: 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.

Methods: 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.

Results: 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%).

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

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

Graphical Abstract

Figure 1:

(upper panel) Flowchart of patient inclusion, exclusion and genetic analysis in the BKSR. Data from 1152 individuals recruited into the BKSR were analysed. After exclusion of individuals without genetic information available, declined consent or multiple inclusions, the analysed cohort consisted of 901 individuals (787 KSFs and 114 NKSFs). Before inclusion in the BKSR, NKSFs underwent ultrasound imaging to exclude nephrolithiasis (NL) and/or nephrocalcinosis (NC). Genetic analysis was performed in a standardized prioritization pathway in 34 known kidney stone genes. N: number of individuals; genetic diagnosis: likely pathogenic or pathogenic variant according to ACMG criteria; LP/P variant: monoallelic LP/P variant, predisposing to nephrolithiasis. (lower panel) Kidney stone disease gene panel used for genetic analysis. Panel of 34 known nephrolithiasis genes used with their inheritance mode, as accepted for classification as ‘Mendelian disease’ in this article, grouped by phenotypes. AD: autosomal dominant; AR: autosomal recessive; XLR: X-linked recessive; MODY: maturity-onset diabetes of the young; FRTS: Fanconi renal tubular syndrome.

Figure 2:

Overall yield of genetic diagnoses: (A) diagnostic yield (Mendelian versus LP/P variants predisposing to nephrolithiasis) in KSFs; (B) diagnostic yield in NKSFs; (C) overview of Mendelian diagnoses in KSFs, sorted by phenotype groups; (D) overview of LP/P variants predisposing to nephrolithiasis in KSFs, sorted by phenotype groups.