Deep biochemical phenotyping reveals prognostic value of rare genetic variants in adult kidney stone disease
Johannes Münch, Jana Petrovska, Joana Figueiro-Silva, Isabel Rubio-Aliaga, Elena M. Cabello, Ivan Ivanovski, Michael Papik, Beatrice Oneda, Daniel G. Fuster, Harald Seeger, Thomas Ernandez, Florian Buchkremer, Gregoire Wuerzner, Nasser A. Dhayat, Alexander Ritter, Stephan Segerer, Beat Roth, Anita Rauch, Pietro Manuel Ferraro, Olivier Bonny, Carsten A. Wagner, Ruxandra Bachmann-Gagescu
Johannes Münch, Jana Petrovska, Joana Figueiro-Silva, Isabel Rubio-Aliaga, Elena M. Cabello, Ivan Ivanovski, Michael Papik, Beatrice Oneda, Daniel G. Fuster, Harald Seeger, Thomas Ernandez, Florian Buchkremer, Gregoire Wuerzner, Nasser A. Dhayat, Alexander Ritter, Stephan Segerer, Beat Roth, Anita Rauch, Pietro Manuel Ferraro, Olivier Bonny, Carsten A. Wagner, Ruxandra Bachmann-Gagescu
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Clinical Research and Public Health Genetics Nephrology

Deep biochemical phenotyping reveals prognostic value of rare genetic variants in adult kidney stone disease

Abstract

BACKGROUND Kidney stone disease (KSD) affects approximately 10% of the population. While genetic factors are known to play a role in KSD, determining the clinical relevance of rare variants in KSD genes identified in adults remains challenging.METHODS The Swiss Kidney Stone Cohort is a multicenter longitudinal, observational study consisting of kidney stone formers (KSFs) (n = 701) and non-kidney stone formers (NKSFs) (n = 200). Blood and urine samples were collected at enrollment and over 3 years for deep biochemical phenotyping. Results were correlated with rare genetic variants in established KSD genes identified through whole-exome sequencing and classified according to American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP) criteria.RESULTS Collectively, we found rare (likely) pathogenic (LP/P) variants representing strong KSD risk factors in 6.8% of KSFs, predominantly in genes involved in renal phosphate handling and cystinuria. Detailed biochemical analyses confirmed that KSFs carrying heterozygous LP/P SLC34A3 variants exhibited significant hyperphosphaturia. In contrast, monoallelic LP/P variants in SLC34A1, SLC9A3R1, or CYP24A1, which were also frequent in NKSFs, did not result in the expected biochemical alterations, calling into question their causative role as strong KSD risk factors. In cystinuria, monoallelic SLC7A9 variants represented intermediate risk factors, since they caused biochemical alterations but required additional factors for KSD occurrence, based on frequent LP/P variants in NKSFs. The presence of strong risk factors was associated with higher kidney stone (KS) recurrence over the 3-year observation period, supporting a predictive value for genetic testing.CONCLUSIONS Correlation of genetic findings with thorough biochemical phenotyping and comparison with NKSFs redefines the clinical relevance of variants in KSD genes and has prognostic value.

Authors

Johannes Münch, Jana Petrovska, Joana Figueiro-Silva, Isabel Rubio-Aliaga, Elena M. Cabello, Ivan Ivanovski, Michael Papik, Beatrice Oneda, Daniel G. Fuster, Harald Seeger, Thomas Ernandez, Florian Buchkremer, Gregoire Wuerzner, Nasser A. Dhayat, Alexander Ritter, Stephan Segerer, Beat Roth, Anita Rauch, Pietro Manuel Ferraro, Olivier Bonny, Carsten A. Wagner, Ruxandra Bachmann-Gagescu

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Figure 1

Variants in monogenic KS genes identified in the SKSC.

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Variants in monogenic KS genes identified in the SKSC. (A) Overview of t...
(A) Overview of the study and inclusion criteria (*see also Supplemental Figure 1 for detailed risk factors). v indicates the visit number, with 7 visits (V1–7) over 3 years for KSFs, and 1 visit (V1) for NKSFs. Visits with measurement of biochemical parameters (blood and urine samples) are indicated above with arrows (values from the baseline visit [V2, red arrow] were used in the following analyses in Figures 2 and 3). (B) WES was performed for KSFs and NKSFs, with analysis of a virtual panel for 39 established KS genes that are involved in the handling of different electrolytes. The described inheritance mode for each gene is indicated as autosomal recessive (AR), autosomal dominant (AD) or X-linked recessive (XLR), with the question mark indicating where the dominant inheritance mode has been debated. (C) Pie charts indicate the number of individuals harboring variants classified according to ACMG/AMP criteria for KSFs (left) and NKSFs (right). Each individual is accounted for only once for this plot. (D) The number of KSFs (blue) and NKSFs (orange) carrying a LP/P variant in 1 of the 39 KSD genes, with a matching mode of inheritance resulting in the diagnosis of monogenic KSD. Light blue bars indicate recessive disease ([presumed] biallelic variants in the indicated gene), and dark blue bars indicate dominant disease (monoallelic variants). No NKSF presented with biallelic LP/P variants. One KSF harbored a monoallelic LP/P variant in SLC9A3R1 together with 2 LP/P variants in SLC7A9, while 1 NKSF carried a monoallelic LP/P variant in 2 genes associated with dominant and recessive disease (SLC9A3R1 and SLC7A9). These individuals are indicated twice in the bar plot. All details for the LP/P variants are described in Supplemental Table 2 for KSFs and Supplemental Table 3 for NKSFs. AD, autosomal dominant; AR, autosomal recessive; B, benign; CT, computed tomography; KS, kidney stones; KSF, kidney stone formers; LB, likely benign; LP, likely pathogenic; NKSF, non-kidney stone formers; P, pathogenic, VUS, variant of uncertain significance, XLR, X-linked recessive.