Abstract: SA-PO570
Monogenic Forms of Kidney Stone Disease in 841 Adult Kidney Stone Formers From the Bern Kidney Stone Registry
Session Information
- Genetic Diseases: Diagnosis
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Anderegg, Manuel Andreas, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Olinger, Eric Gregory, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
- Geraghty, Robert M., Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
- Schaller, André, Department of Medical Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Bargagli, Matteo, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Pohlmeier, Lea, Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
- Sayer, John Andrew, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom
- Fuster, Daniel G., Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Background
Kidney stone disease is increasing worldwide, leads to high morbidity and represents a substantial economic burden to health systems. The detection of monogenic forms of kidney stone disease provides crucial pathophysiological insights and enables precision medicine approaches in affected patients. Previous genetic analysis by whole exome sequencing (WES) or kidney stone disease gene panels in relatively small cohorts of selected, mostly pediatric stone formers detected monogenic forms of kidney stone disease in 10-30% of patients studied. Larger studies using WES in well-characterized unselected cohorts of adult kidney stone formers are missing.
Methods
We conducted WES in 841 adult kidney stone formers participating in the Bern Kidney Stone Registry (BKSR). The BKSR is an unselected cohort of kidney stone formers with detailed phenotypic data available. Inclusion criteria are: ≥ 1 stone episode and age ≥ 18 years. For the initial analysis, we applied a virtual panel of 33 genes previously implicated in monogenic kidney stone disease. Variants in the 33 genes were filtered according to gnomAD allele frequencies (MAF <1%) and predicted consequence on the canonical transcript and were then curated against in silico pathogenicity tools, variant databases and previously reported modes of inheritance.
Results
We detected 184 distinct predicted pathogenic variants in 19 of 33 analyzed genes. Taking into account likely mode of inheritance, this led to a molecular diagnosis for 12.1% of all patients. 30% of the detected variants with predicted pathogenicity have not been previously reported. 70 % of the kidney stone formers with likely monogenetic etiology showed monoallelic inheritance, fitting with previous data showing more frequent recessive inheritance of kidney stone disease in children, but more dominant inheritance patterns in adults.
Conclusion
In an unselected cohort of adult kidney stone formers, we identified a surprisingly high prevalence of monogenetic forms of kidney stone disease. The next steps will include genotype/phenotype correlations of solved individuals. Furthermore, using the detailed phenotypic dataset of the BKSR, we aim to investigate potential multiallelic inheritance patterns and extend the genetic analysis to candidate genes.
Funding
- Government Support – Non-U.S.