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Published on: September 20, 2021
Exome sequencing in patients with medullary sponge kidney
Corentin Tournebize1,2,3, Thomas Robert4,5, Nadia Abid6
1Department of Nephrology, Dialysis, Hypertension, Functional Renal Explorations, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Background:
Medullary sponge kidney (MSK) is characterized by precalyceal dilatation of the renal tubules. This entity is associated with recurrent kidney stone disease (KSD). Although etiopathogenesis is unknown, genetic origin is suspected.
Hypothesis:
The aim of the study was to describe the variants identified in genes associated with urolithiasis and/or cystic kidney disease in MSK using whole-exome sequencing (WES) in patients diagnosed with MSK.Moreover, one hypothesis supported by the only available genetic cohort study is that MSK is due to disruptions in kidney organogenesis involving the GDNF, RET, or GFRα1 genes. We wanted to test that hypothesis in our population.
Methods:
WES was performed between January 2023 and June 2024 in 42 patients diagnosed with MSK. The pathogenicity was assessed using American College of Medical Genetics guidelinesPositive WES group was defined by one or more "likely pathogenic" or "pathogenic"' variants in genes associated with monoallelic urolithiasis and/or cystic kidney disease and/or already described in MSK according to the mode of inheritance.We also searched for rare truncating and missense variants in the RET, GDNF, and GFRα1 from a variant datastore which contains unsorted and unfiltered WES results from ∼8000 French patients. We then checked whether the patients identified had an MSK phenotype.
Results:
Ten patients were identified as WES-positive, involving nine genes: IFT140, PRKCSH, PKHD1, SLC34A3, SLC34A1, SLC26A1, UMOD, COL4A3, and MT-TL1. A total of 140 rare variants of RET (n = 107), GDNF (n = 11), and GFR α1 (n = 22) were identified in the variant datastore, none was associated with MSK.
Conclusions:
MSK was associated with a diverse set of genes related to KSD and/or cystic kidney diseases that underscore the heterogeneity of MSK, both in its presentation and its underlying genetic basis. MSK may represent a macroscopic phenotype with polygenic origins rather than a distinct entity.
Insights
Medullary sponge kidney (MSK) is linked to various genes involved in kidney stone disease and cystic kidney conditions, indicating genetic heterogeneity. This suggests MSK may be a complex phenotype with multiple genetic causes rather than a single distinct entity.
Area of Science:
- Nephrology
- Medical Genetics
Background:
- Medullary sponge kidney (MSK) is a condition characterized by renal tubule dilation, often associated with recurrent kidney stone disease (KSD).
- The precise cause of MSK is unknown, but a genetic basis is suspected.
Purpose of the Study:
- To identify genetic variants in genes associated with urolithiasis and cystic kidney disease in MSK patients using whole exome sequencing (WES).
- To investigate the hypothesis that MSK arises from disruptions in kidney organogenesis involving the GDNF, RET, or GFRα1 genes.
Main Methods:
- Whole exome sequencing (WES) was conducted on 42 MSK patients.
- Variant pathogenicity was assessed using established guidelines. A WES-positive group was defined by pathogenic or likely pathogenic variants in relevant genes.
- Rare variants in RET, GDNF, and GFRα1 were analyzed in a large French patient WES database.
Main Results:
- Ten patients (WES-positive) had variants in nine genes: IFT140, PRKCSH, PKHD1, SLC34A3, SLC34A1, SLC26A1, UMOD, COL4A3, and MT-TL1.
- No association was found between MSK and rare variants in RET, GDNF, or GFRα1 in the larger WES dataset, despite identifying 140 such variants.
Conclusions:
- MSK is associated with a wide array of genes implicated in kidney stone disease and/or cystic kidney diseases, highlighting its genetic heterogeneity.
- The findings suggest that MSK may not be a distinct entity but rather a macroscopic phenotype with polygenic origins.
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