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Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease
Andrea G Cogal1, Jennifer Arroyo1, Ronak Jagdeep Shah1
1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
Kidney International Reports
|November 22, 2021
Summary
Targeted next-generation sequencing (tNGS) improves diagnosis of monogenic urinary stone diseases (USD), like primary hyperoxaluria (PH) and Dent disease (DD). This approach identifies pathogenic variants missed by traditional methods, aiding in better patient management and clinical trial enrollment.
Area of Science:
- Genetics and Genomics
- Nephrology
- Rare Diseases
Background:
- Monogenic urinary stone diseases (USD) like primary hyperoxaluria (PH) and Dent disease (DD) exhibit phenotypic overlap, complicating genetic diagnosis.
- Traditional gene-specific analyses can lead to missed diagnoses in patients with suspected PH or DD.
- Sanger sequencing of known genes often fails to identify all causative genetic variants.
Purpose of the Study:
- To evaluate the diagnostic yield of targeted next-generation sequencing (tNGS) for monogenic USD in patients unresolved by prior Sanger analysis.
- To identify pathogenic variants in known and candidate monogenic USD genes.
- To assess the utility of tNGS in diagnosing PH and DD.
Main Methods:
- Targeted next-generation sequencing (tNGS) was employed, encompassing known and candidate monogenic USD genes.
- Cohorts included 285 PH (PHN) and 59 DD (DDN) families with negative Sanger analysis results.
- Variants were assessed using databases, assessment tools, and categorized per ACMG guidelines.
Main Results:
- tNGS identified pathogenic variants in 14 known monogenic USD genes in 45 families (13.1%), including biallelic and monoallelic cases.
- Significant recurrent genes identified were SLC34A3, CLDN16, and CYP24A1.
- Pathogenic variants were identified in 23.9% of suspected DD cases and 7.3% of suspected PH cases, with a substantial proportion being novel.
Conclusions:
- Targeted next-generation sequencing (tNGS) significantly enhances the diagnostic rate for monogenic urinary stone diseases (USD).
- This approach is valuable for identifying variants missed by conventional methods, improving diagnosis of PH and DD.
- Improved diagnosis through tNGS can optimize patient therapies and facilitate enrollment in clinical trials.
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