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Kidney Week

Abstract: FR-PO595

Clinical Characterization of a Cohort with Suspected Monogenic Stone Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Arnous, Muhammad G., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Cogal, Andrea G., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Seide, Barbara M., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Sas, David J., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Lieske, John C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
Background

Monogenic stone diseases (MSDs) result from pathogenic variants in ~40 genes, displaying early onset, frequent stone events, chronic kidney failure, and positive family history. Targeted next-generation sequencing (tNGS) is a valuable approach for identifying genetic causes. Here, we share tNGS panel analysis results from a large cohort with suspected MSDs.

Methods

Subjects were recruited by Rare Kidney Stone Consortium (RKSC) collaborators with features suggestive of a possible MSD. Genotyping with a tNGS panel that includes 149 known and candidate causes of MSD. All variants were scored for pathogenicity using ACMG criteria. Clinical features were extracted from the RKSC registries and medical records. Urine parameters and eGFR were adjusted for age and sex. Data are reported as medians for continuous variables and percentages for categorical variables. Non-parametric and proportional tests were used for analysis.

Results

A total of 374 families (540 patients) were enrolled and screened. Of these, 131 families (40%; 216 individuals) were resolved with an identified pathogenic change in a total of 20 different genes, while in 243 families no mutation was detected (NMD) (60%, 324 individuals). Families were categorized based on the reason for recruitment into the following groups: Hyperoxaluria, hypercalciuria, cystinuria, and Stones without urine abnormalities. Table 1- shows a summary of the clinical features of resolved cases. Resolved hypercalciuria cases had a lower eGFR (p<0.01). Dent disease patients had a higher urinary calcium excretion than other resolved cases, and primary hyperoxaluria patients manifested hyperoxaluria as expected. Patients with SLC34A1 and SLC34A3 variants required more stone surgeries (p=0.03).

Conclusion

Despite a wide range of etiologies, the clinical characteristics of MSD show an overlap, yet kidney stones, nephrocalcinosis, and kidney failure are prevalent. A candidate gene panel is efficient to screen for the many causes of MSD with a high resolving rate improving diagnostics and allowing appropriate management and treatments.

Table-1 resolved cases with their clinical characteristics

Funding

  • NIDDK Support