Kidney Week

Abstract: SA-PO0116

Genetic Characterization of a Medullary Sponge Kidney Cohort

Session Information

• ADPKD and Cystic Kidney Disease - 3
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Alshareef, Abdulmueti, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Abdulmueti Alshareef, MD

• Cogal, Andrea G., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Andrea G. Cogal

• Zaher, Ahmed Abdelnaby Aly Mahmoud, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Ahmed Abdelnaby Aly Mahmoud Zaher, MBChB

• Elbarougy, Doaa E., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Doaa E. Elbarougy, MBChB

• Sas, David J., Mayo Clinic Minnesota, Rochester, Minnesota, United States

David J. Sas, DO, MPH

• Jayachandran, Muthuvel, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Muthuvel Jayachandran, PhD

• Goldfarb, David S., NYU Langone Health, New York, New York, United States

David S. Goldfarb, MD, FASN

• Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Lieske, John C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

John C. Lieske, MD, FASN

Background

Medullary sponge kidney (MSK) is a congenital disorder characterized by cystic dilatation of the medullary and papillary collecting ducts, and often associated with nephrolithiasis (NL), nephrocalcinosis (NC), urinary tract infections, and distal renal tubular acidosis. Despite its clinical significance, the genetics of MSK remains poorly understood, with prior evidence largely limited to isolated reports involving GDNF and RET

Methods

We genetically screened 252 MSK patients from three independent cohorts: self-identified as having MSK through the MSK Awareness, Support, and Research Facebook page (n=99), and ICD code identified in Mayo Clinic Biobank (n=71), and Tapestry cohorts (n=82). Sequencing panels covered 160–540 kidney disease–related genes. Pathogenic, likely pathogenic (P/LP) and uncertain (VUS) variants were classified according to ACMG criteria. Matched control cohorts were screened to evaluate enrichment of identified variants, and familial clustering was assessed, where possible

Results

Overall, 95 patients (38%) carried at least one P/LP variant and including high likelihood VUS, we identified 121 total variants across 82 genes: 46 associated with monoallelic disorders, 64 with biallelic, and 9 with both inheritance patterns. The most frequently affected genes were PKHD1 (n=8), SLC34A3 (n=7), MYO7A (n=6), SLC12A3 (n=6), and CYP24A1 (n=6). RET variants were identified in 4 patients, supporting a possible role. No P/LP GDNF variants were detected, although the described MSK associated promotor variant was found in one patient. The implicated genes were associated with NL/NC (26%), cystic kidney disease (20%), syndromic/metabolic disorders (20%), tubulopathies/ciliopathies (13%), and renal developmental disorders. Several patients harbored variants in multiple genes, suggesting possible oligogenic contributions. Familial clustering was observed in three pedigrees with variable inheritance patterns and incomplete penetrance. Variant frequencies in the implicated genes were higher than in control populations without MSK.

Conclusion

MSK appears to represent a complex genetic disease rather than a simple monogenic disorder. Broad genetic testing identified possible variants of interest in multiple stone- and cyst-related genes at a higher frequency than observed in control populations, suggesting that multiple genetic risk factors may contribute to MSK susceptibility

Funding

• NIDDK Support