Kidney Week

Abstract: FR-PO228

Genotyping Patients with Medullary Sponge Kidney (MSK)

Session Information

• Mineral Bone Disease: Transplant and Kidney Stones
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 502 Bone and Mineral Metabolism: Clinical

Authors

• Ali, Ahmed E., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Ahmed E. Ali, MD

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

Andrea G. Cogal

• Seide, Barbara M., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Barbara M. Seide

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

David J. Sas, DO, MPH

• 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

• Goldfarb, David S., New York University, New York, New York, United States

David S. Goldfarb, MD, FASN

Group or Team Name

• Rare Kidney Stone Consortium.

Background

The underlying genetics of MSK risk are uncertain, with evidence of increased prevalence of radiologic abnormalities in first-degree relatives of affected patients, GDNF was suggested as causative in a few cases. MSK has a characteristic appearance on excretory urogram, but this imaging is now rarely used; ultrasounds and CT scans are often read as "suggestive of MSK" when nephrocalcinosis is observed. We genetically screened a cohort of patients with a clinical diagnosis of MSK to determine if any had a possible monogenic cause.

Methods

We solicited research participants from a Facebook page (~3000 members): "Medullary Sponge Kidney Awareness, Support, and Research". Participants self-identify as having MSK; we did not require radiologic confirmation. 98 patients replied via email and were sent consent forms and kits for returning saliva to Mayo Clinic. The study was approved by Mayo Clinic IRB. The cohort was screened by targeted next generation sequencing with a panel consisting of 160 known and candidate monogenic urinary stone disease (MUSD) genes. Clinical information from participants was collected.

Results

96 individuals from 87 families were screened. The participants were 94% women, average age 49 y. We identified 9 pedigrees with single pathogenic/likely pathogenic (P/LP) variants in genes associated with monoallelic disease: ATP6V0A4, CASR, PKHD1(2), SLC2A9, SLC34A1(2), SLC34A3(2). An additional 5 pedigrees were heterozygous for P/LP variants in 4 genes associated with biallelic MUSD and 24 pedigrees were heterozygous for variants of unknown significance (VUS) in 16 MUSD genes. Only 1 individual carried the GDNF promoter variant, that we classified as a VUS given its normal population frequency.

Conclusion

We did not identify one known or candidate MUSD gene to explain a significant proportion of the screened MSK cases (including GDNF), but 10.3% had a P/LP variant in a monoallelic MUSD gene, many associated with nephrocalcinosis, that may explain or partially explain the MSK phenotype. The finding of P/LP variants in recessive MUSD genes and many other MUSD gene VUS suggest that MSK individuals may be enriched for risk factor variants. MSK is a complex disease with multiple genetic and environmental inputs. This study supports genetic screening of patients with a clinical MSK diagnosis to identify monogenic causes of nephrocalcinosis.

Funding

• NIDDK Support