Abstract: TH-PO461
Mayo Clinic Experience with TRPC6 Mutations Using Clinical Whole Exome Sequencing
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Mekraksakit, Poemlarp, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Titan, Silvia, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Fervenza, Fernando C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Zand, Ladan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Cornell, Lynn D., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Garg, Arvind K., Mayo Clinic Health System, La Crosse, Wisconsin, United States
- El Ters, Mireille, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Hogan, Marie C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Integration of genomic and research testing and multidisciplinary evaluation in a nephrology cohort with CKD of unknown etiology or suspected monogenic disease provides a diagnosis in approximately a third of families in our center. The TRPC6 gene, a member of the transient receptor potential (TRP) superfamily of cation-selective ion channels, encodes the slit diaphragm-associated canonical TRP cation channel C6 protein expressed in podocytes. Around 20 missense mutations have been reported, including nine gain-of-function and five loss-of-function mutations that affect TRPC6 channel activity. We present our experience at the Mayo Nephrology Clinic with cases of proteinuric chronic kidney disease found to have TRPC6 variants.
Methods
Testing utilized kidney/nephrotic disease panels, single gene analysis, or analysis of kidney-related genes from exome sequencing. The Nephrology Genomics Board, composed of nephrologists, geneticists, and pathologists, interpreted the patients' clinical and genetic data. Kidney biopsy was performed for most patients. Variant classification followed the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Results
Eight probands, all adults, were identified with TRPC6 variants and proteinuric CKD. All variants clustered in Exons 1, 2, and 13. We provided a definitive genetic diagnosis for three probands with pathogenic or likely pathogenic variants, one of which has not been reported previously. In addition, five cases had variants of interest, and among them, three had other first-degree family members with CKD as well. One of the cases with a positive family history had a sibling who was accepted for kidney donation after the donor tested negative for TRPC6 variants.
Conclusion
In summary, TRPC6-related CKD diagnoses have diagnostic and prognostic implications, enabling a more precise diagnosis and changes in management, including the evaluation of safety for living kidney donation. Furthermore, further studies on the functional analysis of TRPC6 variants may provide new insights into diagnostic precision and the mechanisms of the disease.