Abstract: TH-PO463
The Natural History and Genetics of TRPC6-Associated Podocytopathy
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
- Wooden, Benjamin, Columbia University Irving Medical Center, New York, New York, United States
- Jin, Gina, Columbia University Irving Medical Center, New York, New York, United States
- Gupta, Yask, Columbia University Irving Medical Center, New York, New York, United States
- Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States
- Mitrotti, Adele, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
- Kiryluk, Krzysztof, Columbia University Irving Medical Center, New York, New York, United States
- Santoriello, Dominick, Columbia University Irving Medical Center, New York, New York, United States
- D'Agati, Vivette D., Columbia University Irving Medical Center, New York, New York, United States
- Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
- Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
- Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
Background
Pathogenic variants in TRPC6 account for a small but significant proportion of inherited podocytopathy. TRPC6 podocytopathy is caused mainly by gain-of-function mutations increasing the open probability of the encoded channel, making it potentially amenable to inhibitory drug therapy. Understanding the natural history and spectrum of genetic variation is therefore of considerable importance. Here, we report on the outcome data and mutational spectrum of a large cohort of patients with TRPC6-associated podocytopathy.
Methods
A cohort of 86 patients with TRPC6 variants and proteinuric kidney disease from 51 families was assembled. All patients underwent exome/genome sequencing and targeted Sanger sequencing. Affected regions of the TRPC6 protein were visualized using the cBioPortal mutation mapper, and predicted effects of mutations on the TRPC6 protein were generated using several validated in silico scoring systems (REVEL, CADD, PrimateAI, and Polyphen-2). Clinical data were collected and used for genetic correlations.
Results
33 independent TRPC6 variants were identified. The majority of variants had high pathogenicity scores, though only 45% of them have existing ClinVar annotation. Variants were clustered in 3 regions, with one cluster in the early ankyrin repeat, a second in the transient receptor ion channel (TRP_2) domain, and a third at the C-terminal end. Within the cohort, age of onset of kidney disease ranged from <1 year to 53 years, with a median of 19 years. Data regarding progression to ESRD were available for 65% of patients; of these, 68% developed ESRD, with a median age of 31 years (ranging from 1 to 57 years).
Conclusion
TRPC6-associated podocytopathy is a rare cause of genetic FSGS. We have assembled a large cohort of patients, demonstrating high intra- and inter-familial variability in age at presentation and outcomes, and that the resulting kidney disease is progressive and frequently results in ESRD. Granular clinical genetic and kidney pathology correlations are ongoing.
Funding
- NIDDK Support – Actio Biosciences