Abstract
Background:
Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6 to help define the specific features of disease and further facilitate drug development and clinical trials design.
Methods:
The study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed, and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their effect on protein function. In-depth reanalysis of light and electron microscopy specimens for nine available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP.
Results:
Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. Most patients presented in adolescence or early adulthood but with ample variation (average 22, SD ±14 years), with frequent progression to kidney failure but with variability in time between presentation and kidney failure.
Conclusions:
This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.
Clinical Trial registry name and registration number:
A Study to Test BI 764198 in People With a Type of Kidney Disease Called Focal Segmental Glomerulosclerosis, NCT05213624.
Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6 to help define the specific features of disease and further facilitate drug development and clinical trials design.
Methods:
The study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed, and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their effect on protein function. In-depth reanalysis of light and electron microscopy specimens for nine available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP.
Results:
Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. Most patients presented in adolescence or early adulthood but with ample variation (average 22, SD ±14 years), with frequent progression to kidney failure but with variability in time between presentation and kidney failure.
Conclusions:
This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.
Clinical Trial registry name and registration number:
A Study to Test BI 764198 in People With a Type of Kidney Disease Called Focal Segmental Glomerulosclerosis, NCT05213624.
| Original language | English |
|---|---|
| Pages (from-to) | 274-289 |
| Number of pages | 16 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 36 |
| Issue number | 2 |
| Early online date | 1 Oct 2024 |
| DOIs | |
| Publication status | Published - 1 Feb 2025 |
Bibliographical note
Publisher Copyright:© 2024 by the American Society of Nephrology.