Natural history of patients with familial focal segmental glomerulosclerosis associated with TRPC6 variants.

BACKGROUND: Pathogenic variants in the TRPC6 gene have been identified in families affected by adult-onset autosomal dominant focal segmental glomerulosclerosis (FSGS). Although the exact mechanisms leading to kidney disease remain unclear, growing evidence suggests a role of the TRPC6 channel not only in genetic forms of FSGS but also in acquired forms of glomerular diseases. This highlights TRPC6 as a promising target for therapeutic intervention.

METHODS: This single-centre cohort study at the University Hospital in Bern, Switzerland, included patients from families with (likely) pathogenic TRPC6 variants. Patients' family history, as well as clinical and genetic data were obtained through interviews and medical records. The study aimed to analyse the renal and extra-renal disease phenotype, its evolution, and explore potential genotype-phenotype correlations.

RESULTS: Nine individuals from four unrelated families were included. Most patients presented in adulthood with signs of structural nephropathy. Notably, the initial presentation involved sub-nephrotic range proteinuria rather than nephrotic syndrome, with progression to kidney failure over the course of several years. Four out of nine patients exhibited multi-organ (> 3) involvement with unclear genotype-phenotype correlation. Notably, among the four TRPC6 variants identified, we report a novel variant (p.(Trp680*)), which expands the current spectrum of TRPC6 mutations. Additionally, another variant (p.(Arg175Trp)) was associated with infantile onset of disease characterised by steroid-resistant nephrotic syndrome.

CONCLUSION: This study contributes to a broader understanding of the genotype-phenotype variability in TRPC6-associated FSGS and expands the mutational spectrum by identifying a novel TRPC6 variant, underscoring the importance of genetic analysis in guiding patient prognosis and personalised management strategies.