Новый генетический вариант TRPC6 подтвердил роль тестирования при выборе терапии у пациента с FSGS

A novel  TRPC6  variant identified in a young man with focal segmental glomerulosclerosis (FSGS) illustrated how genetic testing can support etiologic assessment and reinforce a phenotypic approach to treatment, according to a case report published in  Frontiers in Genetics. The heterozygous c.131C>T p.(Pro44Leu) variant has not previously been associated with FSGS and was classified as a variant of uncertain significance (VUS). The patient’s young age, subnephrotic proteinuria, FSGS not otherwise specified (NOS) on biopsy, and absence of secondary causes led clinicians to favor supportive therapy rather than immunosuppression. The 21-year-old man presented with frothy urine and proteinuria of 3.17 g/24 h, with mildly elevated creatinine of 103 μmol/L. The patient had no hypertension, diabetes, family history of kidney disease, medication exposures associated with FSGS, low birth weight, or prematurity.  Serum albumin was 47.4 g/L, and he had no edema. Secondary-cause testing, including antinuclear antibodies, viral serologies, complement levels, and serum protein electrophoresis, was unrevealing. Biopsy demonstrated FSGS-NOS, with 1 of 15 glomeruli showing segmental sclerosis, along with interstitial fibrosis and approximately 5% tubular atrophy. Genetic testing was initially deferred because of cost. Without immunosuppression, the patient received losartan, dapagliflozin, ambrisentan, and strict sodium restriction. At follow-up, 24-hour urinary protein declined to 0.7 g, with stable kidney function. Two years after the initial recommendation, repeated counseling led the patient to pursue exome sequencing, which identified the  TRPC6  variant; Sanger sequencing confirmed the finding. The variant was exceptionally uncommon, with a gnomAD allele frequency of 4.0 × 10 −6  (1/234,090 alleles) and no reports in ClinVar, LOVD, or dbSNP. Most in silico tools predicted a benign effect, although SIFT and MutationTaster predicted damage.  Under the 2022 American College of Medical Genetics and Genomics criteria, the variant met PM2 and BP4 and remained a VUS. Structural modeling placed Pro44 on the protein surface, where it could potentially participate in protein-protein interactions, but no functional studies established pathogenicity. Because a VUS should not independently determine treatment, the genetic finding was considered supportive rather than diagnostic. The authors emphasize that patients younger than 30 years with FSGS, particularly those with FSGS-NOS, subnephrotic proteinuria, a family history, or poor response to immunosuppression, merit consideration for genetic evaluation. Earlier identification of monogenic disease could reduce unnecessary corticosteroid or calcineurin inhibitor exposure while providing prognostic and familial information. The report also expands the recognized  TRPC6  variant spectrum and may have implications for emerging targeted therapy. More than 40 pathogenic  TRPC6  variants have been described, predominantly gain-of-function missense variants, and an oral TRPC6 inhibitor, BI 764198, produced a 35% proteinuria response rate in a phase 2 trial.  However, functional validation, familial segregation, and longer follow-up are needed to determine whether p.Pro44Leu is pathogenic. The case ultimately underscores that early genetic testing can complement rather than replace clinical and histopathologic assessment when determining whether young patients with FSGS require immunosuppression. “The surface-exposed, non-core location of p.Pro44Leu was consistent with the patient’s mild clinical phenotype,” stated the authors. “We suggest that structural prediction should be considered alongside clinical features in the interpretation of genetic variants in FSGS to guide risk stratification and therapeutic decision-making.” This article originally appeared on Rare Disease Advisor References: Yang F, Wang X, Li Y, et al.  A novel  TRPC6  variant (c.131C>T, p.(Pro44Leu)) associated with focal segmental glomerulosclerosis: a case report.  Front Genet. Published online August 9, 2026. doi:10.3389/fgene.2026.1913168