Introduction

A 21-year-old Chinese male presented with proteinuria (3.17 g/24h) and mild renal insufficiency (creatinine 103 μmol/L). Renal biopsy confirmed focal segmental glomerulosclerosis (FSGS), not otherwise specified. Genetic testing identified a novel TRPC6 variant, c.131C>T p.(Pro44Leu). The patient achieved significant proteinuria reduction with supportive therapy alone.

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome, often progressing to end-stage kidney disease (Rosenberg and Kopp, 2017; D'Agati et al., 2011). Genetic forms account for many early-onset or familial cases. The international consensus indicates FSGS is a pattern of glomerular injury from diverse etiologies converging on podocyte dysfunction (Romagnani et al., 2025). Some patients present with sub-nephrotic proteinuria and respond poorly to immunosuppression, making etiologic identification essential (Vriese et al., 2018).

TRPC6 encodes a non-selective cation channel localized at the podocyte slit diaphragm (Reiser et al., 2005). Since 2005, more than 40 pathogenic TRPC6 variants have been reported, mostly gain-of-function missense variants (Reiser et al., 2005; Winn et al., 2005; Mukerji et al., 2007; Miao and Zand, 2025; Wooden et al., 2025; Liu et al., 2021). We report a patient with early-onset FSGS carrying a novel TRPC6 variant, c.131C>T p.(Pro44Leu), not previously described in the literature.

Case presentation

A 21-year-old Chinese male (self-identified) presented with throat discomfort and frothy urine. He had no history of hypertension, diabetes, or kidney disease in his family. He denied smoking or alcohol use. Physical examination showed blood pressure 119/77 mmHg, body mass index 20.58 kg/m2, and no edema. Laboratory investigations revealed 24-h urinary protein 3.17 g (reference range <0.15 g/24h), serum albumin 47.4 g/L (reference range 40–55 g/L), creatinine 103 μmol/L (reference range 57–97 μmol/L), and cholesterol 8.75 mmol/L (reference range 3.11–5.17 mmol/L). Secondary etiology screening was unremarkable, including negative results for viral serologies, serum protein electrophoresis, antinuclear antibodies, and complement levels. The patient had no history of medication use associated with FSGS (e.g., pamidronate, interferon, lithium), and no history of low birth weight or prematurity.

Renal biopsy was performed. Immunofluorescence demonstrated IgA (+), IgM (+), and C3 (+∼++). Light microscopy revealed FSGS, not otherwise specified (15 glomeruli; one with ischemic wrinkling, one with segmental sclerosis; approximately 5% tubular atrophy and interstitial fibrosis) (Figure 1A).

FIGURE 1: (A) Light microscopy (Periodic acid-Schiff stain, high magnification, ×400) shows a glomerulus with segmental glomerulosclerosis. Surrounding atrophic tubules and intratubular protein casts are also visible. (B) Clinical timeline of the patient from initial presentation to genetic diagnosis. (C) Multiple sequence alignment of TRPC6 orthologs. Pro44 (red box) is conserved across mammals (human, mouse, guinea pig) but absent or non-conserved in non-mammalian species (lizard, chicken, zebrafish), indicating mammal-specific conservation. (D) Three-dimensional structure of TRPC6 (AlphaFold AF-Q9Y210-F1). Pro44 (arrow) is located on the protein surface (RSA = 72.9%) within a loop region, suggesting involvement in protein-protein interactions rather than structural core maintenance.

Although genetic testing was initially recommended as a means to establish an etiologic diagnosis and guide therapeutic decision-making, the patient declined due to cost concerns. Two years later, following repeated counseling on the potential clinical utility of genetic results, he provided consent. Exome sequencing (KingMed Diagnostics) identified a heterozygous missense TRPC6 variant: NM_004621.6:c.131C>T p.(Pro44Leu) in exon 1 (chr11:101,454,104 G>A, GRCh37). Sanger sequencing confirmed the variant.

The variant is extremely rare in public databases. It is present at very low frequency in gnomAD (allele frequency: 4.0 × 10−6; 1/234,090 alleles in gnomAD exomes), and at slightly higher frequencies in other well-controlled databases (e.g., up to 7.7 × 10−5 in AllofUs). It has not been reported in ClinVar, LOVD, or dbSNP. To our knowledge, no previous literature has described this variant in association with FSGS. An adjacent variant (p.Pro44Ser) is present at very low population frequency in public databases (gnomAD cumulative allele frequency: 0.000138, with only one homozygote reported among over 1.6 million alleles). Using the Franklin platform (2022 ACMG guidelines), the variant met PM2 (extremely low population frequency) and BP4 (most in silico tools predict benign; aggregate score 0.149), whereas SIFT and MutationTaster predicted damaging. It was classified as a variant of uncertain significance (Supplementary Table 1).

Multiple sequence alignment revealed Pro44 is conserved across mammals but absent in non-mammalian vertebrates, suggesting mammal-specific acquisition (Figure 1C). Structural analysis (AlphaFold AF-Q9Y210-F1) showed Pro44 located on the protein surface (relative solvent accessibility 72.9%), suggesting involvement in protein-protein interactions (Figure 1D).

No immunosuppressants were used. The patient received losartan, dapagliflozin, ambrisentan, and strict dietary sodium restriction. At follow-up, 24-h urinary protein decreased to 0.7 g with stable renal function. The clinical timeline is summarized in Figure 1B.