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Fibronectin glomerulopathy (FNG; MONDO:0007671) is a rare autosomal dominant kidney disease marked by persistent proteinuria, microscopic hematuria, hypertension, and massive mesangial and subendothelial fibronectin deposition leading to progressive renal failure. Heterozygous pathogenic variants in the FN1 gene (HGNC:3778) disrupt fibronectin structure or splicing, driving abnormal glomerular accumulation and a slowly progressive course to end-stage renal disease. Clinically, FNG may present from childhood to late adulthood, with variable penetrance and occasional extrarenal malformations in individual cases.
Genetic analysis across 16 unrelated pedigrees (23 probands) demonstrated cosegregation of heterozygous FN1 missense, deletion, and splice variants with FNG ([PMID:18268355]). Segregation analysis in one large Italian family revealed eight affected relatives carrying one of three dominant missense mutations clustered in heparin-binding (Hep-II) and Hep-III domains, confirming autosomal dominant inheritance with age-related penetrance ([PMID:18268355]). Additional case reports and series have since expanded the variant spectrum to include intronic splice-site alterations and in-frame deletions, reinforcing consistent genotype–phenotype correlation.
The FN1 variant spectrum comprises at least nine exonic missense mutations — including the recurrent c.2918A>G (p.Tyr973Cys) — concentrated in functional heparin-binding repeats, two founder alleles (p.Pro1472del, p.Leu1974Pro) identified by haplotype analysis, and splice-site variants (e.g., c.5888-2A>G) that activate cryptic acceptor sites, resulting in in-frame exon deletions ([PMID:27056061]; [PMID:29131116]). The recurrent c.2918A>G (p.Tyr973Cys) variant alone accounts for ~40% of cases in some cohorts and is found in both familial and de novo presentations.
Segregation data include eight additional affected relatives in a single pedigree ([PMID:18268355]), with multigenerational cosegregation observed in six further families. De novo mutations in sporadic cases underscore the necessity of genetic testing in atypical or early-onset presentations despite negative family history.
Functional studies of recombinant Hep-II fragments harboring disease-associated missense mutations (including p.Trp1925Arg and p.Leu1974Arg) revealed significantly reduced heparin, endothelial cell, and podocyte binding, diminished cell spreading, and impaired cytoskeletal reorganization, consistent with a dominant-negative mechanism ([PMID:18268355]). In vitro splicing assays using minigene constructs confirmed that c.5888-2A>G induces a 12-bp exon 37 deletion, directly implicating aberrant splicing in pathogenesis ([PMID:29131116]). Patient-derived induced pluripotent stem cell lines carrying FN1 missense variants reproduce key features of fibronectin deposition and provide a robust cellular model of FNG.
No studies to date have refuted the FN1–FNG association or described alternative genetic etiologies in FN1-positive families. However, phenocopies and atypical histology in early childhood onset highlight the limits of renal biopsy alone and mandate genetic confirmation.
In summary, there is strong genetic and moderate functional evidence supporting a definitive association between FN1 variants and fibronectin glomerulopathy. Genetic testing for FN1 mutations should be considered in all patients with unexplained proteinuria and histologic evidence of fibronectin deposition. Early molecular diagnosis informs prognosis, family counseling, and surveillance for end-stage renal disease.
Key Take-home: FN1 pathogenic variants cause autosomal dominant fibronectin glomerulopathy, and molecular testing enables definitive diagnosis and guides clinical management.
Gene–Disease AssociationStrongIdentified in 16 unrelated families and 23 probands with consistent segregation across pedigrees and concordant pathology data Genetic EvidenceStrong23 pathogenic variants, including missense, splice-site, and deletion alleles in 16 families; segregation observed in one large pedigree of 8 affecteds Functional EvidenceModerateRecombinant FN1 fragments show impaired heparin and cell binding; splice-site assays and patient iPSC models confirm pathogenic impact |