Submission Details

FN1 was first reported in relation to autosomal dominant Glomerulopathy with Fibronectin Deposits 2 (GFND2) in 2008 (Castelletti et al., PMID: 18268355). The condition has genetic heterogeneity and symptoms of proteinuria, microscopic hematuria, renal tubular acidosis, glomerular fibronectin deposits, edema, and high blood pressure that causes end-stage renal failure anywhere between ages 10 and 60 (but the disease may also be indolent). The gene is also associated with Spondylometaphyseal Dysplasia, Corner Fracture Type (SMDCF), which is autosomal dominant. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in phenotypic variability between the two conditions. Therefore, the following disease entities have been split: GFND2 (OMIM #601894), SMDCF (OMIM #184255). The split curation for autosomal dominant SMDCF has been curated separately. 12 variants (missense, small in-frame deletions) that have been reported in over thirty probands in six publications (PMIDs: 18268355, 27056061, 30820325, 31419955, 35395622, 36774238) are included in this curation. The mechanism of pathogenicity is unclear. Some mutations appear have a loss-of-function effect (decreasing binding to heparin). However, another assay demonstrates that a mutation increases heparin binding, and an additional one demonstrates that a different mutation increases FN1 expression in kidney cells. This gene-disease relationship is also supported by experimental evidence (Humphrey's Lab Expression data) and interaction evidence (interaction with COL4A3 and COL4A4, which are both definitive for X-linked Alport Syndrome). In summary, there is moderate evidence supporting the relationship between FN1 and autosomal dominant GFND2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date 9/11/2023 (SOP Version 9).