A novel FN1 variant associated with familial hematuria: TBMN?

• A novel FN1 p.S1539C mutation for hematuria was identified by exome sequencing.
• The discovery broadens the phenotype and mutation spectrums of the FN1 gene.
• Familial hematuria or TBMN may not always be as benign as generally thought.
• TBMN, AS, and GFND may be classified as subtypes of glomerulopathy.

ObjectiveThin basement membrane nephropathy (TBMN), an autosomal dominant inherited condition in general, is characterized clinically by persistent hematuria and pathologically by thinning of glomerular basement membrane. TBMN is occasionally accompanied with proteinuria, hypertension and renal impairment in some cases. The aim of this study is to explore the genetic defect in a Chinese pedigree with familial hematuria.Design and methodsA four-generation Chinese Han pedigree with familial hematuria was recruited. Exome sequencing was conducted in the proband diagnosed as TBMN, followed by verification in the proband and other family members with Sanger sequencing.ResultsA novel missense variant, c.4616C > G (p.S1539C), in the fibronectin 1 gene (FN1), was identified, and it co-segregated with the disease condition in the family. It was not observed in 100 normal controls.ConclusionsA missense variant in the FN1 gene is possibly responsible for familial hematuria or TBMN in this family, which may broaden the phenotype and mutation spectrums of the FN1 gene. A male patient in this family progressed to end-stage renal disease requiring kidney transplantation, supporting that familial hematuria or TBMN may not always be as benign as generally thought. The findings may have new implications for clinical monitoring and genetic counseling of the family, and may also help understand the pathogenesis.