A pedigree with COL4A5 mutation presenting with Alport syndrome and focal segmental glomerulosclerosis lesions: a case report.

Alport syndrome (AS) is a heterogeneous hereditary nephropathy which can be caused by the COL4A3/COL4A4/COL4A5 gene. Patients with AS present with many phenotypes associated with kidney defects, and commonly develop secondary focal segmental glomerulosclerosis (FSGS) late in the course of AS. Evidence supports the pathogenic role of COL4A3/COL4A4/COL4A5 mutations in FSGS. We report a familial hematuria pedigree with two members that have AS and FSGS, respectively. The proband presented with microhematuria, proteinuria, renal dysfunction and sensorineural hearing loss. Pathological examination of his renal biopsy samples revealed FSGS lesions and massive foam cells by light microscopy, irregular GBM, and focal podocyte foot process effacement under electron microscopy, as well as negative α5 (IV) staining by immunofluorescence detection so he was diagnosed as AS. The proband's younger brother had only renal manifestations without obvious extrarenal lesions. Light microscopy examination of renal biopsy samples showed only FSGS lesion without foam cells. Electron microscopy and α5 (IV) staining were not performed and he was diagnosed with FSGS. Using whole-exome sequencing, we identified a novel COL4A5 mutation (c.4456G>A:p.G1486S) in this pedigree, which affected two males (the proband and his brother) and three female family members. The three female family members were heterozygous or the COL4A5 mutation and only presented with microhematuria. Our findings suggest importance of electron microscopy analysis and COL4A3/COL4A4/COL4A5 mutation screening in patients with FSGS lesions under light microscopy. AJTR