Massively parallel sequencing identifies pathogenic variants in the genes affected in Alport syndrome (COL4A3–COL4A5) in as many as 30% of individuals with focal and segmental glomerulosclerosis (FSGS), 10% of those with kidney failure of unknown cause, and 20% with familial immunoglobulin A (IgA) glomerulonephritis. FSGS associated with COL4A3–COL4A5 variants is usually present by the onset of kidney failure and may develop because the abnormal glomerular membranes result in podocyte loss and secondary hyperfiltration.