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. The 
association of COL4A3-COL4A5 variants with kidney failure or IgA 
glomerulonephritis may be coincidental. However, pathogenic variants in these 
conditions occur more often than they should by chance, which suggests that the 
variants are disease-causing. COL4A3-COL4A5 variants are also found in cystic 
kidney diseases after autosomal dominant polycystic kidney disease has been 
excluded. COL4A3-COL4A5 variants should be suspected in individuals with FSGS, 
kidney failure of unknown cause, or familial IgA glomerulonephritis, especially 
where there is persistent hematuria and a family history of hematuria or kidney 
failure.