Digenic Alport syndrome

Digenic Alport syndrome (Orphanet code 653722) is a rare hereditary kidney disease caused by pathogenic variants in two different genes encoding type IV collagen, typically involving combinations of COL4A3, COL4A4, and/or COL4A5. Unlike the classic forms of Alport syndrome that follow a single-gene inheritance pattern (X-linked, autosomal recessive, or autosomal dominant), digenic Alport syndrome results from the combined effect of heterozygous variants in two of these collagen IV genes, which together produce a more severe phenotype than would be expected from either variant alone. This digenic mechanism helps explain some cases where disease severity does not match predictions based on a single identified variant. The disease primarily affects the kidneys, inner ears, and eyes. The hallmark feature is progressive glomerular disease leading to hematuria (blood in the urine), proteinuria (protein in the urine), and progressive decline in kidney function that can ultimately lead to end-stage kidney disease (ESKD). Sensorineural hearing loss, particularly at high frequencies, is a common associated feature. Ocular abnormalities, including anterior lenticonus and retinal flecks, may also occur. The underlying pathology involves abnormal type IV collagen in the glomerular basement membrane, cochlea, and lens capsule, leading to structural and functional deterioration of these tissues. There is currently no cure for digenic Alport syndrome. Treatment focuses on slowing the progression of kidney disease, primarily through the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which reduce proteinuria and delay the onset of end-stage kidney disease. Early initiation of these renoprotective therapies is recommended. Patients who progress to ESKD require renal replacement therapy, including dialysis or kidney transplantation. Hearing aids may be needed for sensorineural hearing loss, and ophthalmologic monitoring is advised for ocular complications. Genetic counseling is important for affected families given the complex inheritance pattern.

Common questions about Digenic Alport syndrome