Autosomal Dominant Alport syndrome

Abstract Autosomal dominant Alport syndrome results from heterozygous pathogenic variants in COL4A3 or COL4A4, and is the commonest monogenic kidney disease, affecting about 1% of the population. It is characterised by persistent glomerular hematuria, a thinned glomerular basement membrane and a family history of kidney disease. The typical Alport hearing loss and ocular abnormalities are not present. Autosomal dominant Alport syndrome is common in cohorts with hematuria, proteinuria or steroid-resistant nephrotic syndrome, kidney cysts, or kidney failure. Clinical features vary even in family members with the same genetic change. Overall, only two-thirds of people with a pathogenic COL4A3 or COL4A4 variant have hematuria because of incomplete penetrance. Missense variants that result in Gly substitutions are associated with proteinuria more often than truncating changes which is different from X-linked disease. However missense variants are not consistently associated with kidney failure, or the age at kidney failure. Sometimes genetic testing is negative even where clinicians strongly suspect AD Alport syndrome clinically. Genetic testing distinguishes autosomal dominant Alport syndrome from X-linked disease which is less common but has a higher risk of kidney failure. Autosomal dominant Alport syndrome with more severe features must also be distinguished from digenic disease especially where only one of the two causative variants is identified. People with autosomal dominant Alport syndrome should be monitored for increased albuminuria and treated from its onset with ACE inhibitors and, if necessary, SGLT2 inhibitors. Genetic testing is currently recommended for all first degree family members whether or not they have hematuria.