Digenic Alport Syndrome

Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the consequences depend on the sex of the affected individual, variant "severity," and the nature of the or change. A man with a pathogenic variant has all his collagen IV 345-heterotrimers affected, and an additional or variant may not worsen disease. A woman with a pathogenic variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further or variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic and variants, 75% of the heterotrimers are affected. The and genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome () or recessive when they affect different chromosomes (). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if and variants are known to be inherited on the same or different chromosomes.