Alport syndrome: deducing the mode of inheritance from the presence of haematuria in family members

The diagnosis of Alport syndrome is suspected when an individual has haematuria or renal failure, together with a hearing loss; haematuria or renal failure, and a family history of Alport syndrome; or a pathognomonic Alport feature, such as lenticonus, fleck retinopathy, a lamellated glomerular basement membrane (GBM), or a GBM that lacks the collagen IV α3α4α5 network. The diagnosis of Alport syndrome is optimally confirmed by the demonstration of a mutation in the COL4A5 gene or two mutations in trans in the COL4A3 or COL4A4 genes. In practice, genetic testing for Alport syndrome is not widely available, and even with testing, causative mutations are not demonstrated in 5% of cases. Often, haematuria is only known in some family members, and the other characteristic features are not present or have not been sought. Where Alport syndrome remains likely, it is important to distinguish between X-linked inheritance, which occurs in 85% of families, and autosomal recessive inheritance, in the remaining 15%. This distinction is important because different modes of inheritance mean that different family members are at risk of being affected. Clinicians generally rely on the presence of haematuria to identify affected individuals in families with suspected Alport syndrome and on the information from three-generational family trees to assess the likely mode of inheritance. While often helpful, this strategy can also be misleading. The major sources of error are families with few members or where few members are tested; families comprising mainly women, where the typical Alport features are absent; families where the father is not available for testing for haematuria; and families with a coincidental renal disease. These difficulties emphasise the helpfulness of genetic testing in distinguishing between X-linked and autosomal recessively inherited forms of Alport syndrome.