Mutations in COL4A5 are typically different in each family and more than 2000 have been reported to date. About 10% are structural, 15% are frameshift, 15% are splicing and 50% are missense changes. Most of the missense variants are Gly substitutions in the intermediate collagenous domain of the corresponding collagen IV alpha 5 chain. Gly is the smallest amino acid and any substitution with a larger residue interferes with the triple helix formed with the collagen IV alpha 3 and alpha 4 chains. The mechanism of disease is Loss of Function.
Genetic testing is the ‘gold standard’ for the diagnosis of XL Alport syndrome. However some people in whom there is a strong clinical suspicion of Alport syndrome have no variant demonstrated in the COL4A5 gene. This is probably because Whole Exome Sequencing which is commonly used for testing has overlooked copy number variants in the past and does not currently detect deep intronic splicing changes. In addition XL Alport syndrome may result from splicing from synonymous variants and other non-canonical splicing substitutions.
There is a genotype-phenotype correlation in XL Alport syndrome in males. Truncating variants have a worse prognosis than missense changes, with earlier onset kidney failure, and an increased likelihood of lenticonus and central fleck retinopathy. The correlation is less obvious in affected females, probably because of Lyonisation of the X chromosome.
COL4A5