COL4A3 and COL4A4 are affected equally often in both AD Alport syndrome and in AR Alport syndrome. Structural variants occur in about 10% of families, truncating in 15%, splicing in 15% and missense in 50%. Most of the missense variants are Gly substitutions that occur because Gly is the smallest amino acid and its substitution with any other amino acid in the collagen IV alpha chain disrupts the triple helix heterotrimer.
Genetic testing is the gold standard for diagnosis of AD and AR Alport syndrome. However even in people with strongly suspected AD Alport syndrome, no mutation may be identified in COL4A3 or COL4A4. This is because Whole Exome Sequencing does not detect deep intronic or other non-canonical splicing variants.
In AD Alport syndrome there is a different genotype-phenotype correlation than for XL disease, and missense variants appear to have a more severe phenotype than null or truncating changes.
COL4A3