Smooth muscle tumors associated with X-linked Alport syndrome: carrier detection in females

Abstract

X-linked Alport syndrome (AS) associated with diffuse esophageal leiomyomatosis (DL) has been reported to be due to deletions removing the 5' ends of both the COL4A5 and COL4A6 genes, encoding the alpha 5 and alpha 6 chains of type IV collagen, respectively, whereas a variety of mutations in COL4A5 has been identified in patients with AS alone. Here we report three additional DL-AS patients who also display deletions removing the 5' ends of both COL4A5 and COL4A6 genes. Furthermore, we tracked the mutation in 15 females belonging to six DL-AS families by gene copy number determination. We found that, like AS, DL is transmitted as an X-linked dominant trait but, contrary to AS, DL is fully penetrant and completely expressed in females. These results are in agreement with our previous work suggesting that DL could be due to a dominant effect of an abnormal alpha 6 (IV) collagen chain. Finally, we have detected a similar deletion of the COL4A5 and COl4A6 genes in a DL affected female who showed no sign of nephropathy, demonstrating the AS carrier status of this DL patient. These results emphasize the importance of molecular analysis of female DL patients for genetic counseling.