Alport syndrome and mental retardation: clinical and genetic dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR).

X linked Alport syndrome (ATS, OMIM 301050) is a hereditary glomerulonephritis resulting from either point mutations or intragenic deletions of the COL4A5 gene encoding the α5 chain of type IV collagen. Contiguous gene syndromes are phenotypically complex disorders associated with the deletion of multiple adjacent genes. There are several examples of such syndromes on the X chromosome. 5 Until recently, the only known contiguous gene syndrome involving the COL4A5 gene was Alport syndrome and diffuse leiomyomatosis (ATS-DL, OMIM 308940), in which the deletion extends towards the centromere to include the first two exons of the adjacent COL4A6 gene. In 1998, we described a new Xq22.3 contiguous gene syndrome which we named AMME (OMIM 300194) because of the distinctive features observed in affected males: Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). After the original publication, clinical re-evaluation of the family showed alterations of cardiac rhythm and morphology on echocardiography. To elucidate the molecular basis of this complex syndrome, we cloned three genes from the deleted region: FACL4, AMMECR1, and KCNE1L, recently renamed KCNE5. Now we report the characterisation of the deletion, which extends for about 2 Mb, and the identification of a second family which bears a smaller deletion of about 1 Mb. Comparison with two other deletions extending beyond COL4A5 in the telomeric direction and generating only ATS allowed us to define the critical region for mental retardation (MR), which contains four candidate genes. We now propose renaming this condition ATS-MR, so that consistent terminology is used to describe the known ATS contiguous gene syndromes.