Rubinstein-Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q38.3;p13.3)

Rubinstein-Taybi syndrome (RTS) is a multiple congenital anomalies and ment al retardation syndrome characterized by facial abnormalities, broad thumbs , and broad big toes. We have shown previously that disruption of the human CREB-binding protein (CBP) gene, either by gross chromosomal rearrangement s or by point mutations, leads to RTS, Translocations and inversions involv ing chromosome band 16p13.3 form the minority of CBP mutations, whereas mic rodeletions occur more frequently (similar to 10%). Breakpoints of six tran slocations and inversions in RTS patients described thus far were found clu stered in a 13-kb intronic region at the 5' end of the CBP gene and could t heoretically only result in proteins containing the extreme N-terminal regi on of CBP, In contrast, in one patient with a translocation t(2;16) (q36.3; p13.3) we show by using fiber FISH and Southern blot analysis that the chro mosome 16 breakpoint lies about 100 kb downstream of this breakpoint cluste r. In this patient, Western blot analysis of extracts prepared from lymphob lasts showed both a normal and an abnormal shorter protein lacking the C-te rminal domain, indicating expression of both the normal and the mutant alle le, The results suggest that the loss of C-terminal domains of CBP is suffi cient to cause RTS, Furthermore, these data indicate the potential utility of Western blot analysis as an inexpensive and fast approach for screening RTS mutations. Am. J, Med. Genet. 92:47-52, 2000, (C) 2000 Wiley-Liss, Inc.