IDENTIFICATION OF A NOVEL TRANSCRIPT DISRUPTED BY A BALANCED TRANSLOCATION ASSOCIATED WITH DIGEORGE-SYNDROME

Most cases of DiGeorge syndrome (DGS) and related abnormalities are as sociated with deletions within 22q11. Shortest region of deletion over lap (SRO) mapping previously identified a critical region (the DGCR) o f 500 kb, which was presumed to contain a gene or genes of major effec t in the haploinsufficiency syndromes. The DGCR also contains sequence s disrupted by a balanced translocation that is associated with DGS-th e ADU breakpoint. We have cloned sequences at the breakpoint and scree ned for novel genes in its vicinity. A series of alternatively spliced transcripts expressed during human and murine embryogenesis, but with no obvious protein encoding potential, were identified. The gene enco ding these RNAs has been named DGCR5 and it is disrupted by the patien t ADU breakpoint. DGCR5 is distinct from the DGCR3 open reading frame (ORF) previously shown to be interrupted by the ADU translocation, alt hough DGCR3 is embedded within a DGCR5 intron and in the same (predict ed) transcriptional orientation. No mutations of DGCR5 have yet been d etected. By analogy to other loci encoding conserved, nontranslated RN As, it is possible that DGCR5 originates from a cis-acting transcripti onal control element in the vicinity of the ADU/VDU breakpoint. Disrup tion of such an element would result in altered transcription of neigh boring genes secondary to a position effect, a hypothesis in keeping w ith recent refinement of the SRO placing the ADU breakpoint outside th e DGCR.