DISRUPTION OF THE CLATHRIN HEAVY CHAIN-LIKE GENE (CLTCL) ASSOCIATED WITH FEATURES OF DGS VCFS - A BALANCED (21-22)(P12-Q11) TRANSLOCATION/

The smallest region of deletion overlap in the patients we have studie d defines a DiGeorge syndrome/velocardio-facial syndrome (DGS/VCFS) mi nimal critical region (MDGCR) of similar to 250 kb within 22q11, A de novo constitutional balanced translocation has been identified within the MDGCR. The patient has some features which have been reported in i ndividuals with DGS/VCFS, including: facial dysmorphia, mental retarda tion, long slender digits and genital anomalies, We have cloned the br eakpoint of his translocation and shown that it interrupts the clathri n heavy chain-like gene (CLTCL) within the MDGCR, The breakpoint of th e translocation partner is in a repeated region telomeric to the rDNA cluster on chromosome 21p, Therefore, it is unlikely that the patient' s findings are caused by interruption of sequences on 21p, The chromos ome 22 breakpoint disrupts the 3' coding region of the CLTCL gene and leads to a truncated transcript, strongly suggesting a role for this g ene in the features found in this patient, Further, the patient's part ial DGS/VCFS phenotype suggests that additional features of DGS/VCFS m ay be attributed to other genes in the MDGCR, Thus, haploinsufficiency for more than one gene in the MDGCR may be etiologic for DGS/VCFS.