Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome

The terminal 22q13.3 deletion syndrome is characterized by severe expressiv e-language delay, mild mental retardation, hypotonia, joint laxity, dolicho cephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpo int in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the transloc ation was reciprocal, with the chromosome 22 breakpoint within the 22q subt elomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317 . Using Southern blot analysis and inverse PCR, we located the chromosome 1 2 breakpoint in an intron of the FLJ10659 gene and located the chromosome 2 2 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Sho rt homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on b oth derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the ce rebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSA P2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. P roSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.