Molecular analyses of duplications on human chromosome 17p. W. Bi¹, X. Shi¹, C.M.B.C. Fonseca¹, C. Shaw¹, G. Weissenberger¹, L. Potocki^1,3, J.R. Lupski^1,2,3. 1) Dept Molecular & Human Genetics, Baylor Col Medicine, Houston, TX; 2) Dept Pediatrics, Baylor Col Medicine, Houston, TX; 3) Texas Children's Hospital, Houston, TX.
   Dup(17)(p11.2p11.2) syndrome is a genomic disorder caused by an interstitial duplication in chromosome 17 sub-band p11.2. We previously reported 7 patients with a common duplication of ~4 Mb that is reciprocal to the common deletion present in >70% of Smith-Magenis syndrome (SMS) patients. Both common deletions and common duplications are mediated by meiotic homologous recombination between non-allelic low-copy repeats, the distal and proximal SMS-REPs. We analyzed the breakpoints in 26 new duplication patients by pulsed-field gel electrophoresis, fluorescence in situ hybridization, and array comparative genomic hybridization. We found that 60% have a common duplication, the reciprocal to the common SMS deletions, and the remaining have uncommon duplications ranging from 1.1 Mb to 15.1 Mb. The patient with 1.1 Mb duplication has the typical features of dup(17)(p11.2p11.2) syndrome, narrowing the critical region of this syndrome from ~4 Mb to 1.1 Mb. The dosage sensitive retinoic acid inducible 1 gene (RAI1) that is responsible for the majority of SMS features is located within this region, implicating RAI1 as the gene responsible for clinical features in the dup(17)(p11.2p11.2) syndrome. Most of the proximal breakpoints in the uncommon duplications mapped within two adjacent BACs very close to the centromere. This contrasts with half of the proximal breakpoints in the uncommon deletions mapping within or adjacent to the proximal SMS-REPs and none close to the centromere. The distal breakpoints in duplications did not cluster and distributed from p11.2 to p13. Therefore, the uncommon duplications in chromosome 17p may be stimulated by centromeric structure and mediated by non-homologous end joining. Note worthily, although uncommon recurrent deletions have been identified in 6 SMS patients, no recurrent reciprocal duplications were identified. Our results suggest that the mechanism applied in the uncommon duplications of 17p may differ from that in the uncommon deletions of 17p.