Novel 22q11 deletions not mediated by Low Copy Repeats involving the Cat Eye Syndrome region. G.R. Jalali1, J.A. Vorstman1, T.H. Shaikh1, A.M. Hacker1, D.M. McGinn1, E.H. Zackai1, A.E. Urban2, B.S. Emanuel1. 1) Div.of Human Genet., Children's Hosp. Phila., Phila, PA; 2) Yale Univ. New Haven, CT.
The majority of deletions responsible for DiGeorge/Velocardiofacial syndromes (DGS/VCFS) are mediated by four copies of low copy repeats (LCRs) in 22q11. The LCRs are large stretches (100-450 kb) of sequence that share 96% sequence identity. They predispose 22q11 to errors in recombination leading to microdeletions and microduplications. Copy number changes within 22q11 where at least one end-point is not within an LCR are rare. We report two patients with essential features of the DGS/VCFS phenotype with novel deletions in the 22q11 region, initially detected by fluorescence in situ hybridization (FISH). Proband 1 (p1) is a 19 year old male and proband 2 (p2) is a 7 year old male. Both patients have congenital cardiac defects; a valvular pulmonary stenosis (p1) and a double aortic arch (p2). P1 has a submucosal cleft palate. P2 has no anatomic abnormalities of the pharyngeal cavity, but he did have nasal regurgitation of food as an infant. Both patients show typical facial features of DGS/VCFS, had recurrent middle ear infections and speech delay. In addition, p1 has a disorder in the anxiety spectrum and in p2 the diagnosis of autism was made. We have used a combination of FISH, Multiplex Ligation-dependent Probe Amplification (MLPA) and high density, oligonucleotide microarrays to map the deletion breakpoints in both cases. Remarkably, in both cases breakpoints are outside the LCRs. The proximal breakpoints of both deletions are centromeric to the common proximal endpoint of the 3 Mb typically deleted region (TDR) in DGS/VCFS, extending into the Cat Eye Syndrome (CES) region. The distal breakpoints also do not localize to LCRs and are proximal to the distal endpoint of the TDR. Further, in p1 the TBX1 gene is not deleted. Additional analysis is currently on-going to characterize the deletion end-points at the nucleotide level. The variant deletions associated with DGS/VCFS reported here underscore the need for improved detection methods such as high density microarrays and MLPA in the detection and diagnosis of genomic disorders resulting from deletions of 22q11.