Detection of known and novel human syndromes by high-density oligonucleotide array comparative genomic hybridization (HOaCGH). Y.S. Fan, D. Barbouth, P. Jayakar, H. Zhu, S. Sacharow, L.J. Elsas. The Dr. John T. Macdonald Foundation Center for Medical Genetics, University of Miami Miller School of Medicine, Miami, FL.
   Genomic imbalance is a major cause of morphological and developmental disorders. Fluorescent in situ hybridization (FISH) has been used for diagnosis of some of the over 40 known dysmorphic syndromes and 3% of idiopathic mental retardation associated with subtelomeric rearrangements. Microarray-based comparative genomic hybridization (aCGH) has shown large-scale DNA copy number variations in the human genome. BAC clone-based arrays targeting to the known microdeletion syndromes and the 41 subtelomeric regions (TaCGH) have been used as a diagnostic tool for clinical cases. We have assessed the clinical utility of three platforms of aCGH: a targeted array (TaCGH), a BAC-clone based array for the whole genome with a ~1M interval (BaCGH) and a high-density oligonucleotide array containing 44,000 probes representing over 30,000 mapped human genes (HOaCGH). Using HOaCGH, we have precisely determined the size and gene involvement of two cases with known microdeletion syndromes (Miller-Deiker; DiGeorge) and fully characterized a new neocentric supernumerary marker chromosome derived from Xp22.3pter. While the number of cases in our study is rapidly growing, we have at this time compared the results of TaCGH and HOaCGH on 32 new patients with developmental delay and dysmorphic features. We have identified a 1p36.3 deletion and 4 novel microdeletions: del(15q11.2q11.2)(0.3Mb, 7 genes), del(15)(q24.1q24.2) (3.04Mb, 56 genes), del(19p13.1p13.2)(3.46 Mb, 101 genes), del(21)(q21.3qq22.12)(6.18Mb, 99 genes). We also identified a 7.47 Mb duplication at Xp11.22p11.23(107 genes). Thus, clinically relevant large genomic alterations have been revealed in 6 out of 32 patients (19%) and 5 of them (83%)are not in the regions targeted by TaCGH. Our study suggests that high density whole genome array CGH is a powerful diagnostic tool for unexplained developmental disorders and further molecular studies of these disorders will lead to new genomic mechanisms of disease.