Summary of clinical implementation of Chromosomal Microarray Analysis (CMA) in 2668 cases. X.Y. Lu, J. Li, A. Patel, M.L. Cooper, W.R. Wells, C.M. Sullivan, T. Sahoo, S.A. Yatsenko, Z. Ou, P. Stankiewicz, J.R. Lupski, C. Chinault, A.L. Beaudet, S.W. Cheung, P.A. Ward. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX.
   Array CGH is a powerful molecular cytogenetic technology that enables detection of genomic imbalances with higher resolution than current clinical methods. We report the outcome of array CGH studies, termed Chromosomal Microarray Analysis (CMA), performed clinically in 2668 postnatal patients referred with variable clinical phenotypes. The initial 930 samples were studied using CMA version 4.0 (V4.0, 362 BAC/PAC clone coverage) and the remaining 1738 samples used CMA version 5.0 (V5.0, 830 BAC/PAC clone coverage). Overall, CMA identified clinically relevant genomic imbalances in 215 patients (8.1%) [V4.0, 66/930 (7.1%) and V5.0, 149/1738 (8.6%)]. Abnormal CMA findings were seen in 95 of 1975 patients (4.8%) with normal karyotypes, and there was a 44.7% higher detection rate among samples studied on V5.0 versus V 4.0. Among 121 cases referred for additional investigation of a known cytogenetic rearrangement, CMA identified genomic imbalances in 72 cases (59%); the remaining 41% had normal results. For 572 cases with unavailable cytogenetic results, 48 (8.4%) had abnormal CMA results. Improved diagnostic potential of CMA is illustrated by 89 cases identified with cryptic microdeletions (57) and the predicted reciprocal microduplications (32) within 12 specific chromosomal regions associated with known genomic disorders; conventional cytogenetics failed to detect 75% of microdeletions and 91% of microduplications in a subset of 68 patients in this group. Overall, CMA identified copy number variations (CNVs) of uncertain significance in 276 probands, requiring parental studies. Of these, 192 (70%) were interpreted as familial variants and 11 (4%) were de novo; the remaining 73 (26%) await parental study to resolve clinical significance. Our experience using CMA in a large clinical cohort demonstrates the significantly improved sensitivity of this technology for diagnosis of genomic imbalances and highlights the need for comprehensive genetic counseling to facilitate accurate clinical correlation.