Purpose Copy number variants (CNVs) have emerged as a major cause of human disease such as autism and intellectual disabilities. Because CNVs are common in normal individuals, determining the functional and clinical significance of rare CNVs in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis (CMA) as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large CNV datasets generated through routine patient care. Methods A consortium of diagnostic laboratories was established [the International Standards for Cytogenomic Arrays (ISCA) consortium] to share CNV and phenotypic data in a central, public database. We present the largest CNV case-control study to date comprising 15,749 ISCA cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 CNV regions. Results Compared to controls, fourteen deletions, and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. Conclusion Given the rapid expansion of clinical CMA testing, very large datasets will be available to determine the functional significance of increasingly rare CNVs. This data will provide an evidenced-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.

Inflammatory myofibroblastic tumor (IMT), a tumor of myofibroblastic spindle cells accompanied by a lymphoplasmacytic and eosinophilic inflammatory infiltrate, and anaplastic large cell lymphoma share clonal aberrations involving the short arm of chromosome 2 in region p21-p23 (1-5). Chromosome 2p23 is the site of the human ALK gene, which codes for anaplastic lymphoma kinase, a tyrosine kinase receptor and member of the insulin growth factor receptor superfamily. Antibodies to the protein product of the ALK gene detect both ALK expression associated with 2p23 rearrangements and other abnormalities in ALK deregulation. ALK rearrangements and/or ALK1 and p80 immunoreactivity have been reported in 36 -60% of IMTs and 8 -33% of "inflammatory pseudotumors" (3, 5, 6 -9). Fusion oncogenes have been identified in a small proportion of IMTs with ALK rearrangements and include TPM3-ALK and TPM4-ALK (4). In anaplastic large cell lymphoma, the clonal abnormalities of ALK include a characteristic translocation t(2, 5)(p23;q35), variant translocations, and a TPM3-ALK fusion oncogene in some cases (2, 10 -15). Various investigators have shown that ALK gene rearrangements and ALK expression are found

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DL-BCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32; q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14; 18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup. Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of mature B cells with an annual incidence of ϳ25,000 cases in the United States. DLBCL is a heterogeneous entity both clinically and morphologically. We have recently shown by gene expression profiling that DLBCL can be classified into two major subgroups. 1 The germinal center B-cell-like (GCB) subgroup expresses genes characteristic of normal GC B cells and is associated with a good outcome after multiagent chemotherapy, whereas the activated B-cell-like (ABC) subgroup expresses genes characteristic of activated blood B cells and is associated with a poor clinical outcome. Nonetheless, considerable molecular heterogeneity exists within each subgroup. A small number of DLBCL cases are unclassifiable and do not express the GCB or ABC sig-

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