Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.
Project description:It is unknown whether pediatric monomorphic post-transplant lymphoproliferative disorders (mPTLD) display similar genetic features than the immunocompetent counterpart and if they resemble adult mPTLD. We have investigated 39 pediatric mPTLD, 33 diffuse large B-cell lymphoma (DLBCL) and six Burkitt lymphoma (BL), by an integrated approach, including fluorescence in situ hybridization, cell of origin determination (COO), targeted gene sequencing and copy-number arrays. According to COO, 24/28 DLBCL (86%) were classified as activated B-cell (ABC) and all six BL were germinal center B cell (GCB)-type. Thirty-three out of 37 investigated mPTLD were positive for EBV infection. Overall, PTLD-BL carried mutations in MYC in addition to ID3 and DDX3X, ARID1A or CCND3 and a higher mutational burden than PTLD-DLBCL (12.3 vs 6.2, P = 0.01). CN profile of PTLD-BL was less complex than in IC-BL (1 vs 6.26; P < 0.005). PTLD-DLBCL showed a very heterogeneous genomic profile characterized by a lower number of mutations (2.4 vs 6.5, P=0.01) and less CNA (2.10 vs 4.36 ; P < 0.05) than in IC patients. Pathway enrichment analysis revealed that epigenetic modifiers and Notch pathway (4 cases each) were the most recurrently affected. In conclusion, these findings further unravel for the first time the molecular heterogeneity of pediatric mPTLD and provide new parameters for the design of more effective therapeutic strategies.