Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. We have implicated NMD and the UPF3B gene as the cause of various forms of intellectual disability (ID) and autism (Nat Genet 39(9):1127-33, 2007; Mol Psychiatry 15(7):767-76, 2010; Eur J Med Genet, 2012, in press). The UPF3B gene has also been implicated in childhood onset schizophrenia and attention deficit hyperactivity disorder (Mol Psychiatry 16(3):238-9, 2011). In expanding our inquiry we identified eleven patients with global developmental delay who carry deletions of the genomic region encompassing the UPF2 gene, another important NMD member and UPF3B interacting protein. We hypothesized that loss of one allele of UPF2 impairs NMD and result in a neurological phenotype. Using RNA-SEQ on lymphoblastoid cells from UPF2 del patients we identified 1009 differently expressed genes (DEGs). 38% of these DEGs overlapped with DEGs identified in the UPF3B patients. This suggested to us that the transcriptome de-regulation in UPF2 and UPF3B patients is similar. More importantly, 95% of all DEGs in either UPF2 or UPF3B patients share the same trend of de-regulation. To gauge into the role of other NMD factors we performed a comprehensive search for copy number variants (CNVs) encompassing all known NMD factors in patients (57,365) and controls (20,474). Our data show that CNVs, especially for UPF2, UPF3A, Y14, SMG6, EIF4A3 and RBM8A are frequent in patients with various neurological disorders and ID in particular. This tells us that the changes in the copy number of these factors are likely at the root of the problem or act as predisposing factors. Our data strengthen the importance of NMD in normal brain development and learning and memory in particular.