A cosegregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorderHow to Cite this Article: van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV, Verbeek NE, van t Slot R, van Es MA, Staal FJ, Freitag CM, BuizerVoskamp JE, Nelen MR, van den Berg LH, van Amstel HKP, van Engeland H, Burbach JPH. 2010. A Cosegregating Microduplication of Chromosome 15q11.2 Pinpoints Two Risk Genes for Autism Spectrum Disorder. Am J Med Genet Part B 153B: 960–966.

High resolution genomic copynumber analysis has shown that inherited and de novo copynumber variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, cosegregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RTPCR analysis revealed over 70 increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1and NIPA1as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosagesensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples 0.94 in patients vs. 0.42 controls, P  0.247, which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale. © 2009 WileyLiss, Inc.