High resolution genomic copy-number analysis has shown that inherited and de novo copy-number 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, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR 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, CYFIP1 and 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 CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive 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.

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Keywords Autism spectrum disorder, Copy-number, Gene expression, Gene-dosage, Genetics
Persistent URL dx.doi.org/10.1002/ajmg.b.31055, hdl.handle.net/1765/28588
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Citation
van der Zwaag, B., Staal, W.G., Hochstenbach, R., Poot, M., Spierenburg, H.A., de Jonge, M.V., … Burbach, J.P.H.. (2010). A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 153(4), 960–966. doi:10.1002/ajmg.b.31055