Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jun 5;153B(4):960-6.
doi: 10.1002/ajmg.b.31055.

A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder

Bert van der Zwaag  1 , Wouter G Staal, Ron Hochstenbach, Martin Poot, Henk A Spierenburg, Maretha V de Jonge, Nienke E Verbeek, Ruben van 't Slot, Michael A van Es, Frank J Staal, Christine M Freitag, Jacobine E Buizer-Voskamp, Marcel R Nelen, Leonard H van den Berg, Hans K Ploos van Amstel, Herman van Engeland, J Peter H Burbach
Affiliations

A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder

Bert van der Zwaag et al. Am J Med Genet B Neuropsychiatr Genet. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Genetic analysis of ASD pedigree with submicroscopic duplication of chromosome 15q11.2. (a) ASD pedigree. The arrow indicates the proband, affected subjects are indicated in black. Subject 1.7 was highly suspect for ASD, full clinical diagnosis was not possible (gray circle, see text). n.a.: no DNA available. (b) FISH results on metaphase spread of subject 3 (arrows indicate the separate chromosomes 15), magnification shows a clearly more intense signal on one of the two chromosomes 15 for subject 3 (red = centromere probe D15Z1, green = RP11-80H14). (c) MLPA analysis results using a 15q11-q13 region specific MS-MLPA kit. Subjects 1, 3, and 7 show a marked increase in the probe signals for TUBGCP and CYFIP1, indicative of a duplication of these probes. (d) RefSeq gene content of the 15q11.2 region (20.20–20.90 Mb, UCSC Genome Browser, May 2006 freeze). Approximate positions of flanking low-copy repeat regions are indicated by a blue bar, segmental duplications in the breakpoint regions are shown above the blue lines. The region duplicated in the ASD pedigree is indicated by a red bar. BP: breakpoint region.
Figure 2
Figure 2
RNA in situ hybridization of Cyfip1 and Nipa1 probes on adjacent embryonic and adult mouse brain sections. (a-d, i, k): Cyfip1 antisense probe, (e-h, j, l): Nipa1 antisense probe. (a-c) Cyfip1 expression was detected throughout the brain during early brain development. From E16.5 onwards, the cortical plate (including the hippocampus) showed a more intense staining compared to surrounding tissues (arrows in c). (d) At E18.5, Cyfip1 expression has become restricted to the forebrain, particularly to the cortical plate of the neocortex and hippocampus (arrows). A low level of expression was also observed in the external granular layer of the cerebellum (asterix). (e) At E12.5, Nipa1 was expressed throughout the embryonic brain, with exception of the forebrain (arrow). (f-h) Expression of Nipa1 in the midbrain, and more posterior brain regions (including the spinal cord) was maintained throughout embryogenesis, and from E14.5 onwards, expression of Nipa1 was also observed in the outer cell layer of the olfactory bulb and the cortical plate of the neocortex (arrows in f, g, h). (i,j) Adjacent E18.5 sections of the forebrain show overlapping expression domains for Cyfip1 and Nipa1 in the cortical plate of the neocortex and in the hippocampus. (k) In adult brain, Cyfip1 was expressed in the external plexiform layer of the olfactory bulb, and in the neuronal layers of the hippocampus, and the cerebellum (arrows). A small subset of neurons in the piriform cortex also shows expression of Cyfip1 (asterix). (l) Nipa1 is widely expressed in the adult brain, expression was observed in the olfactory bulb, the cerebral cortex (including the piriform cortex, asterix), the neuronal cell layer of the hippocampus, and several other brain nuclei (not shown). (m,n). Sense probed sections for Cyfip1 and Nipa1 did not show significant staining. Magnification: a-h, k-n: 12.5 X and i,j: 25 X. Abbreviations: Bg: basal ganglia, Cb: cerebellum, Cp: cortical plate, Fb: forebrain, Hb: hindbrain, Hi: hippocampus, Hyp: hypothalamus, Iz: internediate zone, Li: liver, Lj: lower jaw, Mb: midbrain, Med: medulla oblongata, Nc: neocortex, Ob: olfactory bulb, Th: thalamus, To: tongue, V3: third ventricle.
See this image and copyright information in PMC

References

    1. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9 (5):341–355. - PMC - PubMed
    1. Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The Autism-Spectrum Quotient (AQ): Evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord. 2001;31 (1):5–17. - PubMed
    1. Bittel DC, Kibiryeva N, Butler MG. Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome. Pediatrics. 2006;118 (4):E1276–E1283. - PMC - PubMed
    1. Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MWM, Thompson RJ, Jacobs P. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet. 2001;105 (8):675–685. - PubMed
    1. Burbach JPH, van der Zwaag B. Contact in the genetics of autism and schizophrenia. Trends Neurosci. 2009;32(2):69–72. - PubMed

Publication types