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

Abstract

High resolution genomic copy-number 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 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 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. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAutism spectrum disorders (ASD) are common neurodevelopmental disorders characterized by three core symptoms: impairment in reciprocal social interactions, communicative deficits, and repetitive and restricted patterns of behavior and interests. Relatively mild ASD cases exist, but most patients display severe symptomatology with a high prevalence of mental retardation and epilepsy. Whereas familial and twin studies have indicated a major role for genetics in the etiology of ASD only a few causal factors have been identified [Persico and Bourgeron, 2006]. Recently, a relatively large proportion of ASD cases were shown to carry genomic aberrations, and attention has focused on these copy-number variations (CNVs) as risk factors for developing ASD [Marshall et al., 2008;Morrow et al., 2008;Sebat et al., 2007]. The single most consistently and frequently reported genomic aberration associated with ASD is duplication at chromosome 15q11-q13 [Vorstman et al., 2006]. This region harbors a number of low-copy repeats serving as genomic breakpoints, making it prone to chromosomal rearrangement [Pujana et al., 2002]. Interestingly, the ASD-associated 15q11-q13 duplications largely overlap with deletions that cause PraderWilli/Angelman syndrome (PWS/AS), in which ASD are often a co-morbidity [Veltman et al., 2005]. These data suggest that one or several genes from this region are involved in dosage-sensitive pathway...

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

“…A recent study identified Tmem108 as a binding partner of cytoplasmic FMRP-interacting protein 1/2 (CYFIP1/2) to regulate Arp2/3 by promoting the formation of the wave regulator complex (14). The CYFIP1 gene is located in the 15q11.2 region of the human genome, which is implicated in the development of neurological and neuropsychiatric conditions such as autism spectrum disorder, epilepsy, intellectual disability, and schizophrenia (39)(40)(41). Its copy number variation is linked to both schizophrenia and autism spectrum disorder (40,42).…”

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

“…Duplications affecting the NIPA1 and CYFIP1 in control populations are cataloged at the DGV based on four studies (Pinto et al 2007;Zogopoulos et al 2007;Itsara et al 2009;Shaikh et al 2009) with similar frequencies to our controls (0.5%): this duplication was reported in 24 out of 5056 individuals. NIPA1 encodes a magnesium transporter associated with early endosomes in neuronal and epithelial cells (Rainier et al 2003;van der Zwaag et al 2010). CYFIP1 forms a complex at synapses with the fragile X mental retardation protein (FMRP) and eIF4E (FMRP-CYFIP1-eIF4E complex).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Cyfip1 and Cyfip2 are members of a highly conserved gene family 52 , and dysregulation of Cyfip1 expression levels leads to pathological changes in neuronal maturation and connectivity, both of which may contribute to the development of the neurological symptoms observed in ASD and schizophrenia 63 . A CNV in the 15q11.2 region of the human genome has been implicated in several neurological and neuropsychiatric conditions [64][65][66][67][68][69][70] and a CYFIP1 CNV within 15q11.2 has been linked to ASD 71 , with an upregulation of CYFIP1 mRNA being demonstrated in genomewide expression profiling of ASD patients with 15q11-q13 duplication 72 . A rare CYFIP1 deletion has also been reported in a patient with a mild intellectual disability and a pervasive developmental disorder not otherwise specified 71 .…”