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Contribution of SHANK3 Mutations to Autism Spectrum Disorder

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Contribution of SHANK3 Mutations to Autism Spectrum Disorder REPORT Contribution of SHANK3 Mutations to Autism Spectrum Disorder Rainald Moessner,* Christian R. Marshall,* James S. Sutcliffe, Jennifer Skaug, Dalila Pinto, John Vincent, Lonnie Zwaigenbaum, Bridget Fernandez, Wendy Roberts, Peter Szatmari, and Stephen W. Scherer Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing. Autism (MIM 209850) is a neurodevelopmental disorder variants (CNVs) can have a causal or susceptibility-related that manifests within the first 3 years of life. Narrowly role. There is also the suggestion that de novo CNVs may defined “autism” has a population prevalence of 1.5–2 be a more significant risk factor in sporadic compared with cases per 1,000 children and represents the classic per- familial forms of ASD.9 vasive developmental disorder (PDD).1 The group of PDDs ASD-associated mutations have been reported in two that is also termed “autism spectrum disorders” (ASDs) neuroligin genes (NLGN3 and NLGN4) on the X chro- includes autism, as well as PDD–not otherwise specified mosome,10 RPL10 at Xq28,11 and SHANK3 (also termed (PDD-NOS) and Asperger syndrome. ASDs have a preva- “ProSAP2”) on chromosome 22q13.12 There have been lence of ∼6 cases per 1,000 children.1 The three core char- other associations (reviewed in the work of Persico and acteristics of autism are impairments of reciprocal social Bourgeron13), but they represent extremely rare events, interactions, impairments in communication, and a re- usually of unconfirmed pathogenicity (or associated with stricted range of behaviors and interests. In contrast to a comorbid phenotype), and, in most instances, they have those with autism, patients with Asperger syndrome differ not yet been validated by other studies. in that they show an absence of clinically significant cog- The SHANK3 gene encodes a protein of the postsynaptic nitive and language delay before age 3 years.2 density (PSD) of excitatory synapses, where it may func- ASDs are etiologically heterogeneous. They are associ- tion as a master scaffolder forming large sheets that may ated with a recognized cause in ∼10% of cases, most com- represent the platform for the construction of the PSD monly with fragile X syndrome (MIM 300624), tuberous complex.14 At the PSD complex, SHANK3 has been shown sclerosis (MIM 191100), and cytogenetically detectable to bind to neuroligins,15 which, together with the neurex- chromosome abnormalities.3,4 The most frequent cyto- ins, form a complex at glutamatergic synapses. SHANK3 genetic anomaly is maternally derived duplication of chro- was first identified in rats16 and then in humans17 as a mosome 15q11-q13 (1%–3%)4; however, numerous other gene expressed predominantly in cerebral cortex and cer- chromosomal regions are described,3,4 with a higher fre- ebellum. Moreover, SHANK3 was found disrupted by a quency of events observed in syndromic forms of ASD.5,6 de novo balanced translocation in a child with severe Heritability estimates for ASDs, as determined from twin expressive-language delay, mild mental retardation, and and family studies, are ∼90%,7 and a linkage scan from an other features of the 22q13.3 deletion syndrome (MIM international collaborative study has mapped putative risk 606232).17 Durand and coworkers12 then identified two loci in families with at least two affected individuals.8 The alterations in SHANK3 in subjects with an ASD but not same study also reveals that submicroscopic copy-number observed in control individuals. One is a de novo insertion From The Centre for Applied Genomics (R.M.; C.R.M.; J.S.; D.P.; S.W.S.), Program in Genetics and Genome Biology (R.M.; C.R.M.; J.S.; D.P.; S.W.S.), and Autism Research Unit (W.R.), The Hospital for Sick Children, and Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry (J.V.), University of Toronto, Toronto; Center for Molecular Neuroscience and Vanderbilt Kennedy Center, Vanderbilt University, Nashville (J.S.S.); Department of Pediatrics, University of Alberta, Edmonton (L.Z.); Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s (B.F.); and Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada (P.S.) Received June 2, 2007; accepted for publication August 2, 2007; electronically published October 16, 2007. Address for correspondence and reprints: Dr. Stephen W. Scherer, The Centre for Applied Genomics, The Hospital for Sick Children, 14th Floor, Toronto Medical Discovery Tower, MaRS Discovery District, 101 College Street, Room 14-701, Toronto, Ontario M5G 1L7, Canada. E-mail: [email protected] .on.ca * These two authors contributed equally to this work. Am. J. Hum. Genet. 2007;81:1289–1297. ᭧ 2007 by The American Society of Human Genetics. All rights reserved. 0002-9297/2007/8106-0016$15.00 DOI: 10.1086/522590 www.ajhg.org The American Journal of Human Genetics Volume 81 December 2007 1289 of a G nucleotide in exon 21 of SHANK3, which leads to with ASD will be presented elsewhere (authors’ unpub- a frameshift and presumed loss of function. Since this var- lished data), and only those data relevant to families with iant was present in two affected siblings, it was thought SHANK3 CNVs are described here. The techniques used to result from germline mosaicism in the mother. A second for validation of the initial Affymetrix comparative inten- alteration found in an unrelated family was a de novo sity analysis are described in figure 2, and all data were deletion of terminal 22q13, with the breakpoint in intron compared with the Database of Genomic Variants22 to as- 8ofSHANK3. The same study also reported a larger 800- sess relevance with respect to population controls. The kb deletion in a girl with an autism spectrum phenotype methodologies for calling the CNVs are (or will be) de- that includes severe language delay. Her brother with As- scribed elsewhere (authors’ unpublished data).20,23 Quan- perger syndrome had a partial trisomy of terminal 22q; titative PCR analysis included SYBR green methodology these unbalanced anomalies were the consequence of a (Stratagene)24 and FISH experiments.25 A 12-marker foren- paternal translocation. sic panel (Identifiler [Applied Biosystems]) was employed Because significant genetic and functional data impli- to ascertain that the parents in ASD-affected family 4 are cate SHANK3 as a potential monogenic cause of ASDs, we indeed biological parents. Estimation of population an- sought to further assess the types and frequency of mu- cestry of the subjects described in table 1 was obtained by tations involved and the associated phenotypic outcomes. STRUCTURE software,26,27 with use of 780 autosomal SNPs We therefore screened a sample of 400 probands with an spaced at 3.5–4 Mb across the genome. For comparison, ASD (and, in some cases, their families) for mutations in analysis also included genotypes from unrelated individ- SHANK3, using Sanger dideoxy DNA sequencing and uals representing populations from the HapMap collec- microarray-based comparative intensity analysis. As dis- tion (African, European, and Asian).28 cussed below, we discovered variants in nearly 1% of these Through DNA sequencing of the majority of the coding cases, further implicating SHANK3 and the neurexin-neu- sequences and splice junctions of SHANK3, we identified roligin complex in ASDs. 10 novel nonsynonymous variants (table 1). One of these, The 400 unrelated subjects with ASD were ascertained found in the index patient of family ASD4, represents an at The Hospital for Sick Children in Toronto (225) and in apparent de novo mutation, with an A962G exchange in child diagnostic centers in Hamilton, Ontario (100), and exon 8 leading to a heterozygous Q321R substitution. This in St. John’s, Newfoundland (75). All subjects met Autism change, found only in this single subject and in neither Diagnostic Interview–Revised (ADI-R) and Autism Diag- parent nor an unaffected sibling, was also absent from 372 nostic Observation Schedule (ADOS) criteria conclusively control chromosomes and has not been described in any or on a clinical best estimate.18 Affected and unaffected of the cases or controls reported elsewhere.12 The gestation siblings were also assessed whenever possible, and 249 and delivery, at 38 wk, of this female subject were unevent- (62%) of these families had more than one child with an ful, apart from an in vitro–fertilization procedure. She es- ASD. Blood samples were drawn from the index patients tablishes no eye contact and displays narrow interests and with ASD and their relatives, to facilitate ascertainment verbal repetitive behaviors but understands complex in- of the mode of inheritance of all detected variants. Most structions. The ADI exceeds the autism cutoff in all do- index patients (75%) were screened for fragile X mutations mains (see table 2 for clinical information). Her younger and were karyotyped. Wherever possible, experiments sister, who does not carry the mutation, is developing were performed on blood-derived genomic DNA (80%); normally. otherwise, DNA from cell lines was used. Results from The nine other novel nonsynonymous variants found these families are described in table 1 and figure 1. Find- in patients with ASD but not in controls were inherited ings were confirmed on blood-derived genomic DNA or from an unaffected parent.
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