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1.  The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses 
Molecular Autism  2014;5:34.
Background
There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
Methods
In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Results
Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
Conclusions
TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
doi:10.1186/2040-2392-5-34
PMCID: PMC4228819  PMID: 25392729
2.  Developmental changes in mu suppression to observed and executed actions in autism spectrum disorders 
There has been debate over whether disruptions in the mirror neuron system (MNS) play a key role in the core social deficits observed in autism spectrum disorders (ASD). EEG mu suppression during the observation of biological actions is believed to reflect MNS functioning, but understanding of the developmental progression of the MNS and EEG mu rhythm in both typical and atypical development is lacking. To provide a more thorough and direct exploration of the development of mu suppression in individuals with ASD, a sample of 66 individuals with ASD and 51 typically developing individuals of 6–17 years old were pooled from four previously published studies employing similar EEG methodology. We found a significant correlation between age and mu suppression in response to the observation of actions, both for individuals with ASD and typical individuals. This relationship was not seen during the execution of actions. Additionally, the strength of the correlation during the observation of actions did not significantly differ between groups. The results provide evidence against the argument that mirror neuron dysfunction improves with age in individuals with ASD and suggest, instead, that a diagnosis-independent developmental change may be at the root of the correlation of age and mu suppression.
doi:10.1093/scan/nsr097
PMCID: PMC3594721  PMID: 22302843
autism; mu supression; mirror neuron system; development
4.  A Multi-Site Study of the Clinical Diagnosis of Different Autism Spectrum Disorders 
Archives of general psychiatry  2011;69(3):306-313.
Context
Clinical best estimate diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder-not otherwise specified, Asperger’s disorder) have been used as the diagnostic gold standard, even when information from standardized instruments is available.
Objective
To determine if the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites.
Design
Multi-site observational study collecting clinical phenotype data (diagnostic, developmental and demographic) for genetic research. Classification trees were employed to identify characteristics that predicted diagnosis across and within sites.
Setting
Participants were recruited through 12 university-based autism service providers into a genetic study of autism.
Participants
2102 probands (1814 males) between 4 and 18 years of age (M age=8.93, SD=3.5 years) who met autism spectrum criteria on the Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule and had a clinical diagnosis of an autism spectrum disorder.
Main Outcome Measures
Best estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures.
Results
Though distributions of scores on standardized measures were similar across sites, significant site differences emerged in best estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level and core diagnostic features, varied across sites in weighting of information and cut-offs.
Conclusions
Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing sub-groupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.
doi:10.1001/archgenpsychiatry.2011.148
PMCID: PMC3626112  PMID: 22065253
5.  Evidence for broader autism phenotype characteristics in parents from multiple incidence autism families 
Autism Research  2011;5(1):13-20.
The broader autism phenotype was assessed in parents who have two or more children with ASD (multiplex autism), parents who have no more than one child with ASD (simplex autism), parents who have a child with developmental delay without ASD, and parents who have typically developing children. Clinicians, naive to parent group membership status, rated broader autism phenotype characteristics from videotaped administration of the Broader Autism Phenotype Symptom Scale (BPASS). Differences among groups in BPASS scores in the four assessed domains (social motivation, conversational skills, expressiveness, and restricted interests) were examined using multivariate ANOVA and post-hoc comparisons. Further, ratings of videotapes by observers naive to family status were compared to live, non-naïve ratings by observers who were aware of family status (non-naïve). Findings demonstrate that the BPASS is an instrument resistant to rater bias. Parents from multiplex autism families showed significantly more autism phenotype characteristics than the parents in the other groups. Moreover, the parents from simplex autism families did not differ from the parents of children with developmental delay or typical development. Finally, no differences between live, non-naive ratings and videotaped, naive ratings were observed. These findings suggest that characteristics of the broader autism phenotype, specifically in the social and communication domains, are present in multiplex autism parents to a greater degree than simplex autism and control parents. Further, the results provide support for the notion that genetic transmission mechanisms may differ between families with more than one child with autism and families with only one child with autism.
doi:10.1002/aur.226
PMCID: PMC3237782  PMID: 21905246
broader autism phenotype; autism spectrum disorders; genetics; autism assessment
6.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations 
Nature  2012;485(7397):246-250.
It is well established that autism spectrum disorders (ASD) have a strong genetic component. However, for at least 70% of cases, the underlying genetic cause is unknown1. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes—so-called sporadic or simplex families2,3, we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported4. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19)4, for a total of 677 individual exomes from 209 families. Here we show de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD5. Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes, CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3, and SCN1A. Combined with copy number variant (CNV) data, these results suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics.
doi:10.1038/nature10989
PMCID: PMC3350576  PMID: 22495309
7.  A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders 
Journal of Medical Genetics  2012;49(10):660-668.
Background
The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.
Objective
To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.
Methods
We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.
Results
When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.
Conclusions
The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
doi:10.1136/jmedgenet-2012-101203
PMCID: PMC3494011  PMID: 23054248
Clinical genetics; Obesity; Psychiatry; Complex traits
8.  Evidence for involvement of GNB1L in Autism 
Structural variations in the chromosome 22q11.2 region mediated by non-allelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders. The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (p=0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in autism spectrum disorders as well.
doi:10.1002/ajmg.b.32002
PMCID: PMC3270696  PMID: 22095694
22q11.2; translocation; neurodevelopmental disorders
9.  Genome-scan for IQ discrepancy in autism: evidence for loci on chromosomes 10 and 16 
Human genetics  2010;129(1):59-70.
Performance IQ (PIQ) greater than verbal IQ (VIQ) is often observed in studies of the cognitive abilities of autistic individuals. This characteristic is correlated with social and communication impairments, key parts of the autism diagnosis. We present the first genetic analyses of IQ discrepancy (PIQ–VIQ) as an autism-related phenotype. We performed genome-wide joint linkage and segregation analyses on 287 multiplex families, using a Markov chain Monte Carlo approach. Genetic data included a genome-scan of 387 micro-satellite markers in 210 families augmented with additional markers added in a subset of families. Empirical P values were calculated for five interesting regions. Linkage analysis identified five chromosomal regions with substantial regional evidence of linkage; 10p12 [P = 0.001; genome-wide (gw) P = 0.05], 16q23 (P = 0.015; gw P = 0.53), 2p21 (P = 0.03, gw P = 0.78), 6q25 (P = 0.047, gw P = 0.91) and 15q23–25 (P = 0.053, gw P = 0.93). The location of the chromosome 10 linkage signal coincides with a region noted in a much earlier genome-scan for autism, and the chromosome 16 signal coincides exactly with a linkage signal for non-word repetition in specific language impairment. This study provides strong evidence for a QTL influencing IQ discrepancy in families with autistic individuals on chromosome 10, and suggestive evidence for a QTL on chromosome 16. The location of the chromosome 16 signal suggests a candidate gene, CDH13, a T-cadherin expressed in the brain, which has been implicated in previous SNP studies of autism and ADHD.
doi:10.1007/s00439-010-0899-z
PMCID: PMC3082447  PMID: 20963441
10.  Social attention: a possible early indicator of efficacy in autism clinical trials 
For decades, researchers have sought to clarify the nature of the social communication impairments in autism, highlighting impaired or atypical 'social attention' as a key measurable construct that helps to define the core impairment of social communication. In this paper, we provide an overview of research on social attention impairments in autism and their relation to deficiencies in neural circuitry related to social reward. We offer a framework for considering social attention as a potential moderator or mediator of response to early behavioral intervention, and as an early indicator of efficacy of behavioral and/or pharmacological treatments aimed at addressing the social impairments in autism.
doi:10.1186/1866-1955-4-11
PMCID: PMC3436672  PMID: 22958480
Autism; Autism spectrum disorder; Social reward; Social attention; Oxytocin; Clinical trials; Behavioral intervention
11.  Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations 
Nature genetics  2011;43(6):585-589.
Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity1,2. We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk3. Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.
doi:10.1038/ng.835
PMCID: PMC3115696  PMID: 21572417
12.  Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes 
PLoS Genetics  2011;7(11):e1002334.
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
Author Summary
Deletions and duplications, termed copy number variants (CNVs), have been implicated in a variety of neurodevelopmental disorders including intellectual disability (ID), autism, and schizophrenia. Our understanding of the relevance of large, rare CNVs in a range of neurodevelopmental phenotypes, varying in severity and prevalence, has been difficult because these studies were restricted to the analysis of one disorder at a time using different CNV detection platforms, insufficient sample sizes, and a lack of detailed clinical information. We tested 1,227 individuals with different neurological diseases including dyslexia, autism, and ID using the same CNV detection platform. We observed striking differences in CNV burden and inheritance characteristics among these cohorts and show that ID is the primary correlate of large CNV burden. This correlation is well illustrated by a comparison of autism patients with and without ID—where the latter show only modest increases in large CNV burden compared to controls. We also find significant depletion in the frequency of large CNVs in dyslexia compared to the other cohorts. Further studies on larger sets of individuals using high-resolution arrays and next-generation sequencing are warranted for a detailed understanding of the relative contribution of genetic variants to neurodevelopmental disorders.
doi:10.1371/journal.pgen.1002334
PMCID: PMC3213131  PMID: 22102821
13.  The Broader Autism Phenotype and Its Implications on the Etiology and Treatment of Autism Spectrum Disorders 
Autism Research and Treatment  2011;2011:545901.
The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed the broader autism phenotype (BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD.
doi:10.1155/2011/545901
PMCID: PMC3420416  PMID: 22937250
14.  ERP Evidence of Atypical Face Processing in Young Children with Autism 
Autism involves a basic impairment in social cognition. This study investigated early stage face processing in young children with autism by examining the face-sensitive early negative event-related brain potential component in 3–4 year old children with autism spectrum disorder (ASD), typical development, and developmental delay. Results indicated that children with ASD showed a slower electrical brain response to faces and a larger amplitude response to objects compared to children with typical development and developmental delay. These findings indicate that children with ASD have a disordered pattern of brain responses to faces and objects at an early age.
doi:10.1007/s10803-006-0126-x
PMCID: PMC2989721  PMID: 16897400
Autism; Event-related potentials; Faces; N170; Children
15.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
doi:10.1038/nature07999
PMCID: PMC2943511  PMID: 19404256
16.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
doi:10.1038/nature07953
PMCID: PMC2925224  PMID: 19404257
17.  Evidence for Involvement of GNB1L in Autism 
Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P = 0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well. © 2011 Wiley Periodicals, Inc.
doi:10.1002/ajmg.b.32002
PMCID: PMC3270696  PMID: 22095694
22q11.2; translocation; neurodevelopmental disorders

Results 1-17 (17)