InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Biochemistry, Genetics and Molecular Biology » "Mutations in Human Genetic Disease", book edited by David N. Cooper and Jian-Min Chen, ISBN 978-953-51-0790-3, Published: October 12, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 11

Clinical and Genetic Heterogeneity of Autism

By Yu Wang and Nanbert Zhong
DOI: 10.5772/48700

Article top

Clinical and Genetic Heterogeneity of Autism

Yu Wang1 and Nanbert Zhong1, 2, 3

1. Introduction

Autism (MIM 209850) comprises a heterogeneous group of disorders with a complex genetic etiology, characterized by impairments in reciprocal social communication and presence of restricted, repetitive and stereotyped patterns of behavior [1]. With an early onset prior to age 3 and prevalence as high as 0.9–2.6% [2,3], autism occurs predominantly in males, with a ratio of male: female of 4 to 1. It is one of the leading causes of childhood disability and inflicts serious suffering and burden for the family and society [4].

Diagnosis of autism is based on expert observation and assessment of behavior and cognition, not etiology or pathogenic mechanism. This is further emphasized by the current trend in the DSM-V, in which the category of Asperger syndrome is removed and the diagnostic criteria for autism are modified under the new heading of autism spectrum disorder (ASD). The change in diagnostic criteria is not based on known similarities or differences in causation between these clinically defined categories, but rather on the consensus of opinions of expert clinicians. For autism, several diagnostic instruments are available. Two are commonly used in autism research: the Autism Diagnostic Interview-Revised (ADI-R) that is a semi-structured parent interview [5], and the Autism Diagnostic Observation Schedule (ADOS) uses observation and interaction with the child(ren) [6]. The Childhood Autism Rating Scale (CARS) is used widely in clinical environments to assess severity of autism based on observation of children [7]. The M-CHAT was developed in the late 1990s as a first-stage screening tool for ASD in toddlers’ age 18 to 24 months, with a sensitivity of 0.87 and a specificity of 0.99 in American children [8, 9].

2. Clinical heterogeneity of ASD

Autistic conditions are a spectrum of disorders, rather than a distinct clinical disorder, which means that the symptoms can be present in a variety of combinations with a range of severity. The disease has variable cognitive manifestations, ranging from a non-verbal child with mental retardation to a high-functioning college student with above average IQ with inadequate social skills [10]. Clinical heterogeneity of autism showed three major categories: idiopathic autism, autistic spectrum disorder (ASD), and syndromatic autistics that usually resulted from an identified syndrome with known genetic etiology. Traditionally, ASD includes autism, Asperger syndrome, where language appears normal, Rett syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS), in which children meet some but not all criteria for autism. Rett syndrome (RTT), occurring almost exclusively in females, is characterized by developmental arrest between 5 and 18 months of age, followed by regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and intellectual difficulties. These disorders share deficits in social communication and show variability in language and repetitive behavior domains [1]. Autistic individuals may have symptoms that are independent of the diagnosis. Mental retardation is present in approximately 75% of cases of autism, seizures in 15 to 30% of cases, attention deficit hyperactivity disorder (ADHD) in 59-75% of cases, schizophrenia (SZ) in 5% of cases, obsessive-compulsive disorder (OCD) in about 60% of cases and electroencephalographic abnormalities in 20 to 50% of cases [11]. In addition, approximately 15 to 37% of cases of autism have a comorbid medical condition such as epilepsy, sensory abnormalities, motor abnormalities, sleep disturbances, and gastrointestinal symptoms. Five to 14% of cases had a known genetic disorder or chromosomal anomaly. The 4 most common conditions associated with autistic phenotypes are fragile X syndrome, tuberous sclerosis, 15q duplications, and untreated phenylketonuria. Other conditions associated with autistic phenotypes include Angelman syndrome, Cowden disease, Smith-Lemli-Opitz syndrome, cortical dysplasia-focal epilepsy (CDFE) syndrome, Neurofibromatosis, and X-linked mental retardation.

3. Autism is a complex genetic disorder

It is widely held that autism is largely genetic in origin; several dozen autism susceptibility genes have been identified in the past decade, collectively accounting for about 20% of autistic cases. There is strong evidence from twin and family studies for the importance of complex genetic factors in the development of autism [12, 13]. Family studies have shown that a recurrence rate of autism in siblings of affected proband is as high as 8–10% [12, 14]. Thus, the recurrence risk in siblings is roughly 100 times higher than that found in the general population. The substantial degree of familial clustering in ASD could reflect shared environmental factors, but twin studies strongly point to genetics. Several epidemiological studies among sex-matched twins have clearly demonstrated significant differences of concordance rates in the monozygotic (MZ) and dizygotic (DZ) twins. The largest of these studies [15] found that 60% of the MZ pairs were concordant for autism compared with none of the DZ pairs, suggesting a heritability estimate of >90% assuming a multifactorial threshold model. This is what is observed in every twin study in autism, and is overall consistent with heritability estimates of about 70–80% [15, 16]. One exception is a very recent study with a large sample of twins, which, despite showing a concordance of about 0.6 for MZ twins and 0.25 for DZ twins, comes to the conclusion that shared environment plays a larger role than genetic factors [17]. However, the question of how a shared environment would have a more major role than genetics is not clear. Moreover, studies in families show that first-degree relatives of an autistic proband have a markedly increased risk for autism relative to the population, consistent with a strong familial or genetic effect observed in twins [18]. This is not to dispute the role of the environment but to emphasize that genes play an important role. Similar to other common diseases with genetic contributions, autism was thought to fit a model in which multiple variants, each with small to moderate effect sizes, interact with each other and perhaps in some cases, environmental factors, to lead to autism; a situation referred to as complex genetics [13].

4. Genetic heterogeneity of autism

Although autism is highly heritable, the identification of candidate genes has been hindered by the heterogeneity of the disease. Autism genetics is highly complex, involving many genes/loci and different genetic variations, including translocation, deletion, single nucleotide polymorphism (SNP) and copy number variation (CNV) [13, 19, 20]. The most obvious general conclusion from all of the published genetic studies is the extraordinary etiological heterogeneity of autism. No specific gene accounts for the majority of autism; rather, even the most common genetic forms account for not more than 1–2% of cases [21]. Further, these genes, including those mentioned earlier, represent a diversity of molecular mechanisms that include cell adhesion, neurotransmission, synaptic structure, RNA processing/splicing, and activity-dependent protein translation. Genetic heterogeneity of autistic cases has been documented by identification of single gene mutations and genomic variations including CNV. The mutant genes identified from autistic patients are: FMR1, MECP2, CNTNAP2, PTEN, DHCR7, CACNA1C, UBE3A, TSC2, NF1, ARX, NLGN3, NLGN4, NRXN1, FOXP1, FOXP2, GRIK2, and SHANK3 (Table 1). Genomic variation including copy number deletion or duplication at loci of 1q21.2, 1q42.2, 2q31.1, 3p25.3, 7q11.23, 7q22.1, 7q36.3, 11q13.3, 12q14.2, 15q11-13, 16p11.2, 16q13.3, 17q11.2, 17q12, 17q21.32, 22q13.33, or Xp22.11 may also associate with autism.

5. Genotype/phenotype correlation in ASD

The presence of genetic and phenotypic heterogeneity in autism with a number of underlying pathogenic mechanisms is highlighted in this current review. There are at least three phenotypic presentations with distinct genetic underpinnings: (1) autism with syndromic phenotype characterized by rare, single-gene defects (Table 2); (2) broad autistic phenotypes caused by genetic variations in single or multiple genes, each of these variations being common and distributed continually in the general population but resulting in variant clinical phenotypes when it reaches a certain threshold through complex gene-gene and gene-environment interactions; and (3) severe and specific phenotype caused by 'de-novo' mutations in the patient or transmitted through asymptomatic carriers of such mutations (Table 3) [48, 49]. Understanding the neurobiological processes by which genotypes lead to phenotypes, along with the advances in developmental neuroscience and neuronal networks at the cellular and molecular level, are paving the way for translational research involving targeted interventions of affected molecular pathways and early intervention programs that promote normal brain responses to stimuli and alter the developmental trajectory [50]. Recent genetic results have improved our knowledge of the genetic basis of autism. Nevertheless, identification of phenotypic markers remains challenging due to phenotypic and genotypic heterogeneity.

GeneGenetic alterationLocationReference
FMR1The number of CGG in FMR1 alleles is classified as intermediate mutation (45 to 55), premutation (55 to 200), or full mutation (>200)5’untranslated region
MECP2T158M, T158AMissense mutation
CNTNAP23709delGExon 22
G731S, I869T
R1119H, D1129H, I1253T, T1278I
Exon 14, 17
Exon 20, 21, 23, 24
H275AExon 6
CNV (microdeletion)Promoter
PTENDeletionExon 2
CACNA1CG406RMissense mutation
UBE3AD15S1225' end of UBE3A,
TSC2SNPIntron 4, 9; exon 40
NF1SNPIntron 27
NLGN3R451CMissense mutation,
NLGN41186insTFrameshift mutation
NRXN1De novo 320-kb deletionPromoter and initial coding exons,
Missense structural variant Neurexin1ß signal peptide region
FOXP1De novo intragenic deletionExons 4-14
FOXP2Del CAA; Exon 5,
Frequency of the TT alleleIntron 15
SHANK3De novo Q321RStop codon
1-bp insertionExon 11
De novo 7.9-Mb deletion22q13.2-qter

Table 1.

Genetic alteration identified from autism

Gene/lociChromosomePhenotype (human/mouse)Mechanism involvedRisk of autismReference
CNTNAP27q35-q36.1Recessive EPI syndrome, ASD, ADHD, TS, OCDChromosomal rearrangements and large deletions, disruption of the transcription factor FOXP2, SNPNot conclusive
CHD78q12.1CHARGE Mutations/deletions of gene CHD7, Chromatin remodeling; disruption of the transcription factor FOXP2; SNP;15–50%,
TSC19q34.13Tuberous Sclerosis type I.Mutation in gene TSC1 and subsequent hyperactivation of the downstream mTOR pathway, resulting in increased cell growth and proliferation.Not conclusive
PTEN10q23.31Cowden disease.Mutation of gene PTENNot conclusive
DHCR711q13.4Smith-Lemli-Opitz syndromeMutations of gene DHCR, leading to a deficiency of cholesterol synthesis and an accumulation of 7-dehydrocholesterol15–50%

CACNA1C12p13.33Timothy syndrome. Missense mutations in the calcium channel gene CACNA1H Not conclusive
UBE3A15q11.2Angelman syndromeMaternal deletion, paternal UPD, deletions and epimutations at IC, mutations of UBE3A, Lack of expression of maternally expressed gene UBE3A Not conclusive ,
TSC216p13.3Tuberous Sclerosis type IIMutation in gene TSC2 and subsequent hyperactivation of the downstream mTOR pathway, resulting in increased cell growth and proliferation.Not conclusive
NF117q11.2NeurofibromatosisPolymorphisms within the intron-27, including the (AAAT)(n) and two (CA)nNot conclusive
DMDXp21.2Duchenne muscular dystrophyMutations of DMD gene resulting in absence of dystrophin protein Not conclusive
ARXXp21.3LIS, XLID, EPI, ASDNaturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutationsNot conclusive
FMR1Xq27.3Fragile X syndromeCGG repeat expansion and DNA methylation of FMR1 gene, reduced FMR1 expression 60–67% in males, 23% in female
MECP2Xq28Rett syndromeMutations in MECP2 and CDKL5Overlap in symptoms

Table 2.

Autism plus syndromic ASD caused by rare, single-gene disorders

Mechanism involved in ASDReference
NRXN12p16.3ASD, ID, SCZ,
Language delay
De novo 320-kb deletion that removes the promoter and initial coding exons of the NRXN1 gene, resulting in deletion of neurexin 1a
Missense structural variants in the neurexin 1b signal peptide region
Translocations and intragenic rearrangements in or near NRXN1gene,
FOXP13p13ID, ASD, SLIDe novo intragenic deletion encompassing exons 4-14 of FOXP1, de novo nonsense mutation (c.1573C"/>T) in the conserved fork head DNA-binding domain
Recessive ID
SNP1 and SNP2 of gene GRIK2 were associated with autism
FOXP27q31.1ASD, SLIDirectly bind intron 1 of the CNTNAP2 gene and regulate its expression
Wiedemann syndrome
Overexpression of paternally expressed IGF2, due to a gain of DNA methylation at paternal allele of IC1 and suppression of maternally expressed suppressing factor CDKN1C
15q11-q13Prader-Willi syndromePaternal deletions, maternal UPD at15q11–13, deletions and epimutations of IC, translocations disrupting SNRPN
Maternal duplication of 15q11-13 regionMaternal duplications of 15q11-13 region
SHANK322q13.33ASDMutation at an intronic donor splice site, one missense mutation in the coding region
NLGN4XXp22.32-p22.31ASD, ID, TS, ADHDFrameshift mutation (1186insT)
NLGN3Xq13.1ASDR451C mutation within the esterase domain of neuroligin 3,

Table 3.

Severe and specific phenotype with rare variants of genes

6. Copy number variation (CNV): A paradigm shift in autism

The strong genetic contribution shown in family studies and the association of cytogenetic changes, but apparent lack of common risk factors in autism, led to a hypothesis that rare sub-microscopic unbalanced changes in the form of CNVs likely contribute to the autism phenotype. With the development of microarrays capable of scanning the genome at sub-microscopic resolution, there is accumulating evidence that multiple CNVs contribute to the genetic vulnerability to autism [80]. de novo CNV has been identified in up to 7–10% of sporadic autism [81, 82], but are less frequent in multiplex families, in which CNV accounts only for about 2% of families screened [80, 83] possibly suggest different genetic liabilities in simplex and multiplex autism. Recurrent CNVs at 15q11-13 (1-3% of autism patients), 16p11 (1% of autism patients), and 22q11-13 have been confirmed in multiple studies [80, 83-86]. This hypothesis also has been proven largely successful in identifying autism-susceptibility candidate genes, including gains and losses at SHANK2 [87], SHANK3 [88], NRXN1 [13], NLGN3 and NLGN4 [37], and PTCHD1 [89, 90]. Neurexins and neuroligins are synaptic cell-adhesion molecules (CAMs) that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. The Shank family of proteins provides scaffolding for signaling molecules in the postsynaptic density of glutamatergic synapses. Genes encoding CAMs play crucial roles in modulating or fine-tuning synaptic formation and synaptic specification. Localization and interacting proteins at the synapse is shown in Figure 1.


Figure 1.

Localization of cell-adhesion molecules and their interacting proteins at the synapse. Proteins associated with ASD are underlined.

It is apparent that many different loci, each with a presumably unique yet subtle contribution to neurodevelopment, underlie the phenotype of autism. These observations have resulted in a paradigm shift away from the previously held “common disease-common variant” hypothesis to a “common disease-rare variant” model for the genetic architecture of autism. The central tenet of this model suggests a role for multiple, rare, highly penetrant, genetic risk factors for ASD, many of which are in the form of CNV. To make sense of the contribution of CNVs to autism, a “threshold” model has been proposed [80]. The model posits that different CNVs exhibit different penetrance depending on the dosage sensitivity and function (relative to autism) of the gene(s) they affect. Some CNVs have a large impact on autism susceptibility and these are typically de novo in origin, cause more severe autistic symptoms, are more prevalent among sporadic forms of autism, and are less influenced by other factors like gender and parent of origin. Other CNVs have moderate or mild effects that probably require other genetic (or non-genetic) factors to take the phenotype across the autistic threshold.

7. Epigenetics plays an important role in autism

In addition to structural genetic factors that play causative roles for autism, environmental factors also play an important role in autism by influencing fetal or early postnatal brain development, directly or via epigenetic modifications. Epigenetic modifications include cytosine methylation, post-translational modification of histones, small interfering RNA and genomic imprinting. Involvement of epigenetic factors in autism is demonstrated by the central role of epigenetic regulatory mechanisms in the pathogenesis of Rett syndrome and fragile X syndrome (FXS), both are the monogenic disorders resulted from single gene defects and commonly associated with autism [38-40]. FXS is a result of a triplet expansion of CGG repeats at the 5’ untranslated region of FMR1 gene, which encodes the FMRP (fragile X mental retardation protein). FMRP is proposed to act as a translation regulator of specific mRNAs in the brain and involved in synaptic development and maturation, through its nucleo-cytoplasmic shuttle activity as an RNA-binding protein. It has been shown that FMRP uses its arginine-glycine-glycine (RGG) box domain to bind a subset of mRNA targets that form a G-quadruplex structure. FMRP has also been shown to undergo the post-translational modifications of arginine methylation and phosphorylation [91, 92]. Our recent study demonstrated that alteration of methylation patterns at loci of Neurex1 and ENO2 are associated with autism [Wang and Zhong, manuscript in preparation].

Genomic imprinting is the classic example of regulation of gene expression via epigenetic modifications, such as hypemethylation, that leads to parent of origin-specific gene expression. In addition, a growing number of genes that are not imprinted are regulated by DNA methylation, including Reelin (RELN) [41, 93-96], which has been considered as a candidate for autism. Several of the linkage peaks overlap or are in close proximity to regions that are subject to genomic imprinting on chromosomes 15q11-13, 7q21-31.31, 7q32.3-36.3 and possibly 4q21-31, 11p11.2-13 and 13q12.3, with the loci on chromosomes15q and 7q demonstrating the most compelling evidence for a combination of genetic and epigenetic factors that confer risks for autism [97-101]. Genes in the imprinted cluster on chromosome 15q11–13 include MKRN3, ZNF127AS, MAGE12, NDN, ATP10A, GABRA5, GABRB3, and GABRG3 [102, 103]. Genes in the imprinted cluster on chromosome 7q21.3 include SGCE, PEG10, PPP1R9A, DLX5, CALCR, ASB4, PON1, PON2, and PON3 [104, 105].

Research has recently focused on the connections between the immune system and the early development of brain, including its possible role in the development of autism [106]. Immune aberrations consistent with a deregulated immune response may target neuronal development and differentiation [107, 108]. Our study has suggested that a close contact with natural rubber latex (NRL) could trigger an immunoreaction to Hevea brasiliensis (Hev-b) proteins in NRL and resulted in autism [109]. This led us to a hypothesis that immune reactions triggered by environmental factors could damage synapse formation and neuronal connections, which would result in missing normal structure or function of synaptic proteins that are encoded by genes NLGNs, NRXN1, CNTNAPs, SHANKs, or in deregulation of gene expression of FMR1, PTEN, FOXPs, and GRIK2.

8. Converging molecular pathways of autism

Autism is a heterogeneous disorder with a fundamental question of whether autism represents an etiologically heterogeneous disorder in which a myriad of genetic or environmental risk factors perturb common underlying molecular pathways in the brain [110]. Two recent studies have suggested there could be convergence at the level of molecular mechanisms in autism. The first study on molecular convergence in autism identified protein interactors of known autism or autism-associated genes [111]. This interactome revealed several novel interactions, including between two autism candidate genes, SHANK3 and TSC1. The biological pathways identified in this study include synapse, cytoskeleton and GTPase signaling, demonstrating a remarkable overlap with those identified by the gene expression. The second, an analysis of gene expression in postmortem autism brain, provides strong evidence for a shared set of molecular alterations in a majority of cases of autism. This included disruption of the normal gene expression pattern that differentiates frontal and temporal lobes and two groups of genes deregulated in autistic brains: one related to neuronal function, and the other related to immune/inflammatory responses [111]. Genes associated with neuronal function were enriched in metabolic signal pathways, providing evidence that these changes were causal, rather than the consequence of the disease [112]. In contrast, the immune/inflammatory changes did not show a strong genetic signal, indicating a non-genetic etiology for this process and implicating environmental or epigenetic factors instead. These results provide strong evidence for converging molecular abnormalities in autism, and implicating transcriptional and splicing deregulation as underlying mechanisms of neuronal dysfunction in this disorder.

9. In summary

Autism is a heterogeneous set of brain developmental disorders with complex genetics, involving interactions between genetic, epigenetic and environmental factors. The heterogenerous genetics involves many genes/loci and different genetic variations in autism, such as deletion, translocation, SNP and CNV. Recent studies have also suggested there could be convergence at the level of molecular mechanisms in autism. Although the genetic basis is well documented, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be well established.


This work was supported in part by the “973” program (2012CB517905) granted by the Chinese Ministry of Science and Technology, the Shanghai Municipal Department of Science and Technology (2009JC1412600), and the New York State Office of People with Developmental Disabilities (OPWDD).


1 - Geschwind DH2009Advances in autismAnnu Rev Med. 60367380
2 - Kogan MD, Blumberg SJ, Schieve LA2007Prevalence of parent-reported diagnosis of autism spectrum disorderamong children in the US. Pediatrics. 12413951403
3 - Y. S. Kim, L. Leventhal, Y. J. Koh, 2011Prevalence of autism spectrum disorders in a total population sampleAm. J. Psychiatry. 168904912
4 - Ganz ML2006The Costs of Autism In Moldin, SO and Rubenstein, JLR (eds), Understanding Autism: from Basic Neuroscience to Treatment. CRC Press, Boca Raton, FL, 476498
5 - C. Lord, A. Pickles, J. Mc Lennan, 1997Diagnosing autism: analyses of data from the Autism Diagnostic Interview.Autism Dev Disord. 27501517
6 - C. Lord, S. Risi, L. Lambrecht, 2000The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autismAutism Dev Disord. 30205223
7 - E. Schopler, R. Reichler, B. R. Renner, 1991The childhood autism rating scale. Los Angeles: Western Psychological Services; 1988, Psychol Monogr. 117313357
8 - D. Robins, D. Fein, M. Barton, J. Green, 2001The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disordersAutism Dev Disord. 31131151
9 - MJ Levy. S. Pinto, 2004Early diagnosis of autism spectrum disordersCurr Treat Options Neurol. 6391400
10 - Gillberg C and Coleman M (2000) The biology of autistic syndromes, 3rd ed. Mac Keith, London. 22p.
11 - E. Fombonne, 2001Is there an epidemic of autism? Pediatrics. 107411412
12 - P. Szatmari, M. B. Jones, L. Zwaigenbaum, 1998Genetics of autism: overview and new directions.J Autism and Dev Disord. 28351368
13 - Abrahams BS, Geschwind DH2008Advances in autism genetics: on the threshold of a new neurobiologyNat Rev Genet. 9341355
14 - L. Zwaigenbaum, S. Bryson, W. Roberts, 2005Behavioral markers of autism in the first year of life. Intern J. Dev Neurosci. 23143152
15 - A. Bailey, A. Le Couteur, I. Gottesman, 1995Autism as a strongly genetic disorder: Evidence from a British twin study.Psychological Medicine. 256377
16 - R. E. Rosenberg, J. K. Law, G. Yenokyan, 2009Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med. 163907914
17 - J. Hallmayer, S. Cleveland, A. Torres, 2011Genetic heritability and shared environmental factors among twin pairs with autismArch Gen Psychiatry. 6810951102
18 - P. Bolton, H. Macdonald, A. Pickles, 1994A case-control family history study of autism.Child Psychol Psychiatry. 35877900
19 - J. T. Glessner, K. Wang, G. Cai, 2009Autism genome-wide copy number variation reveals ubiquitin and neuronal genesNature459569573
20 - K. Wang, H. Zhang, Ma D. , 2009Common genetic variants on 514 1 associate with autism spectrum disordersNature
21 - M. Bucan, BS Wang. K. Abrahams, 2009Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.PLoS Genet. 5: e1000536 EOF
22 - A. Maddalena, C. S. Richards, MJ Mc Ginniss, 2001Technical standards and guidelines for Fragile X: The first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality assurance subcommittee of the laboratory practice committee.Genet Med. 3200205
23 - Pfeiffer BE, Huber KM2009The state of synapses in fragile X syndromeNeuroscientist15549567
24 - H. Tan, H. Li, P. Jin, 2009RNA-mediated pathogenesis in fragile X-associated disordersNeurosci Lett. 466103108
25 - D. Goffin, M. Allen, L. Zhang, 2011Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.Nat Neurosci. 15274283
26 - Strauss KA, Puffenberger EG, Huentelman MJ2006Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.N Engl J Med. 35413701377
27 - B. Bakkaloglu, B. J. O’Roak, A. Louvi, 2008Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disordersHum Genet. 82165173
28 - B. J. O’Roak, P. Deriziotis, C. Lee, 2011Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutationsNat Genet. 46585589
29 - AS Roeb. W. Nord, D. E. Dickel, 2011Reduced transcript expression of genes affected by inherited and de novo CNVs in autismEur J Hum Genet. 19727731
30 - S. Conti, M. Condò, A. Posar, 2011Phosphatase and Tensin Homolog (PTEN) Gene Mutations and Autism: Literature review and a case report of a patient with Cowden Syndrome, Autistic Disorder and Epilepsy. J. Child Neurol. 29123126
31 - I. Splawski, DS Stotz. S. C. Yoo, 2006CACNA1H mutations in autism spectrum disorders.J. Biol Chem. 2812208522091
32 - G. Guffanti, Lievers. L. Strik, M. T. Bonati, 2011Role of UBE3A and ATP10A genes in autism susceptibility region 15q11-q13 in an Italian population: a positive replication for UBE3A Psychiatry Res. 1853338
33 - E. L. Nurmi, Y. Bradford, Y. Chen, 2001Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism familiesGenomics77105113
34 - F. J. Serajee, R. Nabi, H. Zhong, (2003) Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: Implications for phosphatidylinositol. J Med Genet. 40119123 .
35 - T. Marui, O. Hashimoto, E. Nanba, 2004Association between theNeurofibro matosis-1 (NF1) locus and autism in the Japanese population. Am J Med Genet B Neuropsychiatr Genet. 131B: 4347
36 - S. Jamain, H. Quach, C. Betancur, 2003Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.Nat Genet. 342729
37 - D. Comoletti, A. De Jaco, L. L. Jennings, 2004The Arg451 Cys- neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci. 2448894893
38 - J. M. Friedman, A. Baross, A. D. Delaney, 2006Oligonucleotide microarray analysis of genomic imbalance in children with mental retardationAm J Hum Genet. 79500513
39 - F. R. Zahir, A. Baross, A. D. Delaney, 2008A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of N RXN1a. Med Genet. 45239243
40 - J. Feng, R. Schroer, J. Yan, 2006High frequency of neurexin 1 signal peptide structural variants in patients with autism. Neurosci Lett. 4091013
41 - F. F. Hamdan, H. Daoud, D. Rochefort, 2010De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairmentAm J Hum Genet. 87671678
42 - H. Li, T. Yamagata, M. Mori, 2005Absence of causative mutations and presence of autism-related allele in FOXP2 in Japanese autistic patients.Brain Dev. 27207210
43 - Z. Mukamel, G. Konopka, E. Wexler, 2011Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.J Neurosci. 311143711442
44 - S. Jamain, C. Betancur, H. Quach, 2002Linkage and association of the glutamate receptor 6 gene with autism.Mol Psychiatry. 7302310
45 - C. M. Durand, J. Perroy, F. Loll, 2012SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.Mol Psychiatry. 177184
46 - A. Kolevzon, G. Cai, L. Soorya, 2011Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilitiesBrain Res. 138098105
47 - Chen CP, Lin SP, Chern SR2010A de novo 7.9 Mb deletion in 22q13.2→qter in a boy with autistic features, epilepsy, developmental delay, atopic dermatitis and abnormal immunological findings. Eur J Med Genet. 53329332
48 - A. Chiocchetti, S. M. Klauck, 2011Genetic analyses for identifying molecular mechanisms in autism spectrum disorders. Encephale. 376874
49 - F. Bonnet-Brilhault, 2011Genotype/phenotype correlation in autism: genetic models and phenotypic characterization. Encephale376874
50 - V. Eapen, 2011Genetic basis of autism: is there a way forward? Curr Opin Psychiatry. 24226236
51 - Vernes SC, Newbury DF, Abrahams BS2008A functional genetic link between distinct developmental language disordersN Engl J Med. 35923372345
52 - D. F. Newbury, S. Paracchini, T. S. Scerri, 2011Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects. Behav Genet. 4190104
53 - M. Poot, V. Beyer, I. Schwaab, 2010Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorderNeurogenetics118189
54 - L. T. Sehested, R. S. Møller, I. Bache, 2010Deletion of 7q34q36.2 in two siblings with mental retardation, language delay, primary amenorrhea, dysmorphic features. Am J Med Genet. 152A: 3115-3119.
55 - I. Teramitsu, L. C. Kudo, S. E. London, 2004Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.Neurosci. 2431523163
56 - S. C. Panaitof, BS Dong. H. Abrahams, 2010Language-related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds. Comp. Neurol. 51819952018
57 - C. Shoubridge, M. H. Tan, T. Fullston, 2010Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell divisionPathogenetics. 3: 1.
58 - Hartshorne TS, Grialou TL, Parker KR2005Autistic-like behavior in CHARGE syndrome.Am J Med Genet A. 133A: 257261
59 - M. Johansson, M. Rastam, E. Billstedt, 2006Autism spectrum disorders and underlying brain pathology in CHARGE associationDev Med Child Neurol. 484050
60 - I. M. Smith, S. L. Nichols, K. Issekutz, 2005Behavioral profiles and symptoms of autism in CHARGE syndrome: preliminary Canadian epidemiological data.Am J Med Genet A. 133A: 248256
61 - Skuse DH, James RS, Bishop DV1997Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function.Nature387705708
62 - Bianconi SE, Conley SK, Keil MF2011Adrenal function in Smith-Lemli-Opitz syndrome.Am J Med Genet A. 155A: 27322738
63 - K. Depil, S. Beyl, Stary-Weinzinger, A(2011Timothy mutation disrupts the link between activation and inactivation in Ca(1protein. J Biol Chem. 286: 31557-31564.
64 - N. Klymiuk, C. Thirion, K. Burkhardt, 2011238 tailored pig model of Duchenne muscular dystrophyReprod Fertil Dev. 24: 231 EOF
65 - N. Valerio, M. Romina, C. Paolo, 2009Recent advances in neurobiology of Tuberous Sclerosis ComplexBrain Dev. 31104113
66 - Bianconi SE, Conley SK, Keil MF2011Adrenal function in Smith-Lemli-Opitz syndrome.Am J Med Genet A. J. 155A: 27322738
67 - A. M. Coutinho, G. Oliveira, C. Katz, 2007MECP2 coding sequence and 3’UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet.144B: 475483
68 - A. Shibayama, E. H. Cook, J. Feng, 2004MECP2 structural and 3’-UTR variants in schizophrenia, autism and other psychiatricdiseases: a possible association with autism.Am J Med Genet B Neuropsychiatr Genet. 128B: 5053
69 - J. T. Glessner, K. Wang, G. Cai, 2009Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 459569573
70 - P. Szatmari, A. D. Paterson, L. Zwaigenbaum, 2007Mapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat Genet. 39319328
71 - H. G. Kim, S. Kishikawa, A. W. Higgins, 2008Disruption of neurexin 1 associated with autism spectrum disorderAm J Hum Genet. 82199207
72 - K. B. Wisniowiecka, M. Nesteruk, S. U. Peters, 2010Intragenic rearrangementsin NRXN1 in three families with autismspectrum disorder, developmental delay, and speech delay. Am J Med Genet B Neuropsychiatr Genet. 153B: 983993
73 - F. F. Hamdan, H. Daoud, D. Rochefort, 2010De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairmentAm J Hum Genet. 87671678
74 - J. P. Casey, T. Magalhaes, J. M. Conroy, 2011Regan RA novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet. 131565579
75 - L. Kent, S. Bowdin, G. A. Kirby, 2008Beckwith Weidemann syndrome: a behavioral phenotype-genotype study.Am J Med Genet B Neuropsychiatr Genet. 147B: 12951297
76 - MJ Govers. V. Descheemaeker, P. J. Vermeulen, 2006Pervasive developmental disorders in Prader-Willi syndrome: the Leuven experience in 59 subjects and controls.Am J Med Genet A. 14011361142
77 - Veltman MW, Thompson RJ, Roberts SE2004Prader-Willi Syndrome-a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders.Eur Child Adolesc Psychiatry. 134250
78 - A. Hogart, D. Wu, J. M. Lasalle, 2010The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13Neurobiol Dis. 38181191
79 - J. Gauthier, N. Champagne, R. G. Lafrenière, 2010De novo mutations in the gene Encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci. 10778637868
80 - Cook EH, Scherer SW2008Copynumber variations associated with neuropsychiatric conditions. Nature. 16919923
81 - J. Sebat, B. Lakshmi, D. Malhotra, 2007Strong association of de novo copy number mutations with autism.Science. 316445449
82 - C. R. Marshall, A. Noor, J. B. Vincent, 2008Structural variation of chromosomes in autism spectrum disorderAm J Hum Genet. 82477488
83 - Morrow EM, Yoo SY, Flavell SW2008Identifying autism loci and genes by tracing recent shared ancestryScience321218223
84 - P. Szatmari, A. D. Paterson, L. Zwaigenbaum, 2007Mapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat Genet. 39319328
85 - L. A. Weiss, Y. Shen, J. M. Korn, 2008Association between microdeletion and microduplication at 1611 2 and autismN Engl J Med. 358: 667-675.
86 - R. A. Kumar, Mohamed. S. Kara, J. Sudi, 2008Recurrent 1611 2 microdeletions in autismHum Mol Genet. 17: 628-638.
87 - S. Berkel, C. R. Marshall, B. Weiss, 2010Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.Nature Genetics. 42489491
88 - C. M. Durand, C. Betancur, T. M. Boeckers, 2007Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.Nature Genetics392527
89 - D. Pinto, A. T. Pagnamenta, L. Klei, 2010Functional impact of global rare copy number variation in autism spectrum disorder.Nature. 466368372
90 - A. Noor, A. Whibley, C. R. Marshall, 2010Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability.Sci Transl Med. 2: 49ra68 EOF
91 - Auerbach BD, Osterweil EK, BearMF(2011Mutations causing syndromic autism define an axis of synaptic pathophysiology.Nature4806368
92 - Evans TL, Blice-Baum AC, Mihailescu MR2012Analysis of the Fragile X mental retardation protein isoforms 1, 2 and 3 interactions with the G-quadruplex forming semaphorin 3F mRNAMol Biosyst. 8642649
93 - J. S. Noh, R. P. Sharma, M. Veldic, 2005DNA methyltransferase1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci USA. 10217491754
94 - D. R. Grayson, Y. Chen, E. Costa, 2006The human reelin gene: Transcription factors (t), repressors (2) and the methylation switch(t/2) in schizophrenia. Pharmacol. Ther. 111272286
95 - N. Sato, N. Fukushima, R. Chang, 2006Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers.Gastroenterology. 30548565
96 - F. J. Serajee, H. Zhong, A. H. Mahbubul, 2006Association of Reelin gene polymorphisms with autismGenomics877583
97 - Y. Numachi, S. Yoshida, M. Yamashita, 2004Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain.Ann. NY Acad Sci. 1025102109
98 - Huang CH, Chen CH.2006Absence of association of a polymorphic GGC repeat at the 50 untranslated region of the reelin gene with schizophrenia. Psychiatry Res. 1428992
99 - D. A. Skaar, Y. Shao, J. L. Haines, 2005Analysis of the RELN gene as a genetic risk factor for autism.Mol. Psychiatry. 10563571
100 - J. Li, L. Nguyen, C. Gleason, 2004Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.Am J Med Genet B Neuropsychiatr. Genet. 1265157
101 - E. Bonora, K. S. Beyer, J. A. Lamb, 2003Analysis of reelin as a candidate gene for autism.Mol. Psychiatry. 8885892
102 - S. Lee, C. L. Walker, B. Karten, 2005Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowthHum Mol Genet. 14627637
103 - A. Kashiwagi, M. Meguro, H. Hoshiya, 2003Predominant maternal expression of the mouse Atp10c in hippocampus and olfactory bulb.Hum Genet. 48194198
104 - D. I. Draganov, J. F. Teiber, A. Speelman, 2005Human paraoxonases (PON1, PON2 and PON3) are lactonases with overlapping and distinct substrate specificities. Lipid Res. 4612391247
105 - R. T. Terry-Lorenzo, D. W. Roadcap, T. Otsuka, 2005Neurabin/protein phosphatase-1 complex regulates dendritic spine morphogenesis and maturation.Mol Biol Cell. 1623492362
106 - Croen LA, Grether JK, Yoshida CK2005Maternal autoimmune diseases, asthma, and allergies, and childhood autism spectrum disorders. Arch Pediatr Adolesc Med. 159151157
107 - D. Braunschweig, P. Ashwood, P. Krakowiak, 2008Autism: maternally derived antibodies specific for fetal brain proteinsNeuroToxicology29226231
108 - Singer HS, Morris CM, Gause CD2008Antibodies against fetal brain in sera of others with autistic children. Neuroimmunol. 194165172
109 - C. Shen, X. L. Zhao, N. Zhong, 2010A proteomic investigation of B lymphocytes in an autisc faily: A pilot study of exposure to natural rubber latx (NRL) may lead to autism. J Mol Neurosci. 43443452
110 - J. T. Glessner, K. Wang, G. Cai, 2009Autism genome-wide copy number variation reveals ubiquitin and neuronal genesNature459569573
111 - Y. Sakai, CA Dawson. B. C. Shaw, 2011Protein interactome reveals converging molecular pathways among autism disorders.Sci Transl Med. 3: 86ra49 EOF
112 - I. Voineagu, X. Wang, P. Johnston, 2011Transcriptomic analysis of autistic brain reveals convergent molecular pathology.Nature474380384