Genetic alteration identified from autism
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:
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.
Gene | Genetic alteration | Location | Reference |
The number of CGG in | 5’untranslated region | ||
T158M, T158A | Missense mutation | ||
3709delG | Exon 22 | ||
G731S, I869T R1119H, D1129H, I1253T, T1278I | Exon 14, 17 Exon 20, 21, 23, 24 | ||
H275A | Exon 6 | ||
CNV (microdeletion) | Promoter | ||
Deletion | Exon 2 | ||
G406R | Missense mutation | ||
D15S122 | 5' end of | , | |
SNP | Intron 4, 9; exon 40 | ||
SNP | Intron 27 | ||
R451C | Missense mutation | , | |
1186insT | Frameshift mutation | ||
Promoter and initial coding exons | , | ||
Missense structural variant | Neurexin1ß signal peptide region | ||
Exons 4-14 | |||
Del CAA; | Exon 5 | , | |
Frequency of the TT allele | Intron 15 | ||
SNP | M867I | ||
Stop codon | |||
1-bp insertion | Exon 11 | ||
22q13.2-qter |
Gene/loci | Chromosome | Phenotype (human/mouse) | Mechanism involved | Risk of autism | Reference |
7q35-q36.1 | Recessive EPI syndrome, ASD, ADHD, TS, OCD | Chromosomal rearrangements and large deletions, disruption of the transcription factor | Not conclusive | ||
8q12.1 | CHARGE | Mutations/deletions of gene | 15–50% | , | |
9q34.13 | Tuberous Sclerosis type I. | Mutation in gene | Not conclusive | ||
10q23.31 | Cowden disease. | Mutation of gene | Not conclusive | ||
11q13.4 | Smith-Lemli-Opitz syndrome | Mutations of gene | 15–50% 3% | , | |
12p13.33 | Timothy syndrome. | Missense mutations in the calcium channel gene | Not conclusive | ||
15q11.2 | Angelman syndrome | Maternal deletion, paternal UPD, deletions and epimutations at IC, mutations of | Not conclusive | , | |
16p13.3 | Tuberous Sclerosis type II | Mutation in gene | Not conclusive | ||
17q11.2 | Neurofibromatosis | Polymorphisms within the intron-27, including the (AAAT)(n) and two (CA)n | Not conclusive | ||
Xp21.2 | Duchenne muscular dystrophy | Mutations of | Not conclusive | ||
Xp21.3 | LIS, XLID, EPI, ASD | Naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations | Not conclusive | ||
Xq27.3 | Fragile X syndrome | CGG repeat expansion and DNA methylation of FMR1 gene, reduced FMR1 expression | 60–67% in males, 23% in female | ||
Xq28 | Rett syndrome | Mutations in | Overlap in symptoms Infancy | , |
Gene | Chromosome | Phenotype (human/mouse) | Mechanism involved in ASD | Reference |
2p16.3 | ASD, ID, SCZ, Language delay | De novo 320-kb deletion that removes the promoter and initial coding exons of the | ||
Missense structural variants in the neurexin 1b signal peptide region | ||||
CNV | , | |||
Translocations and intragenic rearrangements in or near | , | |||
3p13 | ID, ASD, SLI | |||
6q16.3 | ASD, Recessive ID | SNP1 and SNP2 of gene | ||
7q31.1 | ASD, SLI | Directly bind intron 1 of the | ||
11p15.5 | Beckwith- Wiedemann syndrome | Overexpression of paternally expressed | ||
15q11-q13 | Prader-Willi syndrome | Paternal deletions, maternal UPD at15q11–13, deletions and epimutations of | , | |
Maternal duplication of 15q11-13 region | Maternal duplications of 15q11-13 region | |||
22q13.33 | ASD | Mutation at an intronic donor splice site, one missense mutation in the coding region | ||
Xp22.32-p22.31 | ASD, ID, TS, ADHD | Frameshift mutation (1186insT) | ||
Xq13.1 | ASD | R451C mutation within the esterase domain of neuroligin 3 | , |
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].
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
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
Genomic imprinting is the classic example of regulation of gene expression
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
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,
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.
Acknowledgement
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).
References
- 1.
Geschwind DH 2009 Advances in autism Annu Rev Med.60 367 380 - 2.
Kogan MD, Blumberg SJ, Schieve LA 2007 Prevalence of parent-reported diagnosis of autism spectrum disorderamong children in the US. Pediatrics.124 1395 1403 - 3.
Kim Y. S. Leventhal L. Koh Y. J. 2011 Prevalence of autism spectrum disorders in a total population sample Am. J. Psychiatry.168 904 912 - 4.
Ganz ML 2006 The Costs of Autism In Moldin, SO and Rubenstein, JLR (eds), Understanding Autism: from Basic Neuroscience to Treatment. CRC Press, Boca Raton, FL,476 498 - 5.
Lord C. Pickles A. Mc Lennan J. 1997 Diagnosing autism: analyses of data from the Autism Diagnostic Interview. Autism Dev Disord.27 501 517 - 6.
Lord C. Risi S. Lambrecht L. 2000 The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism Autism Dev Disord.30 205 223 - 7.
Schopler E. Reichler R. Renner B. R. 1991 The childhood autism rating scale. Los Angeles: Western Psychological Services; 1988, Psychol Mo nogr.117 313 357 - 8.
Robins D. Fein D. Barton M. Green J. 2001 The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders Autism Dev Disord.31 131 151 - 9.
MJ Pinto Levy. S. 2004 Early diagnosis of autism spectrum disorders Curr Treat Options Neurol.6 391 400 - 10. Gillberg C and Coleman M (2000) The biology of autistic syndromes, 3rd ed. Mac Keith, London. 22p.
- 11.
Fombonne E. 2001 Is there an epidemic of autism? Pediatrics.107 411 412 - 12.
Szatmari P. Jones M. B. Zwaigenbaum L. 1998 Genetics of autism: overview and new directions. J Autism and Dev Disord.28 351 368 - 13.
Abrahams BS, Geschwind DH 2008 Advances in autism genetics: on the threshold of a new neurobiology Nat Rev Genet.9 341 355 - 14.
Zwaigenbaum L. Bryson S. Roberts W. 2005 Behavioral markers of autism in the first year of life. Intern J. Dev Neurosci.23 143 152 - 15.
Bailey A. Le Couteur A. Gottesman I. 1995 Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine.25 63 77 - 16.
Rosenberg R. E. Law J. K. Yenokyan G. 2009 Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med.163 907 914 - 17.
Hallmayer J. Cleveland S. Torres A. 2011 Genetic heritability and shared environmental factors among twin pairs with autism Arch Gen Psychiatry.68 1095 1102 - 18.
Bolton P. Macdonald H. Pickles A. 1994 A case-control family history study of autism. Child Psychol Psychiatry.35 877 900 - 19.
Glessner J. T. Wang K. Cai G. 2009 Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 459 569 573 - 20.
Wang K. Zhang H. Ma D. 2009 Common genetic variants on 5 14 1 associate with autism spectrum disorders - 21.
Bucan M. BS Abrahams Wang. K. 2009 Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 5:e1000536 EOF - 22.
Maddalena A. Richards C. S. MJ Mc Ginniss 2001 Technical 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.3 200 205 - 23.
Pfeiffer BE, Huber KM 2009 The state of synapses in fragile X syndrome 15 549 567 - 24.
Tan H. Li H. Jin P. 2009 RNA-mediated pathogenesis in fragile X-associated disorders Neurosci Lett.466 103 108 - 25.
Goffin D. Allen M. Zhang L. 2011 Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci.15 274 283 - 26.
Strauss KA, Puffenberger EG, Huentelman MJ 2006 Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med.354 1370 1377 - 27.
Bakkaloglu B. O’Roak B. J. Louvi A. 2008 Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders Hum Genet.82 165 173 - 28.
O’Roak B. J. Deriziotis P. Lee C. 2011 Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations Nat Genet.46 585 589 - 29.
AS Nord Roeb. W. Dickel D. E. 2011 Reduced transcript expression of genes affected by inherited and de novo CNVs in autism Eur J Hum Genet.19 727 731 - 30.
Conti S. Condò M. Posar A. 2011 Phosphatase 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.29 123 126 - 31.
Splawski I. DS Yoo Stotz. S. C. 2006 CACNA1H mutations in autism spectrum disorders. J. Biol Chem.281 22085 22091 - 32.
Guffanti G. Strik Lievers. L. Bonati M. T. 2011 Role of UBE3A and ATP10A genes in autism susceptibility region 15q11-q13 in an Italian population: a positive replication for UBE3A Psychiatry Res.185 33 38 - 33.
Nurmi E. L. Bradford Y. Chen Y. 2001 Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families 77 105 113 - 34.
(Serajee F. J. Nabi R. Zhong H. 2003 ) Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: Implications for phosphatidylinositol. J Med Genet.40 119 123 . - 35.
Marui T. Hashimoto O. Nanba E. 2004 Association between theNeurofibro matosis-1 (NF1) locus and autism in the Japanese population. Am J Med Genet B Neuropsychiatr Genet. 131B:43 47 - 36.
Jamain S. Quach H. Betancur C. 2003 Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet.34 27 29 - 37.
Comoletti D. De Jaco A. Jennings L. L. 2004 The Arg451 Cys- neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci.24 4889 4893 - 38.
Friedman J. M. Baross A. Delaney A. D. 2006 Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation Am J Hum Genet.79 500 513 - 39.
Zahir F. R. Baross A. Delaney A. D. 2008 A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of N RXN1a. Me d Genet.45 239 243 - 40.
Feng J. Schroer R. Yan J. 2006 High frequency of neurexin 1 signal peptide structural variants in patients with autism. Ne urosci Lett.409 10 13 - 41.
Hamdan F. F. Daoud H. Rochefort D. 2010 De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment Am J Hum Genet.87 671 678 - 42.
Li H. Yamagata T. Mori M. 2005 Absence of causative mutations and presence of autism-related allele in FOXP2 in Japanese autistic patients. Brain Dev.27 207 210 - 43.
Mukamel Z. Konopka G. Wexler E. 2011 Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk. J Neurosci.31 11437 11442 - 44.
Jamain S. Betancur C. Quach H. 2002 Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry.7 302 310 - 45.
Durand C. M. Perroy J. Loll F. 2012 SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry.17 71 84 - 46.
Kolevzon A. Cai G. Soorya L. 2011 Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities Brain Res.1380 98 105 - 47.
Chen CP, Lin SP, Chern SR 2010 A 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.53 329 332 - 48.
Chiocchetti A. Klauck S. M. 2011 Genetic analyses for identifying molecular mechanisms in autism spectrum disorders. Encephale.37 68 74 - 49.
Bonnet-Brilhault F. 2011 Genotype/phenotype correlation in autism: genetic models and phenotypic characterization.37 68 74 - 50.
Eapen V. 2011 Genetic basis of autism: is there a way forward? Curr Opin Psychiatry.24 226 236 - 51.
Vernes SC, Newbury DF, Abrahams BS 2008 A functional genetic link between distinct developmental language disorders N Engl J Med.359 2337 2345 - 52.
Newbury D. F. Paracchini S. Scerri T. S. 2011 Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects. Behav Genet.41 90 104 - 53.
Poot M. Beyer V. Schwaab I. 2010 Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder 11 81 89 - 54.
Sehested L. T. Møller R. S. Bache I. 2010 Deletion of 7q34 q36.2 in two siblings with mental retardation, language delay, primary amenorrhea, dysmorphic features. Am J Med Genet. 152A: 3115-3119. - 55.
Teramitsu I. Kudo L. C. London S. E. 2004 Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. Neurosci.24 3152 3163 - 56.
Panaitof S. C. BS Abrahams Dong. H. 2010 Language-related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds. Comp. Neurol.518 1995 2018 - 57.
Shoubridge C. Tan M. H. Fullston T. 2010 Mutations 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 division Pathogenetics. 3: 1. - 58.
Hartshorne TS, Grialou TL, Parker KR 2005 Autistic-like behavior in CHARGE syndrome. Am J Med Genet A. 133A:257 261 - 59.
Johansson M. Rastam M. Billstedt E. 2006 Autism spectrum disorders and underlying brain pathology in CHARGE association Dev Med Child Neurol.48 40 50 - 60.
Smith I. M. Nichols S. L. Issekutz K. 2005 Behavioral profiles and symptoms of autism in CHARGE syndrome: preliminary Canadian epidemiological data. Am J Med Genet A. 133A:248 256 - 61.
Skuse DH, James RS, Bishop DV 1997 Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. 387 705 708 - 62.
Bianconi SE, Conley SK, Keil MF 2011 Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 155A:2732 2738 - 63.
A(Depil K. Beyl S. Stary-Weinzinger 2011 Timothy mutation disrupts the link between activation and inactivation in Ca(1 protein. J Biol Chem. 286: 31557-31564. - 64.
Klymiuk N. Thirion C. Burkhardt K. 2011 238 tailored pig model of Duchenne muscular dystrophy Reprod Fertil Dev. 24:231 EOF - 65.
Valerio N. Romina M. Paolo C. 2009 Recent advances in neurobiology of Tuberous Sclerosis Complex Brain Dev.31 104 113 - 66.
Bianconi SE, Conley SK, Keil MF 2011 Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. J. 155A:2732 2738 - 67.
Coutinho A. M. Oliveira G. Katz C. 2007 MECP2 coding sequence and 3’UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet.144B:475 483 - 68.
Shibayama A. Cook E. H. Feng J. 2004 MECP2 structural and 3’-UTR variants in schizophrenia, autism and other psychiatricdiseases: a possible association with autism. Am J Med Genet B Neuropsychiatr Genet. 128B:50 53 - 69.
Glessner J. T. Wang K. Cai G. 2009 Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature.459 569 573 - 70.
Szatmari P. Paterson A. D. Zwaigenbaum L. 2007 Mapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat Genet.39 319 328 - 71.
Kim H. G. Kishikawa S. Higgins A. W. 2008 Disruption of neurexin 1 associated with autism spectrum disorder Am J Hum Genet.82 199 207 - 72.
Wisniowiecka K. B. Nesteruk M. Peters S. U. 2010 Intragenic rearrangementsin NRXN1 in three families with autismspectrum disorder, developmental delay, and speech delay. Am J Med Genet B Neuropsychiatr Genet. 153B:983 993 - 73.
Hamdan F. F. Daoud H. Rochefort D. 2010 De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment Am J Hum Genet.87 671 678 - 74.
Casey J. P. Magalhaes T. Conroy J. M. 2011 Regan RA novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet.131 565 579 - 75.
Kent L. Bowdin S. Kirby G. A. 2008 Beckwith Weidemann syndrome: a behavioral phenotype-genotype study.Am J Med Genet B Neuropsychiatr Genet. 147B:1295 1297 - 76.
MJ Descheemaeker Govers. V. Vermeulen P. J. 2006 Pervasive developmental disorders in Prader-Willi syndrome: the Leuven experience in 59 subjects and controls. Am J Med Genet A.140 1136 1142 - 77.
Veltman MW, Thompson RJ, Roberts SE 2004 Prader-Willi Syndrome-a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders. Eur Child Adolesc Psychiatry.13 42 50 - 78.
Hogart A. Wu D. Lasalle J. M. 2010 The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13 Neurobiol Dis.38 181 191 - 79.
Gauthier J. Champagne N. Lafrenière R. G. 2010 De novo mutations in the gene Encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci.107 7863 7868 - 80.
Cook EH, Scherer SW 2008 Copynumber variations associated with neuropsychiatric conditions. Nature.16 919 923 - 81.
Sebat J. Lakshmi B. Malhotra D. 2007 Strong association of de novo copy number mutations with autism. Science.316 445 449 - 82.
Marshall C. R. Noor A. Vincent J. B. 2008 Structural variation of chromosomes in autism spectrum disorder Am J Hum Genet.82 477 488 - 83.
Morrow EM, Yoo SY, Flavell SW 2008 Identifying autism loci and genes by tracing recent shared ancestry 321 218 223 - 84.
Szatmari P. Paterson A. D. Zwaigenbaum L. 2007 Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet.39 319 328 - 85.
Weiss L. A. Shen Y. Korn J. M. 2008 Association between microdeletion and microduplication at 16 N Engl J Med. 358: 667-675.11 2 and autism - 86.
Kumar R. A. Kara Mohamed. S. Sudi J. 2008 Recurrent 16 Hum Mol Genet. 17: 628-638.11 2 microdeletions in autism - 87.
Berkel S. Marshall C. R. Weiss B. 2010 Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.Nature Genetics.42 489 491 - 88.
Durand C. M. Betancur C. Boeckers T. M. 2007 Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. 39 25 27 - 89.
Pinto D. Pagnamenta A. T. Klei L. 2010 Functional impact of global rare copy number variation in autism spectrum disorder. Nature.466 368 372 - 90.
Noor A. Whibley A. Marshall C. R. 2010 Disruption 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, Bear MF(2011 Mutations causing syndromic autism define an axis of synaptic pathophysiology. 480 63 68 - 92.
Evans TL, Blice-Baum AC, Mihailescu MR 2012 Analysis of the Fragile X mental retardation protein isoforms 1, 2 and 3 interactions with the G-quadruplex forming semaphorin 3F mRNA Mol Biosyst.8 642 649 - 93.
Noh J. S. Sharma R. P. Veldic M. 2005 DNA methyltransferase1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci USA.102 1749 1754 - 94.
Grayson D. R. Chen Y. Costa E. 2006 The human reelin gene: Transcription factors (t), repressors (2) and the methylation switch(t/2) in schizophrenia. Pharmacol. Ther.111 272 286 - 95.
Sato N. Fukushima N. Chang R. 2006 Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers.Gastroenterology.30 548 565 - 96.
Serajee F. J. Zhong H. Mahbubul A. H. 2006 Association of Reelin gene polymorphisms with autism 87 75 83 - 97.
Numachi Y. Yoshida S. Yamashita M. 2004 Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain. Ann. NY Acad Sci.1025 102 109 - 98.
Huang CH, Chen CH. 2006 Absence of association of a polymorphic GGC repeat at the 50 untranslated region of the reelin gene with schizophrenia. Psychiatry Res.142 89 92 - 99.
Skaar D. A. Shao Y. Haines J. L. 2005 Analysis of the RELN gene as a genetic risk factor for autism. Mol. Psychiatry.10 563 571 - 100.
Li J. Nguyen L. Gleason C. 2004 Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Am J Med Genet B Neuropsychiatr. Genet.126 51 57 - 101.
Bonora E. Beyer K. S. Lamb J. A. 2003 Analysis of reelin as a candidate gene for autism. Mol. Psychiatry.8 885 892 - 102.
Lee S. Walker C. L. Karten B. 2005 Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth Hum Mol Genet.14 627 637 - 103.
Kashiwagi A. Meguro M. Hoshiya H. 2003 Predominant maternal expression of the mouse Atp10c in hippocampus and olfactory bulb. Hum Genet.48 194 198 - 104.
Draganov D. I. Teiber J. F. Speelman A. 2005 Human paraoxonases (PON1, PON2 and PON3) are lactonases with overlapping and distinct substrate specificities. Lipid Res.46 1239 1247 - 105.
Terry-Lorenzo R. T. Roadcap D. W. Otsuka T. 2005 Neurabin/protein phosphatase-1 complex regulates dendritic spine morphogenesis and maturation. Mol Biol Cell.16 2349 2362 - 106.
Croen LA, Grether JK, Yoshida CK 2005 Maternal autoimmune diseases, asthma, and allergies, and childhood autism spectrum disorders. Arch Pediatr Adolesc Med.159 151 157 - 107.
Braunschweig D. Ashwood P. Krakowiak P. 2008 Autism: maternally derived antibodies specific for fetal brain proteins 29 226 231 - 108.
Singer HS, Morris CM, Gause CD 2008 Antibodies against fetal brain in sera of others with autistic children. Neuroimmunol.194 165 172 - 109.
Shen C. Zhao X. L. Zhong N. 2010 A 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.43 443 452 - 110.
Glessner J. T. Wang K. Cai G. 2009 Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 459 569 573 - 111.
Sakai Y. CA Shaw Dawson. B. C. 2011 Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 3:86ra49 EOF - 112.
Voineagu I. Wang X. Johnston P. 2011 Transcriptomic analysis of autistic brain reveals convergent molecular pathology. 474 380 384