Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia (SZ). Whole-genome, high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.
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PMID:Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. 1798 66

The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. The patient's deletion is approximately 320 kb in size and includes only the part of the NRXN1 gene that codes for the neurexin1alpha promoter and initial coding exons. The more downstream neurexin1beta promoter and the region surrounding it are intact. Neurexin1beta has been associated with autism in several recent studies, but this is the first reported patient with loss of only neurexin1alpha and not of neurexin1beta. These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development.
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PMID:A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha. 1805 82

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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PMID:Structural variation of chromosomes in autism spectrum disorder. 1825 27

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by deficits in social communication, absence or delay in language, and stereotyped and repetitive behaviors. Results from genetic studies reveal one pathway associated with susceptibility to ASD, which includes the synaptic cell adhesion molecules NLGN3, NLGN4, and NRXN1 and a postsynaptic scaffolding protein SHANK3. This protein complex is crucial for the maintenance of functional synapses as well as the adequate balance between neuronal excitation and inhibition. Among the factors that could modulate this pathway are the genes controlling circadian rhythms. Indeed, sleep disorders and low melatonin levels are frequently observed in ASD. In this context, an alteration of both this synaptic pathway and the setting of the clock would greatly increase the risk of ASD. In this chapter, I report genetic and neurobiological findings that highlight the major role of synaptic and clock genes in the susceptibility to ASD. On the basis of these lines of evidence, I propose that future studies of ASD should investigate the circadian modulation of synaptic function as a focus for functional analyses and the development of new therapeutic strategies.
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PMID:The possible interplay of synaptic and clock genes in autism spectrum disorders. 1841 24

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.
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PMID:Disruption of the neurexin 1 gene is associated with schizophrenia. 1894 20

Autism spectrum disorders (ASDs) are a clinically complex group of childhood disorders that have firm evidence of an underlying genetic etiology. Many techniques have been used to characterize the genetic bases of ASDs. Linkage studies have identified several replicated susceptibility loci, including 2q24-2q31, 7q, and 17q11-17q21. Association studies and mutation analysis of candidate genes have implicated the synaptic genes NRXN1, NLGN3, NLGN4, SHANK3, and CNTNAP2 in ASDs. Traditional cytogenetic approaches highlight the high frequency of large chromosomal abnormalities (3%-7% of patients), including the most frequently observed maternal 15q11-13 duplications (1%-3% of patients). Newly developed techniques include high-resolution DNA microarray technologies, which have discovered formerly undetectable submicroscopic copy number variants, and genomewide association studies, which allow simultaneous detection of multiple genes associated with ASDs. Although great progress has been made in autism genetics, the molecular bases of most ASDs remains enigmatic.
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PMID:Genetics of autism spectrum disorders. 1934 7

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. 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 approximately 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 x 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 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 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.
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PMID:Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. 1940 57

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.
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PMID:A synaptic trek to autism. 1954 94

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
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PMID:Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. 1955 95

In rodents, a single administration of valproic acid (VPA) in utero leads to developmental delays and lifelong deficits in motor performance, social behavior, and anxiety-like behavior in the offspring. Recently, we have demonstrated that VPA mice show alterations in postnatal growth and development, and deficits in olfactory discrimination and social behavior early in development. Based on behavioral and molecular parallels between VPA rodents and individuals with autism, maternal challenge with VPA has been suggested to be a good animal model of autism. Neuroligins (NLGN) are a family of postsynaptic cell-adhesion molecules that play a role in synaptic maturation through association with their presynaptic partners, the neurexins (NRXN). Both NLGNs and NRXN members have been implicated in genetic studies of autism. In the present study, we examined changes at the level of expression of NLGN and NRXN mRNAs in the adult brain from mice exposed in utero to VPA. Mouse brain tissue was processed using in situ hybridization and analyzed with densitometry to examine expression of three NLGN genes (NLGN1, NLGN2, and NLGN3) and three NRXN genes (NRXN1, NRXN2, and NRXN3). Expression levels of NLGN1, NLGN2, NRXN1, NRXN2, and NRXN3 were observed to be similar in VPA and control mice. NLGN3 mRNA expression was found to be significantly lower in the VPA mice relative to control animals in hippocampal subregions, cornu ammonis (CA1) and dentate gyrus, and somatosensory cortex. This lowered expression may be linked to autistic-like behavioral phenotype observed in the VPA mice.
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PMID:Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. 1960 85


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