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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of genetic linkage studies for autism have suggested that a susceptibility locus for the disease is located on the long arm of chromosome 7 (7q). An autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q implicated by genetic studies was identified. A novel gene known as "RAY1" (or "FAM4A1") was found to be directly interrupted by the translocation breakpoint. The gene, which was found to be encoded by 16 exons with evidence of alternative splicing, spanned > or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding region mutations are unlikely to be involved in the etiology of autism. Apparent homologues of RAY1 have also been identified in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes share similar splicing patterns, and their predicted protein products are 98% identical.
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PMID:Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. 1088 44

Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. We identified a male patient with GTS and other anomalies. It was determined that he carried a de novo duplication of the long arm of chromosome 7 [46,XY,dup(7)(q22.1-q31.1)]. Further molecular analysis revealed that the duplication was inverted. The distal chromosomal breakpoint occurred between the two genetic markers D7S515 and D7S522, which define a region previously shown to be disrupted in a familiar case of GTS. Yeast and bacterial artificial chromosome clones spanning the breakpoints were identified by means of FISH analysis. To further characterize the distal breakpoint for a role in GTS, we performed Southern blot hybridization analysis and identified a 6.5-kb SacI junction fragment in the patient's genomic DNA. The DNA sequence of this fragment revealed two different breaks in 7q31 within a region of approximately 500 kb. IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. The cDNA of the human IMMP2L gene was cloned, and analysis of the complete 1,522-bp transcript revealed that it encompassed six exons spanning 860 kb. The possible role of IMMP2L and several other candidate genes within the region of chromosomal rearrangement, including NRCAM, Leu-Rch Rep, and Reelin, is discussed. The 7q31 breakpoint interval has also been implicated in other neuropsychiatric diseases that demonstrate some clinical overlap with GTS, including autism and speech-language disorder.
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PMID:Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome. 1125 43

Human chromosome 7q31 contains putative susceptibility loci for autism (AUTS1) and speech and language disorder (SPCH1). We report here the identification and characterization of a novel gene encoding cortactin-binding protein-2 (CORTBP2), which is located 45 kb telomeric to the cystic fibrosis transmembrane conductance regulator gene (CFTR) at 7q31.3. The full-length (5975-bp) gene was isolated and found to be composed of 23 exons encompassing 170 kb of DNA. In addition to being a positional candidate for AUTS1, CORTBP2 was expressed at highest levels in the brain, as shown by northern blot analysis. Subsequent mutation analysis of CORTBP2 in 90 autistic patients identified two polymorphisms, including a leucine to valine change caused by a T to G substitution in exon 15. However, comparison of allele frequencies between autistic and control populations (n=96) showed no significant difference, suggesting that this variant is not a susceptibility factor for autism.
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PMID:Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31. 1170 66

We report here the identification and characterization of a novel gene (AUTS2) that spans the 7q11.2 breakpoint in a monozygotic twin pair concordant for autism and a t(7;20) (q11.2; p11.2) translocation. AUTS2 is 1.2 Mb and has 19 exons. The predicted protein is 1295 amino acids and does not correspond to any known protein. DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus no autism-specific mutation was observed. Association analysis with two exonic polymorphic sites and linkage analysis of four dinucleotide repeat markers, two within and two flanking AUTS2, was negative. Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here.
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PMID:Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. 1216 Jul 23

We recently identified a novel gene, RAY1 (FAM4A1), which spans a translocation breakpoint at 7q31 in a patient with autism. This gene has more recently been reported to be a suppressor of tumorigenicity, ST7, although controversy surrounds this observation because subsequent reports have failed to corroborate these findings. Our further analysis of this locus reveals that it is composed of a multigene system that includes two noncoding sense strand genes (ST7OT3 and ST7OT4) that overlap with many alternative forms of the coding RAY1/ST7 transcript, and two noncoding genes on the antisense strand (ST7OT1 and ST7OT2). RAY1/ST7 was determined to have at least three different 5' exons with alternative start codons, one of which seems to be used almost exclusively in the brain. We have also identified a third alternative 3' end of RAY1/ST7 that uses exons from ST7OT3. ST7OT3 spans from intron 10 to exon 14 of RAY1/ST7 and includes several exons. ST7OT4 has at least seven exons and is transcribed on the sense strand between RAY1/ST7 exon 1 and a tropomyosin-like sequence, TPM3L2. ST7OT1 overlaps with the RAY1/ST7 exon 1 and promoter. ST7OT2 spans from RAY1/ST7 intron 9 to intron 1, and has multiple isoforms. We screened the exons of RAY1/ST7 and ST7OT1-3 for sequence variants in 90 unrelated autism probands and identified several rare variants, including a Ile361Val substitution. Although these variants were not observed in a control population, it is unclear whether they contribute to the autistic phenotype. We postulate that the apparent noncoding genes at the RAY1/ST7 locus may be regulatory RNAs. The RAY1/ST7 may generate at least 18 possible isoforms, with many more arising if other sense-strand exons from ST7OT3 and ST7 OT4 are used in a selective and possibly tissue-specific manner.
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PMID:The RAY1/ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript system. 1221 98

Analyses of a 6-Mb region spanning the human leukocyte antigen (HLA) region from the HLA-DR to the HFE gene were performed in 37 families of Sardinian ancestry, all of whom had at least one autistic child, to identify genetic markers associated with autism spectrum disorders (ASD) development. In particular, four microsatellites (MIB, D6S265, MOGc, and D6S2239) and three single-nucleotide polymorphisms (SNPs; two in positions -308 and -238 in the promoter of the TNF-alpha and SNP rs2857766 [V142L] in exon 3 of the MOG gene) were analyzed. An intrafamilial case-control method (affected family-based controls) and transmission disequilibrium test analysis were used to evaluate the association of microsatellite and SNP markers with ASD-affected children. Results indicated positive associations with ASD for D6S265*220 (p < 0.01) and MOGc*131 (p < 0.05) and negative associations for MOGc*117 and MIB*346 alleles (p < 0.01) in ASD children. Polymorphism haplotype analysis indicated that D6S265 allele *220 and MOGc allele *131 were significantly more likely to be transmitted together, as a whole haplotype, to ASD children (p < 0.05). Conversely, the D6S265*224-MOGc*117-rs2857766(G) haplotype was significantly less frequently transmitted to ASD children (p < 0.01). The results present novel gene markers, reinforcing the hypothesis that genetic factors play a pivotal role in the pathogenesis of ASD.
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PMID:Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders. 1916 44

Current genomewide association studies account for only a small fraction of the estimated heritabilities of genetically complex neuropsychiatric disorders, indicating they are likely to result from the small effects of numerous predisposing variants, many of which have gone undetected. The statistical power to detect associations of common variants with small effects is increased by conducting joint association tests of a single nucleotide polymorphism (SNP), an additional risk factor (F), and their interaction. F can represent an environmental exposure, another genotype or any source of genetic heterogeneity. In case and control studies, logistic regression makes joint tests straightforward. This analytic method cannot be employed directly when SNP transmission tests are used to detect associations in parent/affected child trios and multiplex families. However, the method can be implemented using the case/pseudocontrol approach. We applied this approach to analyze data from a genomewide association study of multiplex families ascertained for Autism Spectrum Disorder, where sex was used to define the F. Joint analyses revealed two associations exceeding genomewide significance. One novel gene, Ryandine Receptor 2, implicated in calcium channel defects, was identified with a joint P-value of 3.9E-11. Calcium channel defects have been connected to Autism spectrum disorder (ASD) by Timothy Syndrome, which is Mendelian, and a previous targeted sex-specific association analysis of idiopathic Autism. A second gene, uridine phosphorylase 2, with a joint P-value of 2.3E-9, has been previously linked and associated with Autism in independent samples. These findings highlight two Autism candidate genes for follow-up studies.
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PMID:Allowing for sex differences increases power in a GWAS of multiplex Autism families. 2115 Nov 89

Hematopoietic stem cells (HSCs) are rare quiescent cells that continuously replenish the cellular components of the peripheral blood. Observing that the ataxia-associated gene Ataxin-1-like (Atxn1L) was highly expressed in HSCs, we examined its role in HSC function through in vitro and in vivo assays. Mice lacking Atxn1L had greater numbers of HSCs that regenerated the blood more quickly than their wild-type counterparts. Molecular analyses indicated Atxn1L null HSCs had gene expression changes that regulate a program consistent with their higher level of proliferation, suggesting that Atxn1L is a novel regulator of HSC quiescence. To determine if additional brain-associated genes were candidates for hematologic regulation, we examined genes encoding proteins from autism- and ataxia-associated protein-protein interaction networks for their representation in hematopoietic cell populations. The interactomes were found to be highly enriched for proteins encoded by genes specifically expressed in HSCs relative to their differentiated progeny. Our data suggest a heretofore unappreciated similarity between regulatory modules in the brain and HSCs, offering a new strategy for novel gene discovery in both systems.
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PMID:Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery. 2355 80

Chromosomal rearrangements are a source of structural variation within the genome that figure prominently in human disease, where the importance of translocations and deletions is well recognized. In principle, inversions-reversals in the orientation of DNA sequences within a chromosome-should have similar detrimental potential. However, the study of inversions has been hampered by traditional approaches used for their detection, which are not particularly robust. Even with significant advances in whole genome approaches, changes in the absolute orientation of DNA remain difficult to detect routinely. Consequently, our understanding of inversions is still surprisingly limited, as is our appreciation for their frequency and involvement in human disease. Here, we introduce the directional genomic hybridization methodology of chromatid painting-a whole new way of looking at structural features of the genome-that can be employed with high resolution on a cell-by-cell basis, and demonstrate its basic capabilities for genome-wide discovery and targeted detection of inversions. Bioinformatics enabled development of sequence- and strand-specific directional probe sets, which when coupled with single-stranded hybridization, greatly improved the resolution and ease of inversion detection. We highlight examples of the far-ranging applicability of this cytogenomics-based approach, which include confirmation of the alignment of the human genome database and evidence that individuals themselves share similar sequence directionality, as well as use in comparative and evolutionary studies for any species whose genome has been sequenced. In addition to applications related to basic mechanistic studies, the information obtainable with strand-specific hybridization strategies may ultimately enable novel gene discovery, thereby benefitting the diagnosis and treatment of a variety of human disease states and disorders including cancer, autism, and idiopathic infertility.
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PMID:Directional genomic hybridization for chromosomal inversion discovery and detection. 2357 95

Identifying high-confidence candidate genes that are causative for disease phenotypes, from the large lists of variations produced by high-throughput genomics, can be both time-consuming and costly. The development of novel computational approaches, utilizing existing biological knowledge for the prioritization of such candidate genes, can improve the efficiency and accuracy of the biomedical data analysis. It can also reduce the cost of such studies by avoiding experimental validations of irrelevant candidates. In this study, we address this challenge by proposing a novel gene prioritization approach that ranks promising candidate genes that are likely to be involved in a disease or phenotype under study. This algorithm is based on the modified conditional random field (CRF) model that simultaneously makes use of both gene annotations and gene interactions, while preserving their original representation. We validated our approach on two independent disease benchmark studies by ranking candidate genes using network and feature information. Our results showed both high area under the curve (AUC) value (0.86), and more importantly high partial AUC (pAUC) value (0.1296), and revealed higher accuracy and precision at the top predictions as compared with other well-performed gene prioritization tools, such as Endeavour (AUC-0.82, pAUC-0.083) and PINTA (AUC-0.76, pAUC-0.066). We were able to detect more target genes (9/18/19/27) on top positions (1/5/10/20) compared to Endeavour (3/11/14/23) and PINTA (6/10/13/18). To demonstrate its usability, we applied our method to a case study for the prediction of molecular mechanisms contributing to intellectual disability and autism. Our approach was able to correctly recover genes related to both disorders and provide suggestions for possible additional candidates based on their rankings and functional annotations.
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PMID:Disease gene prioritization using network and feature. 2584 70


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