AutDB: A gene reference resource for autism research

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Nucleic Acids Research (Impact Factor: 9.11). 12/2008; 37(Database issue):D832-6. DOI: 10.1093/nar/gkn835
Source: PubMed


Recent advances in studies of Autism Spectrum Disorders (ASD) has uncovered many new candidate genes and continues to do so at an accelerated pace. To address the genetic complexity of ASD, we have developed AutDB (, a publicly available web-portal for on-going collection, manual annotation and visualization of genes linked to the disorder. We present a disease-driven database model in AutDB where all genes connected to ASD are collected and classified according to their genetic variation: candidates identified from genetic association studies, rare single gene mutations and genes linked to syndromic autism. Gene entries are richly annotated for their relevance to autism, along with an in-depth view of their molecular functions. The content of AutDB originates entirely from the published scientific literature and is organized to optimize its use by the research community. The main focus of this resource is to provide an up-to-date, annotated list of ASD candidate genes in the form of reference dataset for interrogating molecular mechanisms underlying the disorder. Our model for consolidated knowledge representation in genetically complex disorders could be replicated to study other such disorders.

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Available from: Sharmila Banerjee-Basu,
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    • "CNVs were quality filtered by considering the length of the CNV event (for both algorithms: ERDS and PennCNV) and for microarray data, the number of SNPs embedded on the CNV region and the number of expected SNPs for that given region (Supplemental Fig. 5), histocompatibility regions, and centromeric and telomeric regions were also filtered out as it is common to find nonpathogenic variants there (both algorithms). For pedigree K21, ERDS and PennCNV calls were compared and the union of each pipeline's set of variants was annotated with in-house tools and the ANNOVAR software (Wang et al. 2010) using dbVar (Lappalainen et al. 2013), DGV (MacDonald et al. 2014), ClinVar (Landrum et al. 2014), DECIPHER (Firth et al. 2009), ENCODE (Rosenbloom et al. 2013), and the SFARI Gene database (Basu et al. 2009) and those variants in which >90% of their total length overlapped reciprocally with variants found in controls were ruled out. ERDS-filtered output for pedigrees SSC_12596 and SSC_12605 were annotated with the same software and criteria. "
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    ABSTRACT: Abstract Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations.
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    • "Copy-number alterations in the nephronophthisis 1 gene (NPHP1; NM_000272.3) which is located in the 2q13 region have been associated with ASD [5]-[9]. The genomic region that surrounds NPHP1 is flanked by two inverted low-copy repeats (LCRs), which include 45-kb direct repeats; therefore, deletion or duplication can easily occur in this region via non-allelic homologous recombination, which results in NPHP1 copy-number changes [10]. "
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    ABSTRACT: Autism spectrum disorder is a neurodevelopmental disorder characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors, and restricted interests. It is a complex condition caused by genetic and environmental factors; the high heritability of this disorder supports the presence of a significant genetic contribution. Many studies have suggested that copy-number variants contribute to the etiology of autism spectrum disorder. Recently, copy-number variants of the nephronophthisis 1 gene have been reported in patients with autism spectrum disorder. To the best of our knowledge, only six autism spectrum disorder cases with duplications of the nephronophthisis 1 gene have been reported. These patients exhibited intellectual dysfunction, including verbal dysfunction in one patient, below-average verbal intellectual ability in one patient, and intellectual disability in four patients. In this study, we identified nephronophthisis 1 duplications in two unrelated Japanese patients with autism spectrum disorder using a high-resolution single-nucleotide polymorphism array. This report is the first to describe a nephronophthisis 1 duplication in an autism spectrum disorder patient with an average verbal intelligence quotient and an average performance intelligence quotient. However, the second autism spectrum disorder patient with a nephronophthisis 1 duplication had a below-average performance intelligence quotient. Neither patient exhibited physical dysfunction, motor developmental delay, or neurological abnormalities. This study supports the clinical observation of nephronophthisis 1 duplication in autism spectrum disorder cases and might contribute to our understanding of the clinical phenotype that arises from this duplication.
    Annals of General Psychiatry 08/2014; 13(1):22. DOI:10.1186/s12991-014-0022-2 · 1.40 Impact Factor
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    • "This is consistent with our unpublished observations showing decreased levels of myelin proteins in post mortem prefrontal cortex tissue in other psychiatric disorders, such as schizophrenia, bipolar and major depressive disorder. Furthermore, dysregulation of synaptic proteins may reflect alterations in synaptic density and a comparison with published data confirms the alterations of STX1A, STXBP1 and SYN2 in autism at the mRNA level [43]. In addition, SRM-MS showed an approximate 70% increase in the levels of CKB in the prefrontal cortex with a small non-significant decrease of this protein in the cerebellum. "
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    ABSTRACT: Background Autism is a neurodevelopmental disorder characterized by impaired language, communication and social skills. Although genetic studies have been carried out in this field, none of the genes identified have led to an explanation of the underlying causes. Here, we have investigated molecular alterations by proteomic profiling of post mortem brain samples from autism patients and controls. The analysis focussed on prefrontal cortex and cerebellum as previous studies have found that these two brain regions are structurally and functionally connected, and they have been implicated in autism. Methods Post mortem prefrontal cortex and cerebellum samples from autism patients and matched controls were analysed using selected reaction monitoring mass spectrometry (SRM-MS). The main objective was to identify significantly altered proteins and biological pathways and to compare these across these two brain regions. Results Targeted SRM-MS resulted in identification of altered levels of proteins related to myelination, synaptic vesicle regulation and energy metabolism. This showed decreased levels of the immature astrocyte marker vimentin in both brain regions, suggesting a decrease in astrocyte precursor cells. Also, decreased levels of proteins associated with myelination and increased synaptic and energy-related proteins were found in the prefrontal cortex, indicative of increased synaptic connectivity. Finally, opposite directional changes were found for myelination and synaptic proteins in the cerebellum. Conclusion These findings suggest altered structural and/or functional connectivity in the prefrontal cortex and cerebellum in autism patients, as shown by opposite effects on proteins involved in myelination and synaptic function. Further investigation of these findings could help to increase our understanding of the mechanisms underlying autism relating to brain connectivity, with the ultimate aim of facilitating novel therapeutic approaches.
    Molecular Autism 07/2014; 5(1):41. DOI:10.1186/2040-2392-5-41 · 5.41 Impact Factor
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