Dataset Information

Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.

ABSTRACT: MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of ?1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.

SUBMITTER: Ishizuka K

PROVIDER: S-EPMC5159472 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.

Ishizuka Kanako K Kimura Hiroki H Yoshimi Akira A Banno Masahiro M Kushima Itaru I Uno Yota Y Okada Takashi T Mori Daisuke D Aleksic Branko B Ozaki Norio N

Nagoya journal of medical science 20161201 4

MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generati ...[more]

PMID: 28008202

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Project description:BackgroundAutism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications) between these two disorders remains unclear.MethodsWe systematically evaluated three lines of evidence: (1) the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3) data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies.ResultsFour of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays.ConclusionsThese findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analyses also suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes be diagnosed as autism spectrum disorder.

Project description:BackgroundRare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.MethodsTo discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.ResultsThrough mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.ConclusionsThe combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.

Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

Dataset Information

Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.

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Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.

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