Dataset Information

Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.

ABSTRACT: Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of <1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), correlated the variants with transcriptional alterations in blood RNAseq data, and performed a case-control association study of the relevant findings in a larger cohort (394 cases and 500 controls). We found 700 differentially methylated CpGs, most of them hypomethylated in the ASD group (83.9%), with cis-acting expression changes at 7.6% of locations. Relevant findings included: (1) hypomethylation caused by rare genetic variants (meSNVs) at six loci (ERMN, USP24, METTL21C, PDE10A, STX16 and DBT) significantly associated with ASD (q-value <0.05); and (2) clustered epimutations associated to transcriptional changes in single-ASD patients (n=4). All meSNVs and clustered epimutations were inherited from unaffected parents. Resequencing of the top candidate genes also revealed a significant load of deleterious mutations affecting ERMN in ASD compared with controls. Our data indicate that inherited methylation alterations detectable in blood DNA, due to either genetic or epigenetic defects, can affect gene expression and contribute to ASD susceptibility most likely in an additive manner, and implicate ERMN as a novel ASD gene.

SUBMITTER: Homs A

PROVIDER: S-EPMC5545709 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.

Homs A A Codina-Solà M M Rodríguez-Santiago B B Villanueva C M CM Monk D D Cuscó I I Pérez-Jurado L A LA

Translational psychiatry 20160712 7

Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of <1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), corre ...[more]

PMID: 27404287

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Project description:Introduction Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes. Multiple intellectual disability (ID) susceptibility genes have been identified in ASDs to date. The trafficking protein particle complex subunit 9 TRAPPC9 (OMIM#611966) in an autosomal recessive intellectual disability (ID) gene associated with not fully penetrant phenotype combining secondary microcephaly, dysmorphic facial features, obesity, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Objectives The aim of this study is to consider TRAPPC9 deficiency in autosomal recessive ID with ASD. Methods We present the observation of two siblings, born to Tunisian consanguineous and healthy parents, followed up for syndromic intellectual disability (ID) associated ASD and microcephaly. A clinical exome sequencing was performed to one child using a Trusight One kit of Illumina. We used sanger sequencing to validate the suspected variant for the other child and to specify the parental segregation. Results A homozygous pathogenic variant in the TRAPPC9 (NM_001160372.4) gene, c.1414C > T (p. Arg472Ter) were identified in one child. Sanger sequencing confirmed the homozygosity profile of this variant for the other child while the parents were both heterozygous carriers. Conclusions Repetitive behaviours, especially hand-flapping, were the mean ASD feature in our patients. The current variant is known in the Tunisian population. It is described to lead to the creation of a premature stop codon and a truncating protein causing a TRAPPC9 deficiency. The impairing neuronal NFkB signalling due to TRAPPC9 deficiency has been suggested to be implicated in ASD. Due to the profound ID seen in both patients, we suggest the classification of ASD related to TRAPPC9 deficiency as “secondary” rather than “primary”. Our results support the implication of TRAPPC9 in secondary ASD and shed the light on the possibility of screening p. Arg472Ter in Tunisian patients with this form of ASD as it is a recurrent mutation in the Tunisian population. Disclosure of Interest None Declared

Project description:Autism is currently considered a multigene disorder with epigenetic influences. To investigate the contribution of DNA methylation to autism spectrum disorders, we have recently completed large-scale methylation profiling by CpG island microarray analysis of lymphoblastoid cell lines (LCL) derived from monozygotic twins discordant for diagnosis of autism and their nonautistic siblings. Methylation profiling revealed many candidate genes differentially methylated between discordant MZ twins as well as between both twins and nonautistic siblings. Bioinformatics analysis of the differentially methylated genes demonstrated enrichment for high level functions including gene transcription, nervous system development, cell death/survival, and other biological processes implicated in autism. The methylation status of two of these candidate genes, BCL-2 and retinoic acid receptor (RAR)-related orphan receptor alpha (RORA), was further confirmed by bisulfite sequencing and methylation-specific PCR, respectively. Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA and BCL-2 proteins in the autistic brain. Our data thus confirm the role of epigenetic regulation of gene expression via differential DNA methylation in idiopathic autism, and furthermore link molecular changes in a peripheral cell model with brain pathobiology in autism. Global methylation profiling was performed on lymphoblastoid cell lines (LCLs) derived from three pairs of male monozygotic twins discordant for diagnosis of autism as determined by the Autism Diagnostic Interview-Revised (ADI-R). As controls, cell lines derived from non-autistic siblings of two pairs of twins were also included in the analyses, in addition to cell lines derived from a set of monozygotic twins unaffected by autism. For all paired analyses, a direct comparison was performed in which the methylation-enriched fractions from two individuals were pooled and hybridized onto the same microarray. In addition, indirect comparisons were performed by co-hybridizing the methylation-enriched (MIRA) fraction with the respective unenriched DNA fraction obtained from the same individual. For each paired analysis (between autistic MZ twins and/or between autistic co-twin and unaffected sibling), a total number of 4 replicates were performed, including direct and indirect comparisons.

Dataset Information

Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.

Publications

Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.

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