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Introduction: Autism Spectrum Disorder (ASD) is a frequent and complex neurodevelopmental disorder, characterized by impairments in social communication and repetitive behaviors and with a high male to female ratio: ~4:1. Genetic factors, including rare Copy Number Variants (CNVs), have a substantial impact in ASD risk 1, and are associated with specific phenotypic manifestations 2. Recent studies reported that rare inherited CNVs are enriched in mothers of ASD children compared with mothers of controls and are preferentially transmitted from mothers to ASD children suggesting a sex bias in CNV transmission; further, the imbalanced transmission of small pathogenic CNVs from unaffected mothers to their sons with ASD has been described 3, 4. An increased prevalence of autism - like personality traits is found in unaffected relatives of ASD children, suggesting a genetic liability of a broader autism phenotype (BAP) 5. The BAP in parents of autistic children can be assessed by the Social Responsiveness Scale (SRS) 6 and Broad Autism Phenotype Questionnaire (BAPQ) 7 reports . The SRS is 65 - item questionnaire to identify sub - clinical social impairments and interpersonal behaviour in individuals . The BAPQ is a 36 - item questionnaire measures social aloofness, rigid personality, and pragmatic language deficits in both parents and children. MA is supported by the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/52485/2014). Patients and parents were genotyped in the context of the Autism Genome Project (AGP), funded by NIMH, HRB, MRC, Autism Speaks, Hilibrand Foundation, Genome Canada, OGI, CIHR.

Autism Spectrum Disorder (ASD) is a common disorder with an heterogeneous clinical presentation and unclear etiology. Rare, highly penetrant, variants explain approximately 20% of ASD genetic liability, while common genetic factors of low effect, which combine in affected individuals to reach a pathological threshold, have not yet been identified. Epigenetic factors may additionally modulate the effect of genetic variants. ASD overlaps with other Neurodevelopmental Disorders (NDD), both in clinical aspects and in causative genetic variants, frequently rendering specific diagnosis difficult1,5. Here we hypothesize that, while genetic variants overlap in a large extent between NDDs, epigenetic factors may regulate the expression, activity or function of genetic factors, leading to the characteristic phenotypic presentation that differentiates ASD from other NDDs. To test this hypothesis, we addressed the role of epigenetic factors in ASD, focusing on microRNAs (miRNAs). These small noncoding RNA molecules negatively regulate gene expression, influencing many biological processes and, because they are released from pathological tissues to plasma in disease situations, may constitute useful biomarkers. We thus profiled miRNAs in plasma from ASD patients and patients with other NDDs. Projeto Autism Spectrum Disorder in the European Union - ASDEU financiado pela DG-SANCO; FCT

Autism Spectum Disorder (ASD) is an impairment in neurodevelopment that can be recognized in the first years of life. Symptoms are diverse and vary in severity, determining prognosis and influencing the integration in the community. ASD is characterized by difficulties in interpersonal interaction, verbal and nonverbal communication, and by uncommon interests, inappropriate and uncontrolled behaviors, and repetitive activities. Specific and early diagnosis allows early and effective intervention that improves learning, communication and social skills of autistic children.

Patients and parents were genotyped in the context of the Autism Genome Project Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder of high complexity ASD is characterized by impaired social interaction and communication and by stereotyped behaviors, and a high heterogeneity in clinical presentation. It is hypothesized that such complex heterogeneous phenotypic behaviors are associated with genetic factors. To further dissect the complex correlations between phenotype and genotype in ASD, in the current study we used powerful machine learning algorithms, like decision trees, to integrate clinical information from diagnostic instruments like the ADI-R and the ADOS as well as adaptive behavior and cognitive scales (VABS and WISC) with genetic data (Copy Number Variants, CNVs). ASD traits in parents were assessed using specific tools SRS and PSPQ. M. Asif is supported by the Fundação para a Ciência e Tecnologia (Portugal) (SFRH/BD/52485/2014).

Autism Spectrum Disorder (ASD) is a common complex disorder, highly heterogeneous and with unclear etiology. While many different rare variants are known to be etiological factors for ASD, they don’t completely explain the genetic variance in this disorder, and common genetic variants could not, thus far, be identified. The possible contribution of epigenetic factors, such as deregulated miRNAs expression, should be addressed. miRNAs are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs. miRNAs play critical roles in several biological processes, and are associated with human pathology. Recent studies have suggested that miRNAs in plasma and serum might be derived from circulating blood cells under healthy conditions, but might be released from pathological tissues during illness. The strong correlation between circulating and tissue miRNAs indicates that circulating miRNAs might be biomarkers for diseases, including central nervous system disorders. We are currently assessing miRNA profiles in plasma from ASD patients and patients with other neurodevelopmental disabilities (eg. psychomotor developmental delay, intellectual disability, etc).

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Copy Number Variants (CNVs) play an important role in susceptibility to ASD, often mediated by the deletion or duplication of genes involved in synaptic structure and function. Increasing evidence suggests a central role for defects in synaptic structure and function in the pathogenesis of non-syndromic ASD. In this study we tested the hypothesis of an enrichment in CNVs encompassing synaptic transmission genes in ASD This work was supported by the fellowships SFRH/BD/79081/2011 to BO, SFRH/BPD/74739/2010 to ICC and SFRH/BPD/64281/2009 to CC from Fundação para a Ciência e a Tecnologia (FCT; Portugal).

This work was supported by the fellowships SFRH/BD/79081/2011 to BO, SFRH/BPD/74739/2010 to ICC and SFRH/BPD/64281/2009 to CC from Fundação para a Ciência e a Tecnologia (FCT; Portugal). Copy Number Variants (CNVs) play an important role in susceptibility to Autism Spectrum Disorders (ASD), in particular when deleting or duplicating genes involved in synaptic structure and function such as glutamatergic synapse genes. Identifying CNVs of etiologic relevance for ASD that include glutamatergic genes may contribute to the understanding of glutamate-related pathogenic mechanisms in this disorder.