Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and verbal and non-verbal communication (DSM-5, 2013), affecting approximately 2% of the general population. In 5 to 40% of cases, genetic factors are identified as the cause of these disorders, with prevalence depending on the technique used (exomes and/or SNP arrays) and the associated intellectual deficit. In the majority of cases, the etiology remains unknown. Studies of microdeletions/microduplications (copy number variants) or Whole Exome Sequencing and Whole Genome Sequencing (Single Nucleotide Variants) show the involvement of numerous genes in the predisposition to autism. ASD remains a genetically heterogeneous disorder, as more than 250 genes have been associated with ASD to date.

The main objective of the project is to continue identifying genetic factors, and also to understand the biological mechanisms involved in the emergence of autistic symptoms.

Identifying biological pathways is an essential step in developing new therapeutic strategies. In addition, one of the major challenges of this study is to better understand the phenotype/genotype relationships in ASD. This requires in-depth knowledge of the phenotypic characteristics of participants with ASD and their families, as well as neurotypical populations. This study combines the scientific expertise of researchers specializing in molecular biology, phenotypic exploration (clinical, cognitive, MRI, EEG, biochemistry, immunology), and the use of pre-therapeutic cellular models (iPSCs, neural precursors, organoids).

The objective of this work is the identification of numerous genes associated with ASD and involved in synaptic formation and regulation: NLGN3-4, SHANK1 and SHANK3, CNTN-6, and CNTNAP4. This work was combined with in-depth phenotypic explorations of ASD participants and their relatives. It has made it possible to clarify the neuroanatomical characteristics of participants with ASD and their genetic substrate, as well as the underlying cognitive processes.

All of this work opens up new prospects for identifying new therapeutic targets using preclinical cell models (IPSCs Induced pluripotent stem cells, neural progenitors, organoids) developed in particular by I-Stem and Human Technopole.

• Aim 1 : To clarify the biological mechanisms associated with genetic variations identified in participants with ASD by studying dedifferentiated cells transformed into induced neurons or organoids. This objective will be achieved using a population of individuals with ASD, a population of relatives and a population of controls.
• Aim 2 : To study the cellular mechanisms affected by the presence of abnormalities identified in participants with ASD. The use of pluripotent cells differentiated into neurons or organoids is a major tool for understanding the pathophysiology of cell development and pathways in autism. These derived neurons are an indispensable proxy for the biological understanding of ASD.
• Aim 3 : To identify new therapeutic approaches, by using pluripotent cells and organoids to perform high-throughput screening of pharmacological compounds.

Inclusion Criteria:

● For all participants :

• 1) Be Included in the "Genes and Autism" protocol (C07-33 or C16-89).

• 2) Affiliated to the social insurance, Universal Health Coverage or any equivalent system.

  →As a Reminder : C07-33 inclusion criteria

  ● Participants with ASD.

• 1) Autistic patients must meet the diagnostic criteria of DSM-IV [American Psychiatric Association, 1994] and the criteria of ADI-R (Autism Diagnostic Interview-Revised, Lord et al., 1994) and ADOS for autism.

..Or.. Patients with Asperger's syndrome must meet the DSM-IV criteria as well as the ASDI criteria for Asperger's syndrome (Asperger Syndrome Diagnostic Interview, Gillberg et al., 2001) and the ADOS for autism spectrum disorders.

..Or.. Patients with ASD must meet diagnostic criteria of DSM-IV and ADOS criteria for autism spectrum disorders

• 2) Be at least 2 years old, with no upper age limit

• 3) Somatic state compatible with blood test

  ● Adult controls and adult relatives of controls

• 1) Be between 18 and 65 years old

• 2) Somatic and intellectual state compatible with blood test

  ● Controls with mental retardation

• 1) Minimum age of 2 yearsIQ < 70Child controls

• 2) Minimum age of 2 years

  →As a Reminder : inclusion criteria C16-89

  ● Probands with ASD

• 1) Meet the diagnostic criteria for ASD of the of DSM-5 [American Psychiatric Association, 2012]. The diagnosis will be based on a consensus between the clinical expertise of expert clinicians, the scores of the Autism Diagnostic Interview-Revised (ADI-R) (Lord et al, 2003) and those of the Autism Diagnosis Observational Scale (ADOS-2) (Lord et al, 1994)

• 2) Be at least 24 months old with no upper age limit

• 3) Somatic state compatible with a blood test

• 4) Affiliation to the Social Insurance

• 5) Signature of informed consent by the applicant or by the holders of parental authority if the subject is a minor or by the guardian if the subject is under guardianship

  ● Controls wihout ASD

• 1) At least 24 months old

• 2) Somatic and Intellectual state compatible with a blood test

• 3) Affiliation in the Social Insurance

• 4) Signature of informed consent by the subject or by holders of parental authority if the subject is a minor, or by the guardian if the subject is under guardianship

  ● Relatives of the probands with ASD or of controls without ASD

• 1) At least 24 months old

• 2) Somatic and intellectual state compatible with blood test

• 3) Affiliation to the Social Insurance

• 4) Signature of informed consent by the subject or by the holders of parental authority if the subject is a minor or by the guardian if the subject is under guardianship

Exclusion Criteria:

• For all participants

  • 1) Refusal to have a blood test

  • 2) Medical illness (including psychiatric disorder) not yet fully stabilised and making participation in the study impossible

  • 3) Person subject to a mesure of lagal protection

  • 4) Known serology : VIH+ or VBH+ or VCH+

    • As a reminder : exclusion criteria C07-33

  • 1) For all participants : Severe Intelectual Deficiency (IQ,35 or developmental age <18 months)

  • 2) Controls : Neurological or psychiatric history other than mental retardation

    o Psychiatric history, except for mental retardation, assessed using the DIGS (Diagnostic Interview for Genetic Studies, Nurnberger et al., 1994) for adults or the Kiddie-SADS (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children, Orvaschel et al., 1982)

    o History of epileptic episodes

    o Immunosuppressive treatment or known immunoinflammatory disease

    →As a reminder : exclusion criteria C16-89

  • 1) Probands with Autism Spectrum Disorder

    o Severe intellectual disability (IQ<35 or developmental age <18 months)

  • 2) Controls (neurotypical development)

    o Identified intellectual disorder or cognitive developmental disorder

    • Personal psychiatric history of schizophrenia, bipolar disorder, substance use disorders (except tobacco), recurrent depression (>2 episodes, lifetime), severe unstabilized anxiety disorder
    • History of epilepsy episodes or severe neurological disease

  • 3) Relatives of the TSA applicants or controls

    • Medical condition (psychiatric or somatic) not compatible with inclusion