Study of the Genetic Factors Involved in Autism and Related Disorders

Overview

The main objective of the study is to define, for Autism Spectrum Disorder, the extent of genetic variation in synaptic pathways that may be targeted for therapeutic development. For this purpose the investigators will take advantage of large, well-characterized cohorts of patients with Autism Spectrum Disorder for genetic screenings. Targeted sequencing of selected synaptic genes, previously associated with Autism Spectrum Disorder, will be carried out in these cohorts with deep coverage of coding regions and a strong focus on previously untested regulatory regions. Genomic data from Copy Number Variant, whole genome sequencing and exome sequencing, available for some of these patients, will be integrated in the overall analysis. The investigators will strongly emphasize the establishment of comprehensive genotype/phenotype correlations.

Detailed description

Aim 1: To identify genetic variants in selected synaptic genes, by targeted sequencing with deep coverage of coding regions and a strong focus on previously untested regulatory regions in Autism Spectrum Disorder

Aim 2: To define the range of clinical phenotypes caused by mutations in synaptic genes by establishing detailed genotype/phenotype correlations and analyzing segregation in families with multiple individuals affected by Autism Spectrum Disorder, Autism Spectrum Disorder traits or other neuropsychiatric disorders

Aim 3: To identify the neuronal phenotypes caused by deleterious synaptic mutations for further translational studies

Interventions

• Genetic DNA from subjects will be stored in the biobank of our study.
  Diagnostic Interview-Revised (ADI-R) criteria for autism and Autism Diagnostic Observation Schedule (ADOS-G) criteria for autism or Autism Spectrum Disorders.

Primary outcome measures

• Prevalence of synaptic gene deleterious mutations in patients with Autism Spectrum Disorder [Time frame: up to 12 months after completion of the inclusion and molecular explorations]

Secondary outcome measures (1)

• Prevalence of the deleterious mutations in the major biological pathways in Autism Spectrum Disorder [Time frame: up to 12 months after completion of the inclusion and molecular explorations]

Eligibility criteria

Inclusion Criteria---------------------------------------------------------------------------------------------------

Probands with Autism Spectrum Disorder

• Meet the diagnostic criteria for ASD of the DSM-5 \[American Psychiatric Association, 2013\] based on a consensus between the clinical expertise of expert clinicians, the scores of the Autism Diagnostic Interview-Revised (ADI-R) (Rutter et al, 2003) and those of the Autism Diagnosis Observation Schedule (ADOS-2) (Lord et al, 2012)
• Be at least 24 months (no upper age limit)
• Somatic and Intellectual state compatible with a blood test
• Affiliation to the social insurance
• Signature of informed consent by the applicant or by holders of parental authority if the subject is a minor or by the guardian if the subject is under guardianship

Controls without ASD

• At least 24 months old
• Somatic and Intellectual state compatible with a blood test
• Affiliation to the social insurance
• 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

• At least 24 months old
• Somatic and Intellectual state compatible with a blood test
• Affiliation to the social insurance
• 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

Exclusion Criteria --------------------------------------------------------------------------------------------------

Probands with Autism Spectrum Disorder

• Severe Intelectual Deficiency (IQ,35 or developmental age <18 months)

●. Personal psychiatric history (schizophrenia, bipolar disorder, substance use disorder (except tobacco), recurrent depression disorder, severe instable anxiety disorder)

• Personal neurologic history (epilepsy, or severe neurological disease)

Relatives of the probands with ASD, of the controls or the controls:

● Medical condition (psychiatric or somatic) not compatible with the inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

France · 6 centers

• Centre de rehabilitation psychosociale, Hopital Saint Egreve — Grenoble
• CIC, CHU Bordeaux — Bordeaux
• CRA, Hopital Charles Perrens, Bordeaux — Bordeaux
• CIC, H. Mondor, Creteil — Créteil
• Albert Chenevier Hospital — Créteil
• Robert Debré Hospital — Paris

Publications

• Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T. Progress toward treatments for synaptic defects in autism. Nat Med. 2013 Jun;19(6):685-94. doi: 10.1038/nm.3193. Epub 2013 Jun 6. PMID 23744158

Identifiers

NCT: NCT04727489 · C16-89

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗