the Phenotypic and Genetic Profile of Patients With Early Onset Schizophrenia Associated With Autism Spectrum Disorder.
Condition: Schizophrenia; Dissociative Disorders
MeSH terms: Schizophrenia; Autism Spectrum Disorder; Dissociative Disorders; Conversion Disorder
Study type: Interventional

Summary: 
      Early onset schizophrenia "early dissociative disorder" is a rare disorder with a low
      incidence of approximately (1/5000 to 1/20000). Its link with autism spectrum disorders
      remains unknown although both are serious neurodevelopmental diseases. As part of the
      2011-2013 Interregional hospital Clinical Research program, University Department of Child
      and Adolescent Psychiatry Pediatric Hospitals of CHU de Nice Lenval identified patients with
      a complex phenotype characterized by an early schizophrenia associated with autism spectrum
      disorders and developmental disabilities in mild to moderate. This phenotype could be a new
      syndrome.

      The goal of our project is to define the genetic causes of this phenotype. The technique of
      high throughput sequencing will be used to obtain the sequence of exomes of these patients
      and their families. This study will therefore be important to give an accurate diagnosis for
      patients and their families. Moreover, we believe that this project will identify new genes
      involved allowing a better understanding of the pathophysiology. Recent studies show the
      involvement of mutations in several genes (eg NRXN1 and UPF3B) in these different clinical
      phenotypes. However, the genetic basis of the childhood and early onset schizophrenia are
      much less well known than those of autism spectrum disorder
    

Detailed description: 
      Introduction: Early-onset Schizophrenia (EOS) is a rare and severe condition displaying early
      dissociative disorder (i.e., age of onset < 18 years). A higher rate of neurodevelopmental
      abnormalities is observed in EOS compared to adult onset schizophrenia (AOS). Thus, patients
      affected by EOS typically present intellectual, learning, communication or neuromotor
      impairments, as well as attention deficit hyperactivity disorder. Early signs of autism
      spectrum disorders (ASD) are also found in 30% of patients with EOS.

      Cytogenetics abnormalities, including copy number variations (CNVs), are frequent in
      neurodevelopmental disorders and have been linked to ASD physiopathology. Implicated genes
      encode proteins playing a role in brain development, synaptic morphology, plasticity and
      neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS
      and ASD, suggesting that schizophrenia can be considered a neurodevelopmental disorder.

      The main objective of the present study is to identify mutations in genes involved in
      neurodevelopmental pathways in our cohort of patients affected by both EOS and ASD.

      Method and analysis: We describe here a multicenter study in a pediatric population named
      "Exploration and characterization of genetic and phenotypic profile of the 'early
      dissociative disorder' associated with autism spectrum disorder (GenAuDiss)". The study
      started in April 2014. The inclusion criteria are: age 7 to 22 years, diagnoses of EOS with
      co-morbid ASD and IQ > 50; as well as parents and siblings of the included patients.

      We perform standardized psychiatric assessments (MINI, K-SADS-PL, PANSS, SANS, TCI 226, and
      AQ) and neurocognitive evaluations (IQ, TMT A/B, and verbal fluency). Then, we study variants
      of the coding part of the DNA (exome), using next generation sequencing (NGS) process on trio
      (mother, father, and child). Divers bio-informatics tools such as RVIS and PolyPhen-2 will be
      used to prioritize the potential candidate genes. The inclusion period of this study will end
      in November 2019.

      Ethics and dissemination: The study protocol was approved by the Ethics Committee 'Sud
      Méditerrané V' (number 14.002) and by the French National Agency for Medicines and Health
      Products Safety (ANSM 2013-A01699-36). All patients, their parents and siblings signed
      informed consent upon enrolment in the study.

      Results of the present study should help to unravel the molecular pathology of EOS, paving
      the way for an early therapeutic intervention
    

Intervention name(s): genetic and phenotypic profile
Intervention type(s): Other
Intervention description(s): Genetic and phenotypic profile, clinical and neurocognitive assessment for child with Schizophrenia and autism, their parents and brotherhood
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: schizophrenia; early dissociative disorder; genetic