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the Phenotypic and Genetic Profile of Patients With Early Onset Schizophrenia Associated With Autism Spectrum Disorder. (GenAuDiss)

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ClinicalTrials.gov Identifier: NCT02565524
Recruitment Status : Recruiting
First Posted : October 1, 2015
Last Update Posted : July 19, 2019
Sponsor:
Information provided by (Responsible Party):
Fondation Lenval

Tracking Information
First Submitted Date  ICMJE July 29, 2015
First Posted Date  ICMJE October 1, 2015
Last Update Posted Date July 19, 2019
Actual Study Start Date  ICMJE May 18, 2014
Estimated Primary Completion Date November 18, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • characterization of the genetic abnormalities associated to Early Onset Schizophrenia phenotypes by performing standard karyotype [ Time Frame: inclusion visit ]
    A standard karyotype at a resolution of 300 to 400 bands per haploid lot. It can diagnose numerical anomalies and certain structural abnormalities such as reciprocal translocations, inversions, deletions. A standard karyotype at a resolution of 300 to 400 bands per haploid lot is established initially. It can diagnose numerical anomalies and certain structural abnormalities such as reciprocal translocations, inversions, deletions Big. The pathological nature of these mutations will be stutied on the gene function and reaches its pattern of expression.
  • characterization of the genetic abnormalities associated to Early Onset Schizophrenia phenotypes by performing search CGG [ Time Frame: inclusion visit ]
    A search of the CGG expansion hypermethylated in the 5 'UTR of the FMR1 gene mutation that causes Fragile X syndrome.
  • characterization of the genetic abnormalities associated to Early Onset Schizophrenia phenotypes by performing whole exome sequencing [ Time Frame: inclusion visit ]
    Whole Exome Sequencing on trio (mother, father and child); This technology has demonstrated its power in recent years to determine the genetic causes of many rare diseases (Ropers, HH., 2012).
Original Primary Outcome Measures  ICMJE
 (submitted: September 29, 2015)
karyotype of genetic abnormalities connected to the phenotype " schizotiste " [ Time Frame: inclusion visit ]
The primary endpoint is based on a number of technical genetic analysis of all subjects. A standard karyotype at a resolution of 300 to 400 bands per haploid lot is established initially. It can diagnose numerical anomalies and certain structural abnormalities such as reciprocal translocations, inversions, deletions Big. The pathological nature of these mutations will be stutied on the gene function and reaches its pattern of expression.
Change History Complete list of historical versions of study NCT02565524 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • Intensity of positive symptoms of schizophrenia [ Time Frame: inclusion visit ]
    Evaluation of the intensity of positive and negative symptoms, general psychopathology and subtypes of schizophrenia by using positive and negative syndrome scale (PANSS)
  • Co-morbid psychiatric diagnosis [ Time Frame: inclusion visit ]
    Evaluation of clinical profile: by using K-SADS-PL scale for DSM IV-TR / DSM-5 co-morbid psychiatric diagnosis of patients and minor siblings and by using MINI assessments for DSM IV-TR / DSM 5 psychiatric diagnosis of parents and major siblings.
  • Evaluation of executive and attentional by the verbal fluency test [ Time Frame: inclusion visit ]
    Evaluation of executive and attentional functions of patients using Trail Making Test (TMT) A and B and verbal fluency;
  • Clinical evaluation of autistic symptoms [ Time Frame: inclusion visit ]
    Clinical evaluation of autistic symptoms by using AQ (Baron-Cohen) in siblings and parents
  • Neurocognitive profile [ Time Frame: inclusion visit ]
    Evaluation of cognitive functioning by Wechsler Intelligence Scale for Children Scale IV (WISC IV).full version in patient and WISC IV abridged version in minor siblings; Wechsler Adult Intelligence Scale-III (WAIS III) in a short form in adult siblings and parents
  • Personality dimensional test [ Time Frame: inclusion visit ]
    Personality dimensional test using computerized version of TCI 226 (Cloninger) in parents
Original Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2015)
  • Intensity of positive symptoms of schizophrenia [ Time Frame: inclusion visit ]
    Clinical and neurocognitive description of the phenotype of "child schizotistes" by: - Evaluation of the intensity of positive symptoms, negative and general psychopathology and subtypes of schizophrenia by positive and negative syndrome scale (PANSS) without by calculating scores of the 3 dimensions of schizophrenia in PANSS: Positive symptoms (7 items of sides 1-7)), negative symptoms (7 items on sides 1 through 7) and general psychopathology (16 sides items in 1 through 7)), based on these scores diagnosis subtype of schizophrenia is established.
  • disorganization by the scale score Difficulty of language and communication [ Time Frame: inclusion visit ]
    Evaluation of the disorganization of the scale score Trouble of Language and Communication A (TLC A).
  • Evaluation of executive and attentional by the verbal fluency test [ Time Frame: inclusion visit ]
    Evaluation of executive and attentional by the verbal fluency test. The response time to the verbal fluency test scores on the Trail Making Test A (TMT A) and TMT B.
  • Evaluation of memory by the working memory test [ Time Frame: inclusion visit ]
    Evaluation of memory by the Trail Making Test A and B (TMT A, TMT B)
  • Clinical evaluation of autistic symptoms by Autism Diagnostic interview R [ Time Frame: inclusion visit ]
    Clinical evaluation of autistic symptoms by Autism Diagnostic interview R (ADI-R)
  • cognitive functioning [ Time Frame: inclusion visit ]
    Evaluation of cognitive functioning by Wechsler Intelligence Scale for Children Scale IV (WISC IV).
  • Conservation of the mutated amino acid [ Time Frame: inclusion visit ]
    A standard karyotype at a resolution of 300 to 400 bands per haploid lot is established initially to evaluate the conservation during evolution of the mutated amino acid (PhyloP scores);
  • nucleotide variation in the protein sequence (standard karyotype) [ Time Frame: inclusion visit ]
    A standard karyotype at a resolution of 300 to 400 bands per haploid lot is established initially to evaluate the prediction of the impact of the nucleotide variation in the protein sequence
  • mutation of DNA on the structure of the protein (standard karyotype) [ Time Frame: inclusion visit ]
    A standard karyotype at a resolution of 300 to 400 bands per haploid lot is established initially to evaluate the prediction of the impact of the mutation on the structure of the protein
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE the Phenotypic and Genetic Profile of Patients With Early Onset Schizophrenia Associated With Autism Spectrum Disorder.
Official Title  ICMJE Exploration and Characterization of the Phenotypic and Genetic Profile of Patients With Early Onset Schizophrenia Associated With Autism Spectrum Disorder and Their First-degree Relatives (GenAuDiss).
Brief 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

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Schizophrenia
  • Dissociative Disorders
Intervention  ICMJE Other: genetic and phenotypic profile
Genetic and phenotypic profile, clinical and neurocognitive assessment for child with Schizophrenia and autism, their parents and brotherhood
Study Arms  ICMJE Experimental: genetic and phenotypic profile
blood sample, clinical and neurocognitive assessment
Intervention: Other: genetic and phenotypic profile
Publications * Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, Poinso F, Bardoni B, Askenazy F, Thümmler S. Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss). BMJ Open. 2018 Jul 5;8(7):e023330. doi: 10.1136/bmjopen-2018-023330.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 29, 2015)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 18, 2020
Estimated Primary Completion Date November 18, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Of the child:

  • ≥ 7 years, <18 (below 7 years the diagnosis of schizophrenia is not possible)
  • Schizophrenia Diagnosis done using the diagnostic tool Kiddie sads
  • Autism Diagnosis done using the diagnostic scale Autism Diagnostic interview (ADI-R)
  • Intelligence quotient (IQ) ≥ 50 at Wechsler Intelligence Scale for Children (WISC) IV abridged version
  • Clinical examination
  • Affiliation to social security
  • Obtaining the authorization of the holders of parental authority

Brothers and sisters:

  • Minor or Major
  • Similarly biological parents
  • Clinical examination
  • Affiliation to social security
  • Obtaining the authorization of the holders of parental authority for minors or informed consent for major

Parents:

  • Biological Parent
  • Clinical examination
  • Affiliation to social security
  • Informed Consent

Exclusion Criteria:

Of the child:

  • Children refusing to participate
  • Children without verbal language

Brothers and sisters:

  • Children refusing to participate
  • Adults protected by law

Parents:

  • Refusing to participate
  • Adults are protected by law
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 7 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Emmanuelle DOR, MD +33(0)4 92 03 03 72 dor.nedonsel@lenval.com
Contact: Olivier BAILET, PhD +33(0)4 92 03 43 94 bailet.o2@chu-nice.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02565524
Other Study ID Numbers  ICMJE 14-HPNCL08
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fondation Lenval
Study Sponsor  ICMJE Fondation Lenval
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Emmanuelle DOR, MD Fondation Lenval
PRS Account Fondation Lenval
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP