A Family Study of Copy Number Variations in Patients With Autism Spectrum Disorder

This 3-year proposal is a family-based cohort study to establish a representative sample of probands with ASD and their parents with well-characterized environmental, clinical phenotypes, endophenotypes, and genetic data to conduct CNV experiments and the genotype-phenotype correlations. Based on our previous findings, probands with CNVs larger than 500kb has been identified and their families will be newly recruit in the present project to reveal the origin of the CNVs and reveal the clinical feature of the families. The significant findings in specific genes will conduct pathway analysis to reveal the etiology in ASD, providing further understanding in the disease.

Study Overview

• Status: Completed
• Conditions: Autism Spectrum Disorder

Detailed Description

Due to its high prevalence, long-term impairment, high genetic component (heritability > 90%), and lack of effective prevention and treatment, ASD has been prioritized for genetic studies. However, despite extensive genetic research, there has been no any conclusive result mainly due to the clinical and genetic heterogeneity of ASD. Given the progress of CNV study in ASD, several challenges remain to be faced with, such as differences in phenotypic definition across different studies; a lack of population norms for CNVs, and a lack of consensus in methods for CNV detection and analysis. In the present study, the large segments of CNV found in ASD probands will be compared with standardized controls from National Center for Genome Medicine (NCGM), Academia Sinica to identify the possible CNVs. The other important issue of CNV research in ASD is to investigate whether the origin of CNVs are inherited or de novo. By collecting the complete background and revealing the CNVs of the parents and siblings, the origin of the CNVs will be uncovered in the present project. The candidate genes from important CNVs will be identified by pathway analysis. Gene expression will be conducted to confirm the pathogenic genes. Notably the present study will help bridge the gap to translate the bench findings to bedside to help early detection of ASD and pave the way developing effective treatment for ASD in the future.

Specific Aims:

With the above-mentioned rationale of this project and limited research budget from NSC, the ultimate goal of this project is to identify the important CNVs to reveal the pathogenic genes for ASD for future translational research in ASD and to prospectively characterize clinical features of ASD individuals with CNV.

The specific aims of this study are as follows,

1. To identify important and pathogenic CNVs by comparing the CNVs and CNPs of the controls provided by NCGM , Academia Sinica;
2. To assess parents and siblings of ASD patients who were found to have ~500 kb CNVs in our previous study using clinical, psychopathological, and social measures for family study and also to conduct CNV analysis in the families to determine the origin of the CNVs;
3. To conduct a follow-up assessments of clinical features, and social and neuropsychological functions of ASD probands with CNV to examine the phenotype changes over time;
4. To study the clinical phenotypes between de novo and inherited groups to reveal the pathogenic CNVs;
5. To conduct pathway analysis of genes involved in the CNVs, and to confirm the pathogenic genes by conducting gene expression analysis;
6. To investigate the associations of clinical phenotypes such as autistic tendency, and social impairments between (1) probands with/without CNVs/controls, and (2) probands/unaffected siblings/controls.

• Study Type: Observational
• Enrollment (Actual): 360

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan
    • National Taiwan Univeristy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Based on our preliminary CNV results of 339 probands, approximately 120 probands had been identified to have CNVs larger than 500kb. In the present project, the parents and siblings of the probands with CNVs larger than 500kb will be recruited (estimated sample size, parents = 200, siblings = 40) and reassess the ~120 probands.

Description

Inclusion Criteria:

1. subjects have a clinical diagnosis of autistic disorder or Asperger disorder defined by the DSM-IV and ICD-10 criteria and ASD defined by the DSM-5, which was made by board-certificated child psychiatrists at the first visit and following visits;
2. their ages range from 3 to 30;
3. subjects have at least one biological parent;
4. both parents are Han Chinese; and
5. subjects and their biological parents consent to participate in this study for complete phenotype assessments and blood withdraw for genetic study.

Exclusion Criteria:

• if they currently meet criteria or have a history of the following condition as defined by DSM-IV: Schizophrenia, Schizoaffective Disorder, or Organic Psychosis.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of autism	Using the Autism Diagnostic Interview-Revised (ADI-R) to assess the developmental and behavioral aspects of autism, including reciprocal social interaction, communication, and repetitive behaviors and stereotyped patterns	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of psychiatric disorders	Using the Schedule for Affective Disorders & Schizophrenia (K-SADS-E) to assess the DSM-IV diagnosis of ADHD and other psychiatric disorders	1 day

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): July 31, 2017
• Study Completion (Actual): July 31, 2017

Study Registration Dates

• First Submitted: August 18, 2014
• First Submitted That Met QC Criteria: August 27, 2014
• First Posted (Estimate): August 29, 2014

Study Record Updates

• Last Update Posted (Actual): September 5, 2021
• Last Update Submitted That Met QC Criteria: September 1, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive
• Other Study ID Numbers: 201403019RINA