Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations

The purpose of this study is to determine cross-sectional and longitudinal medical, behavioral, and cognitive differences between PTEN ASD and other groups, as well as to identify cognitive, neural systems, and molecular biomarkers specific to PTEN ASD. In addition, this study will be creating and maintaining a biorepository and linked phenotypic database for PTEN ASD.

Study Overview

• Status: Recruiting
• Conditions: Autism; ASD; Macrocephaly; PTEN; PTEN Hamartoma Tumor Syndrome

Detailed Description

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/interaction impairments and restricted/repetitive behaviors. ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that, may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%). The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies.

Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be asked to participate in this study if they are 18 months and older. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English.

The study involves 3 on site visits over the course of two years. Study visits will vary in length from about 4 hours to 6 hours. Study visits involve a physical exam, medical history questions, neuropsychological assessments, and a blood draw done for laboratory studies. A subset of participants between the ages of 2 and 11 years old will take part in the EEG portion of the study. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.

• Study Type: Observational
• Enrollment (Estimated): 170

Contacts and Locations

• Study Contact: Name: Rajna Filip-Dhima, MS; Phone Number: 617-919-7068; Email: Rajna.Filip-Dhima@childrens.harvard.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California at Los Angeles
      • Principal Investigator: Julian Martinez, MD, PhD
      • Contact: Julian Martinez, MD, PhD; Email: JulianMartinez@mednet.ucla.edu
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University Medical Center
      • Principal Investigator: Antonio Hardan, MD
      • Contact: Robin Libove; Phone Number: 650-736-1235; Email: rlibove@stanford.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Principal Investigator: Mustafa Sahin, MD, PhD
      • Contact: Anna Cronin; Phone Number: 617-919-3499; Email: Anna.Cronin@childrens.harvard.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Adrienne Victory; Phone Number: 513-636-8016; Email: adrienne.victory@cchmc.org
      • Principal Investigator: David Ritter, MD
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Contact: Beth Crouser; Phone Number: 216-445-5850; Email: crouseb2@ccf.org
      • Principal Investigator: Robyn Busch, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

170 patients will be enrolled for this study, over the age of 18 month old.

Description

Inclusion Criteria

• Individuals above the age of 18 months old at the time of consent who have documentation of a clinical diagnosis of autism spectrum disorder and/or a verified PTEN mutation from a medical or mental health professional for inclusion in the PTEN ASD, PTEN no-ASD or ASD macrocephaly groups.
• Macrocephaly (head circumference greater than or equal to 98th percentile) for inclusion in the ASD macrocephaly group.
• For youths, consent from parents or legal guardian. For adults, consent from self or legal guardian.
• Youths who are able (some young or severely impaired participants may not be able to provide assent) will be asked to provide assent as per IRB guidelines.
• Families with multiple children who meet the above inclusion criteria will be permitted to have as many children participate as they wish. A separate consent form will be filled out for each child enrolled in the study.
• Primary communicative language must be English

Exclusion Criteria

• Unwilling or unable to comply with study procedures and assessments
• Clinically significant medical disease that would prohibit participation in the study procedures.
• For subjects ELIGIBLE FOR OPTIONAL imaging biomarker assessment: contraindications to 3T MRI scanning, such as metal implants/non-compatible medical devices or medical conditions, including vagus nerve stimulator.
• For subjects ELIGIBLE FOR EEG/ERP biomarker assessment: contraindications to EEG/ERP, such as uncooperative or destructive behaviors preventing lead placement or capture by ERP/VEP equipment. Under age 2 or over 11 at the time of enrollment.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
PTEN ASD; PTEN participants with Autism Spectrum Disorder group
PTEN no ASD; PTEN participants without Autism Spectrum Disorder group
Controls; Healthy control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in verbal abilities at 12 months	Verbal and non-verbal ability will be evaluated using Stanford Binet -5 or Mullen Scales of Early Learning (MSEL) at 12 months	12 months
Change in communication ability at 12 months	Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4).	12 months
Change in communication ability at 12 months	Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 12 months.	12 months
Change in verbal abilities at 24 months	Verbal and non-verbal ability will be evaluated using Stanford Binet 5 or Mullen Scales of Early Learning (MSEL) at 24 months	24 months
Change in visual perception at 12 months	Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 12 months	12 months
Change in working memory at 12 months	Working memory will be evaluated using the Stanford Binet 5 at 12 months	12 months
Change in processing speed at 12 months	Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 12 months	12 months
Change in working memory at 24 months	Working memory will be evaluated using the Stanford Binet 5 at 24 months	24 months
Change in processing speed at 24 months	Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 24 months	24 months
Change in visual perception at 24 months	Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 24 months	24 months
Change in communication ability at 24 months	Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4) at 24 months	24 months
Change in communication ability at 24 months	Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 24 months.	24 months

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH); National Center for Advancing Translational Sciences (NCATS); Office of Rare Diseases (ORD)
• Investigators: Study Chair: Antonio Hardan, MD, Stanford University

Publications and helpful links

General Publications

• Frazier TW, Jaini R, Busch RM, Wolf M, Sadler T, Klaas P, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism. Mol Autism. 2021 Jan 28;12(1):5. doi: 10.1186/s13229-020-00406-6.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: May 11, 2015
• First Submitted That Met QC Criteria: June 1, 2015
• First Posted (Estimated): June 3, 2015

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 24, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: MRI; ASD; Autism; EEG; PTEN; germline heterozygous PTEN mutations; 10q23.3; Macrocephaly; PTEN Hamartoma Tumor Syndrome
• Additional Relevant MeSH Terms: Autism Spectrum Disorder; Musculoskeletal Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Neoplastic Syndromes, Hereditary; Neoplasms, Multiple Primary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neoplasms; Autistic Disorder; Hamartoma; Hamartoma Syndrome, Multiple; Megalencephaly
• Other Study ID Numbers: P00013150; 1U54NS092090-01 (U.S. NIH Grant/Contract)