Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome

The purpose of this study is to comprehensively characterize PMS using standardized medical, cognitive, and behavioral measures and to track the natural history of the syndrome using repeated longitudinal assessments. In addition, this study will be aiming to identify biomarkers using neuroimaging, including diffusion tensor imaging and identify genetic factors which contribute to diverse phenotypes in patients with PMS.

Study Overview

• Status: Active, not recruiting
• Conditions: Intellectual Disability; Autism Spectrum Disorder; Phelan-McDermid Syndrome

Detailed Description

Phelan-McDermid syndrome (PMS) or 22q13 Deletion syndrome, caused by a loss of one copy of the SHANK3 gene, is characterized by global developmental delay/intellectual disability, motor skills deficits, delayed or absent speech, and autism spectrum disorder. The goal of this study is to understand more about the PMS phenotype and the biological pathways associated with ID and ASD in the disorder, and to establish the foundation for future clinical trials in PMS and in other ID/ASD-associated disorders that share signaling pathways with PMS.

Individuals with PMS will be asked to participate in this study if they are 18 months or older with pathogenic deletions or mutations of the SHANK3 gene at time of enrollment, as well as healthy controls. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English. Parents and unaffected siblings may also be asked to consent to have blood drawn for analysis.

The study involves 3 on site visits over 2 years. Study visits involve a physical exam, medical history questions, blood work and neuropsychological assessments. 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 (Actual): 207

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

190 subjects with PMS will be enrolled across the 6 sites for this study

Description

Inclusion Criteria:

• Individuals older than 18 months of age with pathogenic deletions or mutations of the SHANK3 gene
• English speaking individuals

Exclusion Criteria:

• Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment
• For subjects involved in 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 involved in 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 age 11 at the time of enrollment.
• Unwilling or unable to comply with study procedures and assessments

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Phelan-McDermid Syndrome

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in global cognitive ability at 12 months	Using Mullen Scales for Early Learning or Stanford Binet-5 to measure global cognitive ability	12 months
Change in adaptive behavior at 12 months	Using Vineland Adaptive Behavior Scales to measure adaptive behavior	12 months
Change in language abilities at 12 months	Using composite of Mullen Subscales, Vineland Subscales and Macarthur Bates Communication Developmental Inventory to measure language	12 months
Change in motor functioning at 12 months	Using composite of Mullen Subscales and Vineland Subscales to measure motor functioning	12 months
Change in autism symptoms at 12 months	Using composite of Autism Diagnostic Observation Schedule and Repetitive Behavior Scales-Revised to measure autism	12 months
Change in global cognitive ability at 24 months	Using Mullen Scales for Early Learning or Stanford Binet-5 to measure global cognitive ability	24 months
Change in adaptive behavior at 24 months	Using Vineland Adaptive Behavior Scales to measure adaptive behavior	24 months
Change is language abilities at 24 months	Using composite of Mullen Subscales, Vineland Subscales and Macarthur Bates Communication Developmental Inventory to measure language	24 months
Change in motor functioning at 24 months	Using composite of Mullen Subscales and Vineland Subscales to measure motor functioning	24 months
Change in autism symptoms at 24 months	Using composite of Autism Diagnostic Observation Schedule and Repetitive Behavior Scales-Revised to measure autism	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); Phelan-McDermid Syndrome Foundation
• Investigators: Study Chair: Alexander Kolevzon, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Bassell J, Srivastava S, Prohl AK, Scherrer B, Kapur K, Filip-Dhima R, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Buxbaum JD, Kolevzon A, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome. Pediatr Neurol. 2020 May;106:24-31. doi: 10.1016/j.pediatrneurol.2020.01.006. Epub 2020 Jan 31.
• Srivastava S, Scherrer B, Prohl AK, Filip-Dhima R, Kapur K, Kolevzon A, Buxbaum JD, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome. Pediatr Neurol. 2019 Jan;90:37-43. doi: 10.1016/j.pediatrneurol.2018.09.008. Epub 2018 Sep 21.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): 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): August 6, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Natural History; ASD; Genotype; EEG; Autism Spectrum Disorder; Intellectual Disability; Phenotype; PMS; Mapping; Phelan-McDermid Syndrome; 22q13 Deletion Syndrome; SHANK3; ID
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Autism Spectrum Disorder; Intellectual Disability; Telomeric 22q13 Monosomy Syndrome
• Other Study ID Numbers: P00013300; 1U54NS092090 (U.S. NIH Grant/Contract)