Genomic Basis of Neurodevelopmental and Brain Outcomes in Congenital Heart Disease (CHD Brain and Genes)

Genomic Basis of Neurodevelopmental and Brain Outcomes in Congenital Heart Disease

Approximately 400 Congenital heart disease patients will participate in the research study which will include one or more research visits for neurodevelopmental testing, brain MRI, and collection of medical history including previously collected genetic sequencing results. The investigators will explore the association between genetic variants, neurodevelopmental deficits, and brain MRI endophenotype. Analyses will compare groups with and without deleterious de novo mutations.

Study Overview

• Status: Completed
• Conditions: Heart Disease Congenital
• Intervention / Treatment: Other: Exposure of interest: Brain MRI; Other: Exposure of interest: neurodevelopmental assessments

• Study Type: Observational
• Enrollment (Actual): 196

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mt. Sinai
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital Philadelphia
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Congenital heart disease patients aged 8 years and older with prior whole exome sequencing or whole genome sequencing results

Description

Inclusion Criteria:

1. Subjects in whom whole exome sequencing or whole genome sequencing has already been performed, either during the CHD GENES study or, for new centers (Utah or USCF/Stanford), after trios in existing biobanks undergo analysis by whole exome sequencing or whole genome sequencing during the Pediatric Cardiac Genomic Consortium 2 grant cycle
2. Presence of deleterious mutations (damaging de novo mutations or stringently defined deleterious missense mutations) identified on sequencing (Cases) OR absence of such known deleterious mutations (Controls)
3. Males or females, age ≥8 years
4. Diagnosis of congenital heart disease
5. Informed consent obtained

Exclusion Criteria:

1. History of cardiac transplant
2. A cardiac surgical procedure within 6 months of enrollment
3. Known clinical genetic syndrome, characterized as a monogenic condition with an identified gene associated with abnormalities of the brain structure or function, structural heart disease, and potentially other associated features.
4. Presence of CNV known to be clinically pathogenic. Variants will be classified as pathogenic using accepted types of variant evidence (e.g., population data, computational data, functional data, segregation data) as detailed in the American College of Medical Genetics and Genomics " Standards and Guidelines for the interpretation of sequence variants" (Richards et al, GIM 2015).
5. Overwhelming acquired brain injury, such as a major stroke or severe ischemic injury, that would overshadow the effect of a genetic mutation on outcome in the opinion of the center investigator
6. Lack of reading fluency in English or Spanish

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Case/CHD with deleterious mutations; Participants with CHD with damaging de novo mutations or stringently defined deleterious missense mutations) on whole exome sequencing or whole genome sequencing	Other: Exposure of interest: Brain MRI; Brain MRI will be conducted in all participants; Other: Exposure of interest: neurodevelopmental assessments; neurodevelopmental testing will be conducted in all participants.
Control/CHD without deleterious mutations; Participants with CHD without damaging de novo mutations or stringently defined deleterious missense mutations) on whole exome sequencing or whole genome sequencing	Other: Exposure of interest: Brain MRI; Brain MRI will be conducted in all participants; Other: Exposure of interest: neurodevelopmental assessments; neurodevelopmental testing will be conducted in all participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopment and behavioral health assessment	The investigators will compare groups with respect to achievement, IQ, learning disability, specific neuropsychological domains (e.g., memory, attention, executive functions, and visual-spatial/motor integration), adaptive function, behavior, social cognition and symptoms of autism spectrum disorder, and quality of life. The primary study outcome for this aim will be the WRAT4 composite score.	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abnormalities in brain structure and microstructure on MRI	The investigators will compare the groups with respect to measured and derived parameters including, but not limited to, 1) regional volumetric and cortical thickness, 2) regional surface metrics, 3) voxel-based DTI eigenvectors and apparent diffusion coefficient (ADC) values, and resting state principal component analysis	Day 1

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jane Newburger, MD, Boston Children's Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2017
• Primary Completion (Actual): June 29, 2020
• Study Completion (Actual): June 29, 2020

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: February 28, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): August 13, 2020
• Last Update Submitted That Met QC Criteria: August 12, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital
• Other Study ID Numbers: 2016-6315; 5U01HL131003-02 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No