Refining the Phenotype and Genotype of CHD2-related Neurodevelopmental Disorders for Clinical Trial Readiness: Insights from 51 caregiver interviews, patient-facing platforms, and a literature review
Abstract number :
2.058
Submission category :
12. Genetics / 12A. Human Studies
Year :
2025
Submission ID :
666
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Emily Bonkowski, ScM, CGC – St. Jude Children's Research Hospital
Edith Fuerte, BSc – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Soham Sengupta, PhD – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Lula Boone, MPH – St. Jude Children's Research Hospital
Melissa Demock, MS – Center for Pediatric Neurological Diseases Research, St. Jude Children's Research Hospital
Esther Yoon, BS – Northwestern University Feinberg School of Medicine
Nitish Chourasia, MD – UTHSC
Heather Mefford, MD, PhD – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Rationale: CHD2-related neurodevelopmental disorders (CHD2-NDD) are characterized by early onset and intractable seizures, global developmental delays, and neuropsychiatric features including autism, ADD/ADHD, and aggressive behaviors. There is no specific treatment available for CHD2-NDD. Clinical trial readiness for genetic disorders like CHD2-NDD requires both a robust and refined understanding genotypic and phenotypic spectra. We interviewed 51 caregivers of individuals with a suspected diagnosis of CHD2-NDD. We then harmonized the data collected with all published cases and all data accessible through patient-facing platforms to evaluate the quality and agreement of the data for future use in clinical trial readiness efforts.
Methods: We conducted one-on-one interviews with caregivers of individuals with a presumed diagnosis of CHD2-NDD. The study team consisted of a geneticist, epileptologist, genetic counselor, MD/PhD trainee, and senior researcher. Genetic test reports were collected. Separately, data was requested from patient-facing platforms RARE-X (N=33), Simons Searchlight (N=18), and Citizen Health (N=40). Only cases that had a verifiable genetic test report within the platform were included. Additionally, a literature review of CHD2-NDD was conducted (N=115). Data was harmonized on common features including seizures, development, neuropsychiatric diagnoses, medications, and other comorbidities. All CHD2 gene variants were reviewed and reassessed with current ACMG criteria and gnomAD (v4.2). Only those with likely pathogenic/pathogenic variants were included in the study for comparison and redundant cases within data sets were removed.
Results: We interviewed 51 families with suspected CHD2-NDD. Of those, 42 participants (19/42 male; age range 2yo to 35yo) could be verified likely pathogenic or pathogenic. Majority of variants were truncating. 85% of participants had seizures, with an average seizure onset of 5.4 yrs. Seizure types included convulsive (n=20, 38%), absence (n=20, 38%), focal (n=7, 17%), myoclonic (n=15, 36%), and photosensitive (17, 40%). Autism spectrum disorder was diagnosed in 25 (60%) participants and suspected in 4 (10%). ADHD and aggressive behavior were present in 16 (38%) and 19 (45%) of participants, respectively. In the patient-facing platforms, the outcomes of interest were recorded as follows: seizures (95-100%), developmental delay (87-100%), autism (48-88%), aggressive behavior (69-75%), and developmental regression (38-48%).
Conclusions: We sought to refine the phenotype and genotype of CHD2-NDD using data collected from caregiver interviews, data in patient-facing platforms, and published cases. Notably, a non-insignificant proportion of presumed CHD2-NDD cases did not have likely pathogenic or pathogenic variants and genetic test reports in patient-facing databases could not be validated. Limitations in using patient-facing databases included incomplete datasets, differences in how outcomes were described or captured, extensive data cleaning requirements, and varying levels of data curation. Broad collaboration on data collection standards are needed to maximize patient community efforts and impact for clinical trial readiness.
Funding: N/A
Genetics