Abstracts

This is a Late Breaking abstract

Rationale: Chromodomain Helicase DNA Binding Protein 2 (CHD2)-related disorders (CHD2-RD) are a group of rare neurodevelopmental disorders caused by pathogenic variants in the gene encoding CHD2, which leads to haploinsufficiency. CHD2 protein is expressed ubiquitously and regulates chromatin remodeling, thereby influencing gene expression. Individuals with CHD2-RD exhibit a wide range of phenotypes, including epilepsy, intellectual and developmental disability, and autistic traits. While some individuals with CHD2-RD live healthy and independent lives, most individuals do not. A better understanding of the lived experience of people with CHD2-RD and their caregivers is necessary to identify appropriate outcome measures, collect relevant natural history data, and design patient-centered endpoints for clinical trials.

Methods: Data were collected from three sources: an extensive online literature review, qualitative interviews with key opinion leaders and caregivers, and an online survey conducted in 2020 of caregivers of individuals diagnosed with CHD2-RD.

Results: A comprehensive literature review indicated epilepsy, developmental delay, and autism spectrum disorder (ASD) or autistic traits were the most frequently reported disease domains (Figure 1A). This was reflected in an observational study of 44 individuals diagnosed with CHD2-RD with a median age of 11 (range: 2.3-28.5) years, with 18 (41%) females. Developmental delay was the second most common initially recognized symptom. Additionally, 24 (~55%) participants reported having a diagnosis of ASD and another 15 (34%) reported having autistic features. Our literature review suggests a broad epilepsy and seizure profile in CHD2-RD (Figure 1B), and this is recapitulated in the observational study which found that 93% of participants are diagnosed with epilepsy (of various seizure types), with a median age of seizure onset being 24 months (regardless of presenting syndrome). The most common seizure types were tonic-clonic (67%), myoclonic (62%), and absence (48%). Specific epilepsy syndromes included Lennox-Gastaut Syndrome (14%), Doose (5%), Jeavons (11%), and ESES/CSWS (13%). Seizures remain poorly controlled amongst most of the sample, as 75% of participants note having a recent seizure (within the past 6 months).

Conclusions: Early-onset seizures, developmental delay, and behavioral difficulties are hallmark symptoms of CHD2-RD. Our results show that the early-onset, refractory seizures and autistic traits reported in the literature are confirmed by caregivers of people with CHD2-RD. As novel treatment approaches and clinical trials form for CHD2-RD, it will be necessary to identify which core domains of disease matter most to patients and caregivers through a formal interview-based conceptual model study. Our current research suggests that primary endpoints for clinical trials for CHD2-RD should include assessments for seizure management, autistic behaviors, and cognition, as well as measures of independence and daily living skills. This information may be utilized in developing meaningful measures of improvement for those with CHD2-RD during clinical trials.

Funding: This study was supported in part by the Coalition to Cure CHD2.