CHD2 – here is what you need to know in 2023

Chromodomain. Today is International CHD2 Awareness Day and we are publishing this blog post in time for our CHD2 webinar where we present the result of a four-week sprint to analyze harmonized clinical data. We also updated our gene page on CHD2, which was long overdue. In addition to becoming a more well-known gene, here are three things to know about CHD2 in 2023.

Figure. Cartoon depicting the function of CHD2. In brief, CHD2 stands for chromodomain DNA helicase binding protein 2, which is involved in chromatin remodeling. DNA is typically tightly packed around histones and therefore inaccessible to transcription. CHD2 is one of the many proteins involved in making DNA accessible for transcription and gene expression [created with BioRender].

CHD2. The CHD2-related neurodevelopmental disorders were identified in 2013. Our contribution from the European side came through the analysis of individuals with SCN1A-negative Dravet Syndrome, and we saw CHD2 variants in two individuals in our first group of individuals who underwent exome sequencing at the Sanger Center. Prior to our discovery, CHD2 was reported as a novel gene for developmental and epileptic encephalopathies by Carvill and collaborators. The inclusion in a Dravet-like cohort emphasizes some of the features that are frequently seen in individuals with CHD2, namely fever-sensitive seizures and photosensitivity. Here are three things to know about CHD2 in 2023.

1 – Family Advocacy. This blog post would not have been written if it weren’t for the Coalition to Cure CHD2 (CCC), the advocacy organization for families affected by CHD2. As with many other genetic epilepsies, family advocacy groups play an important part in connecting the community and propelling projects forward, including Natural History Studies (NHS) like the one we are presenting in our webinar. Typically, the impact that family foundations have to the patient community outweighs what we as academic scientists can do. This is particularly important for Natural History Studies and clinical trial readiness.

2 – Expanding phenotypes. While CHD2-related disorders had initially been reported in Dravet-like epilepsies, the phenotype has expanded. However, it has not expanded in a manner similar to other neurodevelopmental disorders, where a broader and less specific phenotype is identified over time. In contrast, CHD2 has been found to be linked to specific, previously largely unreported seizure types such as atonic-myoclonic-absence seizures (AMA) and new-onset adult presentations. Therefore, the epilepsy history in the CHD2-related epilepsies requires particular attention. Individuals may present with a range of unusual seizure types, prominent photosensitivity, fever sensitivity, and self-induced seizures.

3 – Impact on neurodevelopment. One reason why CHD2 is the “gene that tricked me” is the fact that it was completely unrelated to other epilepsy-related genes and is ubiquitously expressed. However, haploinsufficiency exclusively affects the Central Nervous System. CHD2 is a member of larger gene family and pathogenic variants in CHD1, CHD2, CHD4, CHD7 and CHD8 have been linked to a range of neurological phenotypes, including autism spectrum disorder, intellectual disability and epilepsy. Lamar and Carvill hypothesize in their review that CHD2 haploinsufficiency affects cortical inhibitory interneuron development, potentially resulting in effects on cortical neuronal networks. However, how this more global impairment results in the specific features of CHD2-related disorders remains unclear.

Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.