Authors :
Presenting Author: Jan Magielski, – Children's Hospital of Philadelphia
Kim Thalwitzer, MD – Heidelberg University Hospital; Julie Xian, BA – Children’s Hospital of Philadelphia; Jillian McKee, MD, PhD – Children's Hospital of Philadelphia; Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia; Elise Brimble, BSc, MSc, MS – Ciitizen Natural History Registry Invitae; Nasha Fitter, BS, MBA – Ciitizen Natural History Registry Invitae; Heather Mefford, MD, PhD – St. Jude Children’s Research Hospital; Rhys Thomas, MRCP – Newcastle University; David Lewis-Smith, MRCP – Newcastle University; Stephanie Prince, MD – Coalition to Cure CHD2; Christina Sanlnocencio, PhD – Coalition to Cure CHD2; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
CHD2 is one of the most prevalent monogenic causes of epileptic encephalopathy. Disease-causing variants in CHD2 are observed in individuals with SCN1A-negative Dravet syndrome and individuals with Doose syndrome (myoclonic atonic epilepsy, MAE). While photosensitivity and atonic-myoclonic-absence seizures have been described as characteristic features of CHD2-related disorders, the phenotypic spectrum is highly variable, and no genotype-phenotype associations have been discovered to date.
Methods: We conducted an analysis of 37 individuals aged one to twenty two years old with
CHD2-related disorders across 97,010 phenotypic annotations. We harmonized longitudinal time-stamped clinical data provided by the Ciitizen® platform, a wholly owned subsidiary of Invitae Corporation, including reconstructed seizure histories, medication strategies, and phenotypes over time. We assessed the landscape of
CHD2-related disorders and contrasted it with clinical features of individuals with a
SCN1A diagnosis (n=55), MAE (n=236), and a broader epilepsy cohort (Pediatric Epilepsy Learning Health System and our local cohort, n=31,966).
Results: The most prevalent features characterizing
CHD2-related disorders are seizures (90%), involuntary movements (84%), abdominal symptoms (73%), and global developmental delay (70%). Over 80% of individuals presented with behavioral features, with hyperactivity and short attention span in 40%. A total of 90% had seizure onset by seven years of age. Generalized seizures were more prevalent (85%) than focal seizures (21%), and motor seizures were observed more frequently (76%) and with an earlier onset than atonic seizures (27%). Levetiracetam, lamotrigine, clobazam, and valproate were the most commonly used ASMs. Median age of genetic diagnosis was six years, and over a half of variants were protein-truncating or frameshift variants. Individuals with
CHD2-related disorders were significantly more likely to present with motor seizures (generalized tonic, bilateral tonic-clonic), EEG with photoparoxysmal response, aggressive behavior, and language impairment when compared to the
SCN1A cohort and the broader epilepsy cohort. Individuals with
CHD2-related disorders were more likely to have bilateral tonic-clonic seizures than individuals with
CHD2-negative MAE.
Conclusions: We mapped the landscape of
CHD2-related disorders and identified clinical features enriched in individuals with
CHD2 disease-causing variants compared to individuals with
SCN1A-positive Dravet syndrome, MAE, and a broader epilepsy population. Further efforts to characterize this group of conditions will remain critical for precision medicine approaches and future clinical trial readiness.
Funding: Children's Hospital of Philadelphia; National Institute of Neurological Disorders and Stroke.