Adult Phenotype of CHD2-Associated Disorders

Marlene Rong; Quratulain Zulfiqar Ali; Angel Aledo-Serrano; Allan Bayat; Orrin Devinsky; Farah Qaiser; Ilakkiah Chandran; Anum Ali; Alfonso Fasano; Anne S Bassett; Danielle M Andrade

doi:10.1212/NXG.0000000000200194

Adult Phenotype of CHD2-Associated Disorders

Neurol Genet. 2024 Nov 25;10(6):e200194. doi: 10.1212/NXG.0000000000200194. eCollection 2024 Dec.

Affiliation

¹ From the Institute of Medical Science (M.R.), University of Toronto; Adult Genetic Epilepsy (AGE) Program (M.R., Q.Z.A., F.Q., I.C., A.A., D.M.A.), Krembil Neurosciences Institute, Toronto Western Hospital, University Health Network, Canada; Epilepsy Unit (A.A.-S.), Vithas Clinical Neuroscience Institute, Vithas Madrid University Hospitals; Faculty of Experimental Sciences (A.A.-S.), Francisco de Vitoria University, Madrid, Spain; Department of Drug Design and Pharmacology (A.B.), University of Copenhagen; Department for Genetics and Personalized Medicine (A.B.), Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (A.B.), University of Southern Denmark, Odense; NYU Langone Epilepsy Center (O.D., F.Q., A.A.); Edmond J. Safra Program in Parkinson's Disease (A.F.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN; Division of Neurology (A.F., D.M.A.), Department of Medicine, University of Toronto; Krembil Brain Institute (A.F., D.M.A.); Clinical Genetics Research Program (A.S.B.), Centre for Addiction and Mental Health; The Dalglish Family 22q Clinic (A.S.B.), Toronto General Hospital, University Health Network; Department of Psychiatry (A.S.B.), University of Toronto, Ontario; Toronto Congenital Cardiac Centre for Adults (A.S.B.), Division of Cardiology, Department of Medicine, and Department of Psychiatry, University Health Network and Toronto General Hospital Research Institute and Campbell Family Mental Health Research Institute (A.S.B.), Toronto, Ontario, Canada.

Abstract

Background and objectives: Pathogenic CHD2 variants are associated with neurodevelopmental disorders and developmental and epileptic encephalopathy. While pediatric CHD2 phenotypes have been readily explored, adult phenotypes are not well understood. We aimed to investigate the phenotypic spectrum of adult patients with CHD2 variants.

Methods: Patients 18 years or older with likely pathogenic or pathogenic (LP/P) CHD2 variants were included. We used standardized tools to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder, and adaptive behavioral skills of patients.

Results: In this prospective study, 14 unrelated adult patients (age range: 18-45 years, median: 21 years) with LP/P CHD2 variants were described. Eleven novel variants were identified. No genotype-phenotype correlations were identified. 79% of adults still have ongoing seizures. Photosensitivity was present in 64% of adult patients. Autism spectrum disorder was diagnosed in 71% of patients. Only 29% were able to read and understand material at a sixth-grade level or higher. Behavioral issues were reported in 100% of adult patients, and 71% had internalizing features, such as anxiety. Self-injurious behaviors were present in 50%. Only 43% could ambulate independently. Additional characteristics included reflux (36%), constipation (71%), and abnormal pain responsiveness (43%). 1 patient presented with nonepileptic breath-holding spells leading to cyanosis. No patient could perform all basic activities of daily living independently, all the time. Higher seizure severity was associated with worse nonseizure outcomes (p = 0.04).

Discussion: Most adults with CHD2 continue to have seizures, and seizure severity is associated with worse comorbidities such as maladaptive behaviors, gait, gastrointestinal, sleep, and abnormal pain responsiveness. Longevity has not been systematically studied in this group of patients. Here we describe a group of adult patients (up to 45 years of age) and the natural history of this condition. These data may provide prognostic insights for families of pediatric patients and help identify key points to be addressed in future precision trials for patients with CHD2 variants.