Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy
Angela Clara-Hwang1, Stefani Stefani1, Tracy Lau1
1From the Department of Neuromuscular Disorders (A.C.-H., T.L., B.A., R.K., R.M., S.E., H.H.); Department of Clinical and Experimental Epilepsy (A.C.-H.), UCL Queen Square Institute of Neurology; The Francis Crick Institute (A.C.-H.), London, United Kingdom; Cyprus Paediatric Neurology Institute (S.S., P.N.), Nicosia, Cyprus; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M. Scala, P.S.), Università Degli Studi di Genova; U.O.C. Genetica Medica (M. Scala, F.Z.), IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Pediatric Psychiatry and Neurology (P.B.), Santobono-Pausilipon Children's Hospital, Naples, Italy; Medical Genetics Unit (F.M.), IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Paediatric Neurology (S.B.), Tbilisi State Medical University, GA; Department of Pediatric Neurology (V.M.S., V.G.), Indira Gandhi Institute of Child Health, Bangalore, India; MediClub Hospital (U.G.), Baku, Azerbaijan; Department of Clinical and Functional Neurology (A.M., A.-L.P., C.B., D.M.V.), University Hospital of Lyon, Pierre-Bénite, France; Division of Pediatric Neurology (A.G., H.P.), Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (J. de Bellescize), University Hospitals of Lyon; Pediatric and Fetal Imaging Department (S.C.), Femme-Mere-Enfant Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, France; Department of Neuropediatrics (A.W.), Jena University Hospital, Jena, Germany; MVZ Mitteldeutscher Praxisverbund Humangenetik GmbH (A.S.), Johannesstr. 147, Erfurt, Germany; Pediatric Neurology Unit (A.R.-P.), Pediatrics Department, Hospital Universitari Germans Trias I Pujol, Universitat Autonoma de Barcelona, Spain; Department of Genetics (N.C., G.L.), Hospices Civils de Lyon, France; NeuroMyoGene Institute (N.C., G.L.), CNRS UMR 5261-INSERM U1315, Claude Bernard Lyon 1 University, France; Hunter Genetics (H.G.), Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia; John Hunter Children's Hospital (J. Brown), Australia; Institute of Medical Genetics (T.F., K.S., A.R.), University of Zurich, Zurich, Switzerland; (A.R.), University Children's Hospital Zurich; University of Zurich Research Priority Program ITINERARE: Innovative Therapies in Rare Diseases, AdaBD: Adaptive Brain Circuits in Development and Learning, Switzerland; Neuroradiology Unit (M. Severino.), IRCCS Giannina Gaslini Institute, Genoa, Italy; University of Nicosia Medical School (P.N.), Nicosia, Cyprus.
Objectives:
To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy.
Background:
CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants.
Results:
We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10).
Discussion:
Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.
