Deep Phenotyping of Loss-of-function GABRB3 Variants in a Cohort of 57 Patients with Neurodevelopmental Disorders and Epilepsy
Abstract number :
3.116
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
405
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Sebastian Oritz, MD – Filadelfia Epilepsy Center
Mary Chebib, PhD – Faculty of Medicine and Health, The University of Sydney
Philip Ahring, PhD – Faculty of Medicine and Health, The University of Sydney
Absalom Nathan, PhD – Western Sydney University
Rikke Møller, MD – Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre
Presenting Author: Cordelia Katharine Lindhard Smidth, BA – Stanford Univeristy
Rationale: Pathogenic variants in the GABRB3 gene, encoding the β-3 subunit of the GABA_A receptor, are associated with a spectrum of epilepsy syndromes, neurodevelopmental disorders, and neuropsychiatric conditions. Variants can be divided into Gain-of-Function (GOF) and Loss-of-Function(LOF), here we present a deep characterization of a large cohort of LOF variants, aiming to identify the phenotypic spectrum in a cohort of 57 patients, 10 of which are novel.
Methods:
Patients with LOF GABRB3 variants were recruited and included through GeneMatcher, patient advocacy groups, international collaborations and literature review. Clinical data were collected on seizure onset and offset, semiology, developmental trajectory, medical history, examination, EEG, and neuroimaging. Additional data on genetic findings, pregnancy, birth, neonatal period, feeding, developmental milestones, behavior, and psychiatric comorbidities were included. EEGs were reviewed by an epileptologist when possible. Developmental and cognitive levels were classified according to DSM-5. Seizure and epilepsy types were classified per the International League Against Epilepsy criteria.
Results:
Inheritance was de novo (n=41), paternal (n=6), maternal (n=5) and unknown (n=5). All patients except one (n=56) exhibited epilepsy, with a mean onset age of 17 months (range: 0.1 months to 12 years). In 42% of patients, fever was an eliciting factor. Intellectual disability was present in 77% of patients, with severity ranging from mild to severe. Seizure freedom was achieved in 35% of cases, with a mean age of seizure offset at 8 years and 5 months. Neurological abnormalities were described in 33% of patients, including cerebral palsy, hypotonia, strabismus, spastic tetraparesis and right hemiplegia. Motor developmental delay was present in 12%, delayed or impaired verbal skills was reported in 53% of cases. Neuropsychiatric features such as ADHD, autism spectrum disorder, anxiety, and aggressive behavior were noted in 47% of patients. MRI scans were pathological in 8 patients; exhibiting cerebral atrophy, gray matter heterotopia, delayed myelination and multifocal white matter hyperintensity.
Conclusions: Deep phenotyping of a cohort of 57 patients carrying LOF variants in the β-3 subunit of the GABA_A receptor, exhibit variability in seizure onset, treatment response and intellectual outcomes. The disparate phenotypical presentation, despite all classified with an electrophysiological LOF characterization, highlight a requisite for further research into underlying biological mechanisms to provide targeted therapeutic strategies.
Funding:
Affiliations:
Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre "Filadelfia", Dianalund, Denmark. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Genetics