The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing.

Autor: von Brauchitsch S; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Haslinger D; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany., Lindlar S; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany., Thiele H; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Bernsen N; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Zahnert F; Epilepsy Center Hessen, Department of Neurology, Philipps University Marburg, Marburg, Germany., Reif PS; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Balcik Y; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Au PYB; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Alberta, Calgary, Canada., Josephson CB; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; O'Brien Institute for Public Health, University of Calgary, Alberta, Calgary, Canada.; Centre for Health Informatics, University of Calgary, Alberta, Calgary, Canada., Altmüller J; Berlin Institute of Health at Charité, Core Facility Genomics, Universitätsmedizin Berlin, Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Strzelczyk A; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Knake S; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.; Epilepsy Center Hessen, Department of Neurology, Philipps University Marburg, Marburg, Germany., Rosenow F; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany., Chiocchetti A; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany., Klein KM; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Alberta, Calgary, Canada.; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.
Jazyk: angličtina
Zdroj: Epilepsia open [Epilepsia Open] 2023 Jun; Vol. 8 (2), pp. 497-508. Date of Electronic Publication: 2023 Mar 17.
DOI: 10.1002/epi4.12719
Abstrakt: Objective: The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach.
Methods: Fifty-two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed.
Results: Median age was 27 years (range 20-57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10).
Significance: Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown-up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.
(© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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