The Phenotypic and Genotypic Spectrum of Epilepsy and Intellectual Disability in Adults: Implications for Genetic Testing
Abstract number :
1.381
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204237
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Sophie von Brauchitsch, MD – University Hospital, Goethe-University Frankfurt, Germany; Denise Haslinger, PhD – Goethe-University Frankfurt; Silvia Lindlar, - – Goethe-University Frankfurt; Natalie Bernsen, - – Goethe-University Frankfurt; Felix Zahnert, MD – Philipps University Marburg; Philipp Reif, MD – Goethe-University Frankfurt; Yunus Balcik, MD – Goethe-University Frankfurt; Holger Thiele, PhD – University of Cologne; Ping Yee Au, MD, PhD – University of Calgary; Colin Josephson, MD, MSc – University of Calgary; Janine Altmüller, PhD – Universitätsmedizin Berlin; Adam Strzelczyk, MD, MHBA – Goethe University Frankfurt; Susanne Knake, MD – Philipps-University Marburg; Felix Rosenow, MD, MHBA – Goethe-University Frankfurt; Andreas Chiocchetti, PhD – Goethe-University Frankfurt; Karl Martin Klein, MD, PhD – University of Calgary
Rationale: Adult patients with epilepsy and intellectual disability (ID) may include grown-up patients with developmental and epileptic encephalopathy (DEE) but also patients with ID and later onset of epilepsy. Particularly, the relative contribution of the latter group and its implications for genetic testing has not been clearly delineated yet. Therefore, we aimed to clarify the phenotypic and genotypic spectrum of adult patients with epilepsy and ID and inform the genetic testing approach in this patient cohort.
Methods: Out of 1413 patients with epilepsy recruited for genetic research at two level 4 epilepsy centers in Germany, 52 adult patients (30 male, 22 female) with at least mild ID and no known genetic or acquired cause were included and phenotyped. Exome sequencing was performed including available parents and evaluated using multiple strategies. Variants were classified according to ACMG criteria. The identified variants were compared with commercially available gene panels of different size to simulate their diagnostic yield. Cluster analysis of the two features age of onset of epilepsy and developmental delay was performed using k-means clustering. The Silhouette method was used to identify the optimal cluster number.
Results: Median age of the 52 included patients was 27 years (range, 20-57 years) with median seizure onset at 3 years (range, 0-26 years) and developmental delay at 1 year (range, 0-12 years). Likely pathogenic or pathogenic variants were identified in 14/52 patients (27%). The simulated yield of commercial gene panels varied between 7/14 identified variants in small panels (≤144 genes) and 14/14 in large panels (≥1478 genes). The phenotypic features of patients with and without an identified pathogenic variant did not show significant differences. Cluster analysis with the optimal number of 3 clusters identified a cluster with early onset of epilepsy and developmental delay (i.e., DEE, blue in figure), a cluster with early onset of developmental delay but later onset of epilepsy (≥8 years, ID with epilepsy, red in figure) and a third cluster with late onset of developmental delay and variable onset of epilepsy (yellow in figure). Smaller gene panels particularly missed genes in patients with early onset of developmental delay and later onset of epilepsy.
Conclusions: Our data indicate that adult patients with epilepsy and ID are more heterogeneous than pediatric cohorts. They not only include 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.
Funding: The study was supported by the federal state Hessen, Germany, through the LOEWE program.
Genetics