De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy
| Autor: | Laurent Guibaud, Kristin Lindstrom, F. Tran Mau-Them, Alice Masurel, John M. Graham, Yannis Duffourd, Renske Oegema, A. A. Sharkov, Markus Zweier, M. J. van den Boogaard, Thibaud Jouan, Ekaterina R. Lozier, Agnes Chen, M. T. Cho, Sergey Korostelev, Laurence Faivre, Henry J. Lin, F. A. Konovalov, Anaïs Begemann, Patricia I. Dickson, Jennifer Friedman, K.L.I. van Gassen, Boris Keren, Laurence Duplomb, C. Thauvin-Robinet, Moin Vera, Isabelle Marey, Margaret G. Au, Christophe Philippe, Thomas Schmitt-Mechelke, Floor E. Jansen, B. Urteaga, Caroline Nava, Stan F. Nelson, Julian A. Martinez-Agosto, Anita Rauch, Fanny Mochel, Antonio Vitobello |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Central Nervous System Male Heterozygote Adolescent data sharing 030105 genetics & heredity Biology developmental epileptic encephalopathies 03 medical and health sciences Epilepsy Young Adult Neurodevelopmental disorder Seizures medicine Transcriptional regulation Humans Genetics(clinical) Child Gene Genetics (clinical) Exome sequencing Genetics Genetic heterogeneity Neurodegeneration High-Throughput Nucleotide Sequencing Nuclear Proteins Electroencephalography Middle Aged medicine.disease 030104 developmental biology Phenotype Neurodevelopmental Disorders Mutation IRF2BPL Female Carrier Proteins exome sequencing Interferon regulatory factors |
| Zdroj: | Genetics in Medicine, 21(4), 1008. Lippincott Williams and Wilkins |
| ISSN: | 1098-3600 |
| Popis: | Purpose: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. Methods: We combined ES analysis and international data sharing. Results: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2–binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. Conclusions: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies. |
| Databáze: | OpenAIRE |
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