Journal article
De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.
- Tran Mau-Them F UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. frederic.tran-mau-them@u-bourgogne.fr.
- Guibaud L Universite Claude Bernard Lyon I, CHU de Lyon, Lyon, France.
- Duplomb L INSERM UMR1231 GAD, F-21000, Dijon, France.
- Keren B Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.
- Lindstrom K Division of Genetics and Metabolic Phoenix Children's Hospital, Phoenix, Arizona, USA.
- Marey I Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.
- Mochel F Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.
- van den Boogaard MJ Department of Genetics, University Medical Center, Utrecht, The Netherlands.
- Oegema R Department of Genetics, University Medical Center, Utrecht, The Netherlands.
- Nava C Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.
- Masurel A Centre de Reference maladies rares « Anomalies du Developpement et syndrome malformatifs » de l'Est, Centre de Genetique, Hopital d'Enfants, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
- Jouan T UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
- Jansen FE Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
- Au M Department of Pediatrics, Division of Medical Genetics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, Los Angeles, California, USA.
- Chen AH Division of Pediatric Neurology, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, California, USA.
- Cho M GeneDx, Gaithersburg, Maryland, USA.
- Duffourd Y INSERM UMR1231 GAD, F-21000, Dijon, France.
- Lozier E Genomed Ltd., Moscow, Russia.
- Konovalov F Genomed Ltd., Moscow, Russia.
- Sharkov A Genomed Ltd., Moscow, Russia.
- Korostelev S Genomed Ltd., Moscow, Russia.
- Urteaga B INSERM UMR1231 GAD, F-21000, Dijon, France.
- Dickson P Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
- Vera M Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
- Martínez-Agosto JA Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
- Begemann A Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.
- Zweier M Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.
- Schmitt-Mechelke T Division of Pediatric Neurology, Children's Hospital, Lucerne, Switzerland.
- Rauch A Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.
- Philippe C UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
- van Gassen K Department of Genetics, University Medical Center, Utrecht, The Netherlands.
- Nelson S Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
- Graham JM Department of Pediatrics, Division of Medical Genetics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, Los Angeles, California, USA.
- Friedman J Department of Neurosciences and Pediatrics UCSD/Rady Children's Hospital San Diego, Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
- Faivre L INSERM UMR1231 GAD, F-21000, Dijon, France.
- Lin HJ Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
- Thauvin-Robinet C UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
- Vitobello A UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. antonio.vitobello@u-bourgogne.fr.
- 2018-09-01
Published in:
- Genetics in medicine : official journal of the American College of Medical Genetics. - 2019
IRF2BPL
data sharing
developmental epileptic encephalopathies
exome sequencing
Adolescent
Adult
Carrier Proteins
Central Nervous System
Child
Electroencephalography
Epilepsy
Female
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Mutation
Neurodevelopmental Disorders
Nuclear Proteins
Phenotype
Seizures
Whole Exome Sequencing
Young Adult
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1038/s41436-018-0143-0
- PMID 30166628
- Persistent URL
- https://sonar.ch/global/documents/47628
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