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Genet Med. 2018 Aug 31. doi: 10.1038/s41436-018-0143-0. [Epub ahead of print]

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

Author information

1
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. frederic.tran-mau-them@u-bourgogne.fr.
2
INSERM UMR1231 GAD, F-21000, Dijon, France. frederic.tran-mau-them@u-bourgogne.fr.
3
Universite Claude Bernard Lyon I, CHU de Lyon, Lyon, France.
4
Service de Radiologie, Hopital-Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France.
5
INSERM UMR1231 GAD, F-21000, Dijon, France.
6
Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.
7
Division of Genetics and Metabolic Phoenix Children's Hospital, Phoenix, Arizona, USA.
8
Inserm U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epinière, ICM, Paris, France.
9
Reference Center for Adult Neurometabolic Diseases, Pitie-Salpêtrière University Hospital, Paris, France.
10
Department of Genetics, University Medical Center, Utrecht, The Netherlands.
11
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.
12
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
13
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
14
Department of Pediatrics, Division of Medical Genetics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, Los Angeles, California, USA.
15
Division of Pediatric Neurology, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, California, USA.
16
GeneDx, Gaithersburg, Maryland, USA.
17
Genomed Ltd., Moscow, Russia.
18
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia.
19
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
20
Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
21
Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.
22
Division of Pediatric Neurology, Children's Hospital, Lucerne, Switzerland.
23
Department of Neurosciences and Pediatrics UCSD/Rady Children's Hospital San Diego, Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
24
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. antonio.vitobello@u-bourgogne.fr.
25
INSERM UMR1231 GAD, F-21000, Dijon, France. antonio.vitobello@u-bourgogne.fr.

Abstract

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.

KEYWORDS:

IRF2BPL; data sharing; developmental epileptic encephalopathies; exome sequencing

PMID:
30166628
DOI:
10.1038/s41436-018-0143-0

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