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. 2019 Apr;21(4):1008-1014.
doi: 10.1038/s41436-018-0143-0. Epub 2018 Aug 31.

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

F Tran Mau-Them  1   2 , L Guibaud  3   4 , L Duplomb  5 , B Keren  6 , K Lindstrom  7 , I Marey  6 , F Mochel  6   8   9 , M J van den Boogaard  10 , R Oegema  10 , C Nava  6 , A Masurel  11 , T Jouan  12   5 , F E Jansen  13 , M Au  14 , Agnes H Chen  15 , M Cho  16 , Y Duffourd  5 , E Lozier  17 , F Konovalov  17 , A Sharkov  17   18 , S Korostelev  17 , B Urteaga  5 , P Dickson  19 , M Vera  19 , Julián A Martínez-Agosto  20 , A Begemann  21 , M Zweier  21 , T Schmitt-Mechelke  22 , A Rauch  21 , C Philippe  12   5 , K van Gassen  10 , S Nelson  20 , J M Graham Jr  14 , J Friedman  23 , L Faivre  5   11 , H J Lin  19 , C Thauvin-Robinet  12   11 , A Vitobello  24   25
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Free article

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

F Tran Mau-Them et al. Genet Med. 2019 Apr.
Free article

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.

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