Subjects

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.

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Additional information

Parental consent was obtained for conducting the study and for showing images from their affected children.

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Acknowledgements

We thank the patients and their families for their participation. We thank the Integragen Society and CNRGH (Centre National de Recherche en Génétique Humaine) for exome analysis in some cases. This work was supported by grants from the Regional Council of Burgundy (PARI) and the FEDER. We also thank the National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), the Heart GO Sequencing Project (HL-103010), and the Rare Disease Initiative Zürich (RADIZ), Clinical Research Priority Program for Rare Diseases of the University of Zurich.

Author information

Author notes

  1. These authors contributed equally: F. Tran Mau-Them, C. Thauvin-Robinet, A. Vitobello.

Affiliations

  1. UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France

    • F. Tran Mau-Them MD
    • , T. Jouan BS
    • , C. Philippe PhD
    • , C. Thauvin-Robinet MD, PhD
    •  & A. Vitobello PhD
  2. INSERM UMR1231 GAD, F-21000, Dijon, France

    • F. Tran Mau-Them MD
    • , L. Duplomb PhD
    • , T. Jouan BS
    • , Y. Duffourd MsC
    • , B. Urteaga MsC
    • , C. Philippe PhD
    • , L. Faivre MD, PhD
    •  & A. Vitobello PhD
  3. Universite Claude Bernard Lyon I, CHU de Lyon, Lyon, France

    • L. Guibaud MD, PhD
  4. Service de Radiologie, Hopital-Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France

    • L. Guibaud MD, PhD
  5. Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France

    • B. Keren MD, PhD
    • , I. Marey MD
    • , F. Mochel MD
    •  & C. Nava MD, PhD
  6. Division of Genetics and Metabolic Phoenix Children’s Hospital, Phoenix, Arizona, USA

    • K. Lindstrom MD
  7. 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

    • F. Mochel MD
  8. Reference Center for Adult Neurometabolic Diseases, Pitie-Salpêtrière University Hospital, Paris, France

    • F. Mochel MD
  9. Department of Genetics, University Medical Center, Utrecht, The Netherlands

    • M. J. van den Boogaard MD, PhD
    • , R. Oegema MD, PhD
    •  & K. van Gassen PhD
  10. 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

    • A. Masurel MD
    • , L. Faivre MD, PhD
    •  & C. Thauvin-Robinet MD, PhD
  11. Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands

    • F. E. Jansen MD
  12. Department of Pediatrics, Division of Medical Genetics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, Los Angeles, California, USA

    • M. Au MBE, MS
    •  & J. M. Graham Jr MD, ScD
  13. Division of Pediatric Neurology, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, California, USA

    • Agnes H. Chen MD
  14. GeneDx, Gaithersburg, Maryland, USA

    • M. Cho ScM, CGC
  15. Genomed Ltd., Moscow, Russia

    • E. Lozier MS
    • , F. Konovalov PhD
    • , A. Sharkov MD
    •  & S. Korostelev MD
  16. Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia

    • A. Sharkov MD
  17. Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA

    • P. Dickson MD
    • , M. Vera MD, PhD
    •  & H. J. Lin MD
  18. Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland

    • A. Begemann MD
    • , M. Zweier PhD
    •  & A. Rauch MD
  19. Division of Pediatric Neurology, Children’s Hospital, Lucerne, Switzerland

    • T. Schmitt-Mechelke MD
  20. Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

    • Julián A. Martínez-Agosto MD, PhD
    •  & S. Nelson MD
  21. Department of Neurosciences and Pediatrics UCSD/Rady Children’s Hospital San Diego, Rady Children’s Institute for Genomic Medicine, San Diego, California, USA

    • J. Friedman MD

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Conflict of interest

The authors declare no conflicts of interest.

Corresponding authors

Correspondence to F. Tran Mau-Them MD or A. Vitobello PhD.

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DOI

https://doi.org/10.1038/s41436-018-0143-0