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.


We combined ES analysis and international data sharing.


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.


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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


  1. 1.

    Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664–685.

  2. 2.

    McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15:304–316.

  3. 3.

    Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–521.

  4. 4.

    Kobayashi Y, Tohyama J, Akiyama T, Magara S, Kawashima H, Akasaka N, et al. Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. Brain Dev. 2017;39:266–270.

  5. 5.

    Weber YG, Biskup S, Helbig KL, Von Spiczak S, Lerche H. The role of genetic testing in epilepsy diagnosis and management. Expert Rev Mol Diagn. 2017;17:739–750.

  6. 6.

    Trump N, McTague A, Brittain H, et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet. 2016;53:310–317.

  7. 7.

    Hardies K, Weckhuysen S, De Jonghe P, Suls A. Lessons learned from gene identification studies in Mendelian epilepsy disorders. Eur J Hum Genet. 2016;24:961–967.

  8. 8.

    Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–438.

  9. 9.

    Lelieveld SH, Wiel L, Venselaar H, Pfundt R, Vriend G, Veltman JA, et al. Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes. Am J Hum Genet. 2017;101:478–484.

  10. 10.

    Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.

  11. 11.

    Niyazov DM, Kahler SG, Frye RE. Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment. Mol Syndromol. 2016;7:122–137.

  12. 12.

    Brocke KS, Neu-Yilik G, Gehring NH, Hentze MW, Kulozik AE. The human intronless melanocortin 4-receptor gene is NMD insensitive. Hum Mol Genet. 2002;11:331–335.

  13. 13.

    Dissen GA, Lomniczi A, Heger S, Neff TL, Ojeda SR. Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology. 2012;153:350–361.

  14. 14.

    Budhidarmo R, Nakatani Y, Day CL. RINGs hold the key to ubiquitin transfer. Trends Biochem Sci. 2012;37:58–65.

  15. 15.

    von Mikecz A, Chen M, Rockel T, Scharf A. The nuclear ubiquitin-proteasome system: visualization of proteasomes, protein aggregates, and proteolysis in the cell nucleus. Methods Mol Biol. 2008;463:191–202.

  16. 16.

    Zheng Q, Huang T, Zhang L, Zhou Y, Luo H, Xu H, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci. 2016;8:303.

  17. 17.

    Fourcade S, Ferrer I, Pujol A. Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: a paradigm for axonal degeneration. Free Radic Biol Med. 2015;88:18–29.

  18. 18.

    Mueller JK, Koch I, Lomniczi A, et al. Transcription of the human EAP1 gene is regulated by upstream components of a puberty-controlling tumor suppressor gene network. Mol Cell Endocrinol. 2012;351:184–198.

  19. 19.

    Stadhouders R, Cico A, Stephen T, et al. Control of developmentally primed erythroid genes by combinatorial co-repressor actions. Nat Commun. 2015;6:8893.

  20. 20.

    Yeung KT, Das S, Zhang J, Lomniczi A, Ojeda SR, Xu CF, et al. A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2. Mol Cell Biol. 2011;31:2287–2298.

Download references


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.


  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


  1. Search for F. Tran Mau-Them MD in:

  2. Search for L. Guibaud MD, PhD in:

  3. Search for L. Duplomb PhD in:

  4. Search for B. Keren MD, PhD in:

  5. Search for K. Lindstrom MD in:

  6. Search for I. Marey MD in:

  7. Search for F. Mochel MD in:

  8. Search for M. J. van den Boogaard MD, PhD in:

  9. Search for R. Oegema MD, PhD in:

  10. Search for C. Nava MD, PhD in:

  11. Search for A. Masurel MD in:

  12. Search for T. Jouan BS in:

  13. Search for F. E. Jansen MD in:

  14. Search for M. Au MBE, MS in:

  15. Search for Agnes H. Chen MD in:

  16. Search for M. Cho ScM, CGC in:

  17. Search for Y. Duffourd MsC in:

  18. Search for E. Lozier MS in:

  19. Search for F. Konovalov PhD in:

  20. Search for A. Sharkov MD in:

  21. Search for S. Korostelev MD in:

  22. Search for B. Urteaga MsC in:

  23. Search for P. Dickson MD in:

  24. Search for M. Vera MD, PhD in:

  25. Search for Julián A. Martínez-Agosto MD, PhD in:

  26. Search for A. Begemann MD in:

  27. Search for M. Zweier PhD in:

  28. Search for T. Schmitt-Mechelke MD in:

  29. Search for A. Rauch MD in:

  30. Search for C. Philippe PhD in:

  31. Search for K. van Gassen PhD in:

  32. Search for S. Nelson MD in:

  33. Search for J. M. Graham Jr MD, ScD in:

  34. Search for J. Friedman MD in:

  35. Search for L. Faivre MD, PhD in:

  36. Search for H. J. Lin MD in:

  37. Search for C. Thauvin-Robinet MD, PhD in:

  38. Search for A. Vitobello PhD in:

Conflict of interest

The authors declare no conflicts of interest.

Corresponding authors

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

Supplementary information

About this article

Publication history