NBEA: Developmental disease gene with early generalized epilepsy phenotypes

Maureen S Mulhern¹, Constance Stumpel², Nicholas Stong¹, Han G Brunner^{2

3}, Louise Bier¹, Natalie Lippa¹, James Riviello⁴, Rob P W Rouhl^{5

6

7}, Marlies Kempers⁸, Rolph Pfundt³, Alexander P A Stegmann², Mary K Kukolich⁹, Aida Telegrafi¹⁰, Anna Lehman¹¹; CAUSES study; Elena Lopez-Rangel¹¹, Nada Houcinat^{12

13}, Magalie Barth¹⁴, Nicolette den Hollander¹⁵, Mariette J V Hoffer¹⁵, Sarah Weckhuysen^{16

17

18}; EuroEPINOMICS-RES-MAE working group; Jolien Roovers^{16

17}, Tania Djemie^{16

17

18}, Diana Barca¹⁹, Berten Ceulemans²⁰, Dana Craiu¹⁹, Johannes R Lemke²¹, Christian Korff²², Heather C Mefford²³, Candace T Meyers²³, Zsuzsanna Siegler²⁴, Susan M Hiatt²⁵, Gregory M Cooper²⁵, E Martina Bebin²⁶, Lot Snijders Blok^{3

27}, Hermine E Veenstra-Knol²⁸, Evan H Baugh¹, Eva H Brilstra²⁹, Catharina M L Volker-Touw²⁹, Ellen van Binsbergen²⁹, Anya Revah-Politi¹, Elaine Pereira³⁰, Danielle McBrian⁴, Mathilde Pacault³¹, Bertrand Isidor³¹, Cedric Le Caignec³¹, Brigitte Gilbert-Dussardier^{32

33}, Frederic Bilan^{32

33}, Erin L Heinzen^{1

34}, David B Goldstein¹, Servi J C Stevens², Tristan T Sands^{1

4}

Affiliations

¹ Columbia University Medical Center, Institute for Genomic Medicine, New York, NY.
² Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
³ Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴ Department of Neurology, Columbia University Department of Neurology, New York, NY.
⁵ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
⁶ Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, Maastricht, the Netherlands.
⁷ School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
⁸ Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁹ Cook Children's Hospital, Fort Worth, TX.
¹⁰ GeneDx, Gaithersburg, MD.
¹¹ Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
¹² University of Burgundy-Franche-Comté, UMR1231 GAD, INSERM, Dijon, France.
¹³ Dijon Bourgogne University Hospital Center, Rare Diseases Reference Center "Developmental Anomalies and Informational Syndromes," Genetic Center, FHU-TRANSLAD, Dijon, France.
¹⁴ Department of Biochemistry and Genetics, Angers University Hospital Center, Angers, France.
¹⁵ Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶ Center for Molecular Neurology, VIB, Neurogenetics Group, Antwerp, Belgium.
¹⁷ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹⁸ Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁹ Pediatric Neurology Clinic, Al Obregia Hospital, Carol Davila University of Medicine, Bucharest, Romania.
²⁰ Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
²¹ Institute for Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
²² Pediatric Neurology Unit, Child and Adolescent Department, University Hospitals, Geneva, Switzerland.
²³ Department of Pediatrics, University of Washington, Seattle, WA.
²⁴ Bethesda Children's Hospital, Department of Neurology, Budapest, Hungary.
²⁵ HudsonAlpha Institute for Biotechnology, Huntsville, AL.
²⁶ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
²⁷ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
²⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
²⁹ University Medical Center Utrecht, Department of Genetics, Utrecht, the Netherlands.
³⁰ Division of Clinical Genetics, Department of Pediatrics, New York-Presbyterian Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY.
³¹ Genetics Service, Nantes University Hospital Center, Nantes, France.
³² Genetics Service, Poitiers University Hospital Center, Poitiers, France.
³³ University of Poitiers, EA3808 NEUVACOD, Poitiers, France.
³⁴ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY.

PMID: 30269351
PMCID: PMC6249120
DOI: 10.1002/ana.25350

NBEA: Developmental disease gene with early generalized epilepsy phenotypes

Maureen S Mulhern et al. Ann Neurol. 2018 Nov.

. 2018 Nov;84(5):788-795.

doi: 10.1002/ana.25350. Epub 2018 Oct 25.

Authors

Affiliations

¹ Columbia University Medical Center, Institute for Genomic Medicine, New York, NY.
² Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
³ Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴ Department of Neurology, Columbia University Department of Neurology, New York, NY.
⁵ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
⁶ Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, Maastricht, the Netherlands.
⁷ School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
⁸ Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁹ Cook Children's Hospital, Fort Worth, TX.
¹⁰ GeneDx, Gaithersburg, MD.
¹¹ Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
¹² University of Burgundy-Franche-Comté, UMR1231 GAD, INSERM, Dijon, France.
¹³ Dijon Bourgogne University Hospital Center, Rare Diseases Reference Center "Developmental Anomalies and Informational Syndromes," Genetic Center, FHU-TRANSLAD, Dijon, France.
¹⁴ Department of Biochemistry and Genetics, Angers University Hospital Center, Angers, France.
¹⁵ Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶ Center for Molecular Neurology, VIB, Neurogenetics Group, Antwerp, Belgium.
¹⁷ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹⁸ Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁹ Pediatric Neurology Clinic, Al Obregia Hospital, Carol Davila University of Medicine, Bucharest, Romania.
²⁰ Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
²¹ Institute for Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
²² Pediatric Neurology Unit, Child and Adolescent Department, University Hospitals, Geneva, Switzerland.
²³ Department of Pediatrics, University of Washington, Seattle, WA.
²⁴ Bethesda Children's Hospital, Department of Neurology, Budapest, Hungary.
²⁵ HudsonAlpha Institute for Biotechnology, Huntsville, AL.
²⁶ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
²⁷ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
²⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
²⁹ University Medical Center Utrecht, Department of Genetics, Utrecht, the Netherlands.
³⁰ Division of Clinical Genetics, Department of Pediatrics, New York-Presbyterian Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY.
³¹ Genetics Service, Nantes University Hospital Center, Nantes, France.
³² Genetics Service, Poitiers University Hospital Center, Poitiers, France.
³³ University of Poitiers, EA3808 NEUVACOD, Poitiers, France.
³⁴ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY.

PMID: 30269351
PMCID: PMC6249120
DOI: 10.1002/ana.25350

Abstract

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

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Conflict of interest statement

Potential Conflicts of Interest

There are no potential conflicts of interest relevant to this manuscript.

Figures

**Figure 1:**
Mutational landscape of *NBEA* Domain organization of the NBEA protein is based on Uniprot. Boxes indicate functional domains; beach type PH (BPH), BEACH domain, and WD-40 repeat domains (lined) are shown. The positions of variants described in our cohort are shown above the protein and those described in other cohorts are shown below. Black circles represent nonsense, frameshift, and splice site variants, and light circles represent missense variants. All variants identified in a person with a NDD are represented with circle, and the variant identified in a control individual is represented with a triangle.

See this image and copyright information in PMC

References

1. Wang X, Herberg FW, Laue MM, et al. Neurobeachin: A protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. J Neurosci 2000;20:8551–8565. - PMC - PubMed
1. Barrett S, Beck JC, Bernier R, et al. An autosomal genomic screen for autism. Collaborative linkage study of autism. Am J Med Genet 1999;88:609–615. - PubMed
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NBEA: Developmental disease gene with early generalized epilepsy phenotypes

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NBEA: Developmental disease gene with early generalized epilepsy phenotypes

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Conflict of interest statement

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