De novo variants in neurodevelopmental disorders with epilepsy

doi:10.1038/s41588-018-0143-7

. 2018 Jul;50(7):1048-1053.

doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.

De novo variants in neurodevelopmental disorders with epilepsy

Henrike O Heyne^{1

2

3

4}, Tarjinder Singh^{5

6}, Hannah Stamberger^{7

8

9}, Rami Abou Jamra¹⁰, Hande Caglayan¹¹, Dana Craiu¹², Peter De Jonghe^{7

8

9}, Renzo Guerrini¹³, Katherine L Helbig¹⁴, Bobby P C Koeleman¹⁵, Jack A Kosmicki^{5

6}, Tarja Linnankivi¹⁶, Patrick May¹⁷, Hiltrud Muhle¹⁸, Rikke S Møller^{19

20}, Bernd A Neubauer²¹, Aarno Palotie⁵, Manuela Pendziwiat¹⁸, Pasquale Striano²², Sha Tang²³, Sitao Wu²³; EuroEPINOMICS RES Consortium; Annapurna Poduri²⁴, Yvonne G Weber²⁵, Sarah Weckhuysen^{7

8

9}, Sanjay M Sisodiya^{26

27}, Mark J Daly^{5

6}, Ingo Helbig^{14

18}, Dennis Lal^{5

6

28}, Johannes R Lemke²⁹

Collaborators, Affiliations

Collaborators

Affiliations

¹ University of Leipzig Hospitals and Clinics, Leipzig, Germany. hheyne@broadinstitute.org.
² Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. hheyne@broadinstitute.org.
³ Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig Hospitals and Clinics, Leipzig, Germany. hheyne@broadinstitute.org.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. hheyne@broadinstitute.org.
⁵ Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁷ Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
⁹ Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁰ University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹¹ Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey.
¹² 'Carol Davila' University of Medicine Bucharest, Department of Clinical Neurosciences (No. 6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
¹³ Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
¹⁴ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁵ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
¹⁸ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
¹⁹ Danish Epilepsy Centre, Dianalund, Denmark.
²⁰ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
²¹ Department of Pediatric Neurology, University Hospital Giessen, Giessen, Germany.
²² Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini' Institute, Genoa, Italy.
²³ Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
²⁴ Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA, USA.
²⁵ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁶ Department of Clinical and Experimental Epilepsy, NIHR, University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK.
²⁷ The Epilepsy Society, Chalfont-St-Peter Bucks, UK.
²⁸ Cologne Center for Genomics (CCG), Cologne, Germany.
²⁹ University of Leipzig Hospitals and Clinics, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.

PMID: 29942082
DOI: 10.1038/s41588-018-0143-7

De novo variants in neurodevelopmental disorders with epilepsy

Henrike O Heyne et al. Nat Genet. 2018 Jul.

. 2018 Jul;50(7):1048-1053.

doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.

Authors

Collaborators

Affiliations

¹ University of Leipzig Hospitals and Clinics, Leipzig, Germany. hheyne@broadinstitute.org.
² Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. hheyne@broadinstitute.org.
³ Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig Hospitals and Clinics, Leipzig, Germany. hheyne@broadinstitute.org.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. hheyne@broadinstitute.org.
⁵ Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁷ Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
⁹ Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁰ University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹¹ Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey.
¹² 'Carol Davila' University of Medicine Bucharest, Department of Clinical Neurosciences (No. 6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
¹³ Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
¹⁴ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁵ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
¹⁸ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
¹⁹ Danish Epilepsy Centre, Dianalund, Denmark.
²⁰ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
²¹ Department of Pediatric Neurology, University Hospital Giessen, Giessen, Germany.
²² Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini' Institute, Genoa, Italy.
²³ Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
²⁴ Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA, USA.
²⁵ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁶ Department of Clinical and Experimental Epilepsy, NIHR, University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK.
²⁷ The Epilepsy Society, Chalfont-St-Peter Bucks, UK.
²⁸ Cologne Center for Genomics (CCG), Cologne, Germany.
²⁹ University of Leipzig Hospitals and Clinics, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.

PMID: 29942082
DOI: 10.1038/s41588-018-0143-7

Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

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De novo variants in neurodevelopmental disorders with epilepsy

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De novo variants in neurodevelopmental disorders with epilepsy

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