Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition-Reference-Cited by-同舟云学术

Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

Published:2023-04-03 Issue:9 Volume:146 Page:3885-3897
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Martins Custodio Helena¹²,Clayton Lisa M¹²,Bellampalli Ravishankara¹²,Pagni Susanna¹²,Silvennoinen Katri¹²³^ORCID,Caswell Richard⁴^ORCID,Ambrose John C,Arumugam Prabhu,Bevers Roel,Bleda Marta,Boardman-Pretty Freya,Boustred Christopher R,Brittain Helen,Brown Matthew A,Caulfield Mark J,Chan Georgia C,Giess Adam,Griffin John N,Hamblin Angela,Henderson Shirley,Hubbard Tim J P,Jackson Rob,Jones Louise J,Kasperaviciute Dalia,Kayikci Melis,Kousathanas Athanasios,Lahnstein Lea,Lakey Anna,Leigh Sarah E A,Leong Ivonne U S,Lopez Javier F,Maleady-Crowe Fiona,McEntagart Meriel,Minneci Federico,Mitchell Jonathan,Moutsianas Loukas,Mueller Michael,Murugaesu Nirupa,Need Anna C,O'Donovan Peter,Odhams Chris A,Patch Christine,Perez-Gil Daniel,Pereira Marina B,Pullinger John,Rahim Tahrima,Rendon Augusto,Rogers Tim,Savage Kevin,Sawant Kushmita,Scott Richard H,Siddiq Afshan,Sieghart Alexander,Smith Samuel C,Sosinsky Alona,Stuckey Alexander,Tanguy Mélanie,Tavares Ana Lisa Taylor,Thomas Ellen R A,Thompson Simon R,Tucci Arianna,Welland Matthew J,Williams Eleanor,Witkowska Katarzyna,Wood Suzanne M,Zarowiecki Magdalena,Brunklaus Andreas⁵⁶^ORCID,Guerrini Renzo⁷,Koeleman Bobby P C⁸,Lemke Johannes R⁹¹⁰^ORCID,Møller Rikke S¹¹¹²,Scheffer Ingrid E¹³¹⁴^ORCID,Weckhuysen Sarah¹⁵¹⁶¹⁷¹⁸,Zara Federico¹⁹²⁰,Zuberi Sameer⁵⁶^ORCID,Kuchenbaecker Karoline²¹^ORCID,Balestrini Simona¹²⁷^ORCID,Mills James D¹²²²,Sisodiya Sanjay M¹²^ORCID,

Affiliation:

1. University College London Queen Square Institute of Neurology, Department of Clinical and Experimental Epilepsy , London, WC1N 3BG , UK

2. Chalfont Centre for Epilepsy , Chalfont St Peter SL9 0RJ , UK

3. Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital , Kuopio 70210 , Finland

4. Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust , Exeter EX2 5DW , UK

5. Paediatric Neuroscience Research Group, Royal Hospital for Children , Glasgow G51 4TF , UK

6. Institute of Health and Wellbeing, University of Glasgow , Glasgow G12 8TB , UK

7. Neuroscience Department, Meyer Children’s Hospital IRCSS, University of Florence , 50139 Florence , Italy

8. Department of Genetics, University Medical Centre Utrecht , 3584CX Utrecht , The Netherlands

9. Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 , Germany

10. Center for Rare Diseases, University of Leipzig Medical Center , Leipzig 04103 , Germany

11. Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre , DK-4293 Dianalund , Denmark

12. Department of Regional Health Research, University of Southern Denmark , DK-5230 Odense , Denmark

13. Epilepsy Research Centre, Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital , Melbourne, VIC 3084 , Australia

14. Murdoch Children's Research Institute , Parkville, VIC 3052 , Australia

15. Applied and Translational Neurogenomics Group, VIB Centre for Molecular Neurology, VIB , Antwerp 2610 , Belgium

16. Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp , Antwerp 2650 , Belgium

17. Department of Neurology, University Hospital Antwerp , Antwerp 2650 , Belgium

18. µNEURO Research Centre of Excellence, University of Antwerp , Antwerp 2610 , Belgium

19. Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini , 16147 Genoa , Italy

20. Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa , 16132 Genoa , Italy

21. University College London Division of Psychiatry , London W1T 7BN , UK

22. Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience , 1105 AZ Amsterdam , The Netherlands

Abstract

AbstractDravet syndrome is an archetypal rare severe epilepsy, considered ‘monogenic’, typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors.In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.

Funder

Wellcome Trust Strategic Award

The Muir Maxwell Trust

The Amelia Roberts Fellowship

The Fidelity Foundation

Dravet syndrome UK

The Wellcome Trust, Cancer Research UK

Medical Research Council

National Institute for Health Research

University College London Hospitals Biomedical Research Centre

UK Department of Health’s NIHR Biomedical Research Centres

Publisher