Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/32658
Title: Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.
Austin Authors: Martins Custodio, Helena;Clayton, Lisa M;Bellampalli, Ravishankara;Pagni, Susanna;Silvennoinen, Katri;Caswell, Richard;Brunklaus, Andreas;Guerrini, Renzo;Koeleman, Bobby P C;Lemke, Johannes R;Møller, Rikke S;Scheffer, Ingrid E ;Weckhuysen, Sarah;Zara, Federico;Zuberi, Sameer;Kuchenbaecker, Karoline;Balestrini, Simona;Mills, James D;Sisodiya, Sanjay M
Affiliation: University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK.;Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK.
The Florey Institute of Neuroscience and Mental Health
Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, EX2 5DW, UK.
Paediatric Neuroscience Research Group, Royal Hospital for Children, Glasgow, G51 4TF, UK.;Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8TB, UK.
Neuroscience Department, Meyer Children's Hospital IRCSS, University of Florence, 50139 Florence, Italy.
Department of Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584CX, Utrecht, The Netherlands.
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany.;Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, 04103, Germany.
Danish Epilepsy Centre, Department of Epilepsy Genetics and Personalized Medicine, DK-4293 Dianalund, Denmark.;Department of Regional Health Research, University of Southern Denmark, DK-5230 Odense, Denmark.
Epilepsy Research Centre
Applied and Translational Neurogenomics Group, VIB Centre for Molecular Neurology, VIB, Antwerp 2610, Belgium.;Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp 2650, Belgium.;Department of Neurology, University Hospital Antwerp, Antwerp 2650, Belgium.;µNEURO Research Centre of Excellence, University of Antwerp, Antwerp 2610, Belgium.
Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genoa, Italy.;Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo 3, 16132 Genoa, Italy.
University College London Division of Psychiatry, Maple House, London, W1T 7BN, UK.
Issue Date: 1-Sep-2023
Date: 2023
Publication information: Brain : a Journal of Neurology 2023-09-01; 146(9)
Abstract: Dravet syndrome is an archetypal rare severe epilepsy, considered "monogenic", typically caused by loss-of-function SCN1A variants. Despite a recognisable 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. Polygenic risk scores for intelligence are 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/32658
DOI: 10.1093/brain/awad111
ORCID: 0000-0002-2271-8094
0000-0003-0713-4602
0000-0002-7728-6903
0000-0002-4435-6610
0000-0002-2311-2174
0000-0002-4489-4697
0000-0001-9726-603X
0000-0001-5639-1969
Journal: Brain : a Journal of Neurology
PubMed URL: 37006128
ISSN: 1460-2156
Type: Journal Article
Subjects: SCN1A
Dravet syndrome
blended phenotypes
polygenic risk scores
polymorphism
Appears in Collections:Journal articles

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