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Martins Custodio, Helena; Clayton, Lisa M; Bellampalli, Ravishankara; Pagni, Susanna; Silvennoinen, Katri; Caswell, Richard; 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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition
  • Beteiligte: Martins Custodio, Helena; Clayton, Lisa M; Bellampalli, Ravishankara; Pagni, Susanna; Silvennoinen, Katri; Caswell, Richard; 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; [...]
  • Erschienen: Oxford University Press (OUP), 2023
  • Erschienen in: Brain
  • Sprache: Englisch
  • DOI: 10.1093/brain/awad111
  • ISSN: 0006-8950; 1460-2156
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Dravet 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.</jats:p><jats:p>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.</jats:p>