학술논문
Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.
Document Type
Article
Author
Custodio, Helena Martins; Clayton, Lisa M; Bellampalli, Ravishankara; Pagni, Susanna; Silvennoinen, Katri; Caswell, Richard; Consortium, Genomics England Research; 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
Source
Subject
*EPILEPSY
*FOCAL cortical dysplasia
*DISEASE risk factors
*MONOGENIC & polygenic inheritance (Genetics)
*PHENOTYPES
*EARLY death
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Language
ISSN
0006-8950
Abstract
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. 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. [ABSTRACT FROM AUTHOR]