Martins Custodio, Helena;
Clayton, Lisa M;
Bellampalli, Ravishankara;
Pagni, Susanna;
Silvennoinen, Katri;
Caswell, Richard;
Genomics England Research Consortium;
... Sisodiya, Sanjay M; + view all
(2023)
Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.
Brain
, Article awad111. 10.1093/brain/awad111.
(In press).
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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.
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