Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

2023-09-01

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

SCN1A

Dravet syndrome

blended phenotypes

polygenic risk scores

polymorphism

Journal Article

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10.1093/brain/awad111

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.

link

Brain : a Journal of Neurology 2023-09-01; 146(9)

Brain : a Journal of Neurology

1460-2156