Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition
- Creators
- Martins Custodio H.
- Clayton L. M.
- Bellampalli R.
- Pagni S.
- Silvennoinen K.
- Caswell R.
- Ambrose J. C.
- Arumugam P.
- Bevers R.
- Bleda M.
- Boardman-Pretty F.
- Boustred C. R.
- Brittain H.
- Brown M. A.
- Caulfield M. J.
- Chan G. C.
- Giess A.
- Griffin J. N.
- Hamblin A.
- Henderson S.
- Hubbard T. J. P.
- Jackson R.
- Jones L. J.
- Kasperaviciute D.
- Kayikci M.
- Kousathanas A.
- Lahnstein L.
- Lakey A.
- Leigh S. E. A.
- Leong I. U. S.
- Lopez J. F.
- Maleady-Crowe F.
- Mcentagart M.
- Minneci F.
- Mitchell J.
- Moutsianas L.
- Mueller M.
- Murugaesu N.
- Need A. C.
- O'donovan P.
- Odhams C. A.
- Patch C.
- Perez-Gil D.
- Pereira M. B.
- Pullinger J.
- Rahim T.
- Rendon A.
- Rogers T.
- Savage K.
- Sawant K.
- Scott R. H.
- Siddiq A.
- Sieghart A.
- Smith S. C.
- Sosinsky A.
- Stuckey A.
- Tanguy M.
- Tavares A. L. T.
- Thomas E. R. A.
- Thompson S. R.
- Tucci A.
- Welland M. J.
- Williams E.
- Witkowska K.
- Wood S. M.
- Zarowiecki M.
- Brunklaus A.
- Guerrini R.
- Koeleman B. P. C.
- Lemke J. R.
- Moller R. S.
- Scheffer I. E.
- Weckhuysen S.
- Zara F.
- Zuberi S.
- Kuchenbaecker K.
- Balestrini S.
- Mills J. D.
- Sisodiya S. M.
- Others:
- Martins Custodio, H.
- Clayton, L. M.
- Bellampalli, R.
- Pagni, S.
- Silvennoinen, K.
- Caswell, R.
- Ambrose, J. C.
- Arumugam, P.
- Bevers, R.
- Bleda, M.
- Boardman-Pretty, F.
- Boustred, C. R.
- Brittain, H.
- Brown, M. A.
- Caulfield, M. J.
- Chan, G. C.
- Giess, A.
- Griffin, J. N.
- Hamblin, A.
- Henderson, S.
- Hubbard, T. J. P.
- Jackson, R.
- Jones, L. J.
- Kasperaviciute, D.
- Kayikci, M.
- Kousathanas, A.
- Lahnstein, L.
- Lakey, A.
- Leigh, S. E. A.
- Leong, I. U. S.
- Lopez, J. F.
- Maleady-Crowe, F.
- Mcentagart, M.
- Minneci, F.
- Mitchell, J.
- Moutsianas, L.
- Mueller, M.
- Murugaesu, N.
- Need, A. C.
- O'Donovan, P.
- Odhams, C. A.
- Patch, C.
- Perez-Gil, D.
- Pereira, M. B.
- Pullinger, J.
- Rahim, T.
- Rendon, A.
- Rogers, T.
- Savage, K.
- Sawant, K.
- Scott, R. H.
- Siddiq, A.
- Sieghart, A.
- Smith, S. C.
- Sosinsky, A.
- Stuckey, A.
- Tanguy, M.
- Tavares, A. L. T.
- Thomas, E. R. A.
- Thompson, S. R.
- Tucci, A.
- Welland, M. J.
- Williams, E.
- Witkowska, K.
- Wood, S. M.
- Zarowiecki, M.
- Brunklaus, A.
- Guerrini, R.
- Koeleman, B. P. C.
- Lemke, J. R.
- Moller, R. S.
- Scheffer, I. E.
- Weckhuysen, S.
- Zara, F.
- Zuberi, S.
- Kuchenbaecker, K.
- Balestrini, S.
- Mills, J. D.
- Sisodiya, S. M.
Description
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.
Additional details
- URL
- https://hdl.handle.net/11567/1158050
- URN
- urn:oai:iris.unige.it:11567/1158050
- Origin repository
- UNIGE