Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome *†John C. Mulley, ‡Bree Hodgson, §Jacinta M. McMahon, ‡Xenia Iona, §Susannah Bellows, ¶Saul A Mullen, **Kevin Farrell, ††Mark Mackay, ‡‡Lynette Sadleir, §§Andrew Bleasel, ¶¶Deepak Gill, ¶¶Richard Webster, ***Elaine C. Wirrell, †††Michael Harbord, ‡‡‡Sanyjay Sisodiya, §§§Eva Andermann, ¶¶¶Sara Kivity, §Samuel F. Berkovic, §****Ingrid E. Scheffer, and ‡Leanne M. Dibbens *Department of Genetic Medicine, Directorate of Genetics and Molecular Pathology, SA Pathology at Women’s and Children’s Hospital, Adelaide, South Australia, Australia; †School of Paediatrics and Reproductive Health, Discipline of Pediatrics and School of Molecular and Biomedical Sciences, Discipline of Genetics, The University of Adelaide, Adelaide, South Australia, Australia; ‡Division of Health Sciences, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia; §Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia; ¶Department of Medicine at Box Hill Hospital, Monash University, Box Hill, Victoria, Australia; **Division of Neurology, Department of Paediatrics, University of British Columbia, Vancouver, British Columbia, Canada; ††Departments of Neurology and Paediatrics, Royal Children’s Hospital, Parkville, Victoria, Australia; ‡‡Departments of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; §§Westmead Hospital, The University of Sydney, Sydney, New South Wales, Australia; ¶¶Department of Neurology, Children’s Hospital at Westmead, Sydney, Australia; ***Department of Neurology, Mayo Clinic, Rochester, Minnesota, U.S.A.; †††Department of Paediatrics and Child Health, Flinders Medical Centre, Adelaide, South Australia, Australia; ‡‡‡Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, U.K.; §§§Neurogenetics Unit, Departments of Neurology & Neurosurgery and Human Genetics, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada; ¶¶¶Schneider Children’s Medical Centre, Petaq Tikva, Israel; and ****Florey Neuroscience Institutes and Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, Victoria, Australia SUMMARY Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS + ) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A muta- tion inherited have predicted SCN9A susceptibility vari- ants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS + families could be explained by highly penetrant SCN9A mutations. KEY WORDS: Clinical heterogeneity, Genetic modifier, Genetic susceptibility, Dravet syndrome, Febrile seizures, Genetic epilepsy with febrile seizures plus, SCN1A, SCN9A, Susceptibility gene. Dravet syndrome (DS) is a debilitating infantile-onset encephalopathy. Mutations in the sodium channel subunit gene SCN1A account for 70–80% of cases (Marini et al., 2007) and mutations in GABRG2 and PCDH19 and homo- zygous SCN1B mutations can cause a clinical picture suggestive of DS (Harkin et al., 2002; Depienne et al., 2009; Patino et al., 2009). However, the cause in approxi- mately 20–30% of cases remains elusive. Possibilities include de novo dominant mutation in unknown genes or a multifactorial etiology. Genetic epilepsy with febrile seizures plus (GEFS + ) has heterogeneous phenotypes, with both complex and familial autosomal dominant inheritance. A sodium channel SCN9A mutation is known in a family variously diagnosed as auto- somal dominant febrile seizures (FS) or GEFS + (Peiffer et al., 1999; Scheffer et al., 2000; Singh et al., 2009). SCN9A variation has also been suggested as a genetic modi- fier that exacerbates mild SCN1A mutation–associated GEFS + and as a susceptibility gene for DS (Singh et al., 2009). We examined additional multiplex FS and GEFS + fami- lies for highly penetrant SCN9A mutations and explored the possibility of SCN9A contributing to a multifactorial etiology for Dravet syndrome. Accepted June 13, 2013; Early View publication July 29, 2013. Address correspondence to Leanne M. Dibbens, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA 5000, Australia. E-mail: leanne.dibbens@unisa. edu.au Wiley Periodicals, Inc. © 2013 International League Against Epilepsy e122 Epilepsia, 54(9):e122–e126, 2013 doi: 10.1111/epi.12323 BRIEF COMMUNICATION