Authors :
Stefan Wolking, University of Tübingen; Patrick May, University of Luxembourg; Davide Mei, University of Florence; Rikke S. Møller, Danish Epilepsy Centre and University of Southern Denmark; Simona Balestrini, UCL Institute of Neurology and Epil
Rationale: Variants in STX1B, encoding the presynaptic protein syntaxin-1B, have been described as a cause of fever-associated epilepsy such as GEFS+. We set out to expand the spectrum of STX1B-related epilepsies and to establish genotype-phenotype correlations by identifying further disease-related variants. Methods: Different next-generation sequencing datasets from several Center research projects or diagnostic testing services were used to identify the reported variants. All subjects are of European descent. Clinical data and EEGs were reviewed, including already published cases. We compared patient STX1B missense variants to variants identified in almost 150,000 control individuals stored in the genome Aggregation database (gnomAD,
http://gnomad.broadinstitute.org/ ). To estimae the pathogenicity of the variants, mutational density and paralog conservation were calculated usingnewly developed in silico prediction tools. Results: We describe fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients: 1) Six sporadic patients or families with febrile and afebrile seizures with a benign course, generally good drug response, normal development and without permanent neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) eleven patients with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. There are plausible explanations for genotype-phenotype correlations, such that haploinsufficiency causes rather benign phenotypes, whereas missense variants in functionally critical regions, e.g. in the SNARE motif of syntaxin-1B, cause more severe phenotypes Conclusions: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. Funding: Foundation on Epilepsy, by the National Institute for Health Research (NIHR) Biomedical Research Centre Oxford with funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme; Epilepsy Research UK, project grant (P1104); Wellcome Trust Strategic Award (WT104033AIA), the Muir Maxwell Trust and the Epilepsy Society, UK; National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K NS077364, NS077274, NS077303, and NS077276); Canadian Institutes of Health Research (201503MOP-342469, DKP); European Union Programme of the Seventh Framework Programme Development of Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy, “DESIRE” (602531, DKP); National Institute for Health Research (DKP); Medical Research Council (DKP); Waterloo Foundation (DKP); Charles Sykes Epilepsy Research Trust (DKP); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley NHS Foundation Trust (DKP).