SCN1A mutation spectrum in a cohort of Bulgarian patients with GEFS+ phenotype

Abstract

Background. Dravet syndrome (DS) is the most severe form of Generalized Epilepsy with Febrile Seizures plus (GEFS+) syndrome with a clear genetic component in 85% of the cases. It is characterized by fever-provoked seizure onset around six months of age and subsequent developmental deterioration later in life. Methods.In the current study, 60 patients with fever-provoked seizures and suspicion either of GEFS+ (50 patients) or of DS (10 patients) were referred for SCN1A gene sequence analysis.Results. SCN1A gene sequencing revealed clinically significant variants in 11 patients (18.3%); seven pathogenic (11.7%) and four likely pathogenic (6.7%). Five of these variants have not been reported previously. Among the preselected group of ten DS patients, five had pathogenic SCN1A variants which confirmed diagnosis of DS. In four patients with preliminary diagnosis GEFS+, the detected SCN1A variant enabled us to specify the diagnosis of DS in these patients. Thus, SCN1A sequencing led to confirmation of the genetic diagnosis in 50% (5/10) of DS patients, as well as clarification of the diagnosis of DS in 8% of GEFS+ patients (4/50).In this study, four patients with truncating mutations had refractory seizures and additional psychomotor abnormalities. Additionally, pathogenic missense mutations were detected in three children with comparable phenotypes, which support the observations that missense mutations in critical channel function regions can cause a devastating epileptic condition.Conclusions. This is the first systematic screening of SCN1A gene in our country, which expands the spectrum of SCN1A variants with five novel variants from Bulgaria and demonstrates the clinical utility of confirmatory SCN1A testing, which helps clinicians make early and precise diagnoses. It is important for a better followup, choice of proper treatment, avoidance of development of refractory seizures and neuropsychological complications. Identification of pathogenic variants in SCN1A in the milder GEFS+ and severe DS cases, will help to offer adequate prenatal diagnosis and improve the genetic counselling provided to affected families.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox–Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality

“…DS case definitions were based on clinical diagnosis and review of medical records across most studies, with a mix of diagnostic criteria using International Classification of Diseases (ICD), Ninth Revision or Tenth Revision (ICD‐10) codes (five articles), 18,30,39–41 ILAE diagnostic criteria (20 articles), 14,16,18–23,25–30,32–35,37,38 or SCN1A mutation presence (two articles) 34,42 …”

“…Most used the 2017 revised criteria (seven articles), 14,20,22,26,[33][34][35] followed by the 1989 criteria (six articles) 15,16,23,24,30,31 and the 2010 revised version (three articles). 18,29,32 The ILAE version used was not reported in seven articles, 17,19,21,25,27,28,36 and a mix of criteria iterations was used in two articles. 37,38 Except for five articles, the most recent ILAE criteria available were used.…”

“…Genotype outcomes were reported in 63 studies. Of these, 57 studies included only individuals with DS, [18][19][20][21]23,[25][26][27][28][29][30]32,34,35,40,42,[54][55][56]58,59,62,63,65,[67][68][69][70]72,[74][75][76] five included individuals with DS or LGS, 14,33,37,38,71 and one included only individuals with LGS. 52 Studies were predominantly limited to Europe (30 articles) and Asia (20 articles), with considerably fewer studies based in North America (three articles), South America (two articles), Oceania (four articles), and Africa (two articles).…”

“…37,38 Except for five articles, the most recent ILAE criteria available were used. 16,23,29,30,37 DS case definitions were based on clinical diagnosis and review of medical records across most studies, with a mix of diagnostic criteria using International Classification of Diseases (ICD), Ninth Revision or Tenth Revision (ICD-10) codes (five articles), 18,30,[39][40][41] ILAE diagnostic criteria (20 articles), 14,16,[18][19][20][21][22][23][25][26][27][28][29][30][32][33][34][35]37,38 or SCN1A mutation presence (two articles). 34,42 Case definitions for LGS also varied across all included studies, with most individuals being identified based on medical records.…”

“…Overall, 35 studies included information on diagnosis; 29 reported outcomes specific to DS, and six reported outcomes specific to LGS. Studies reporting on DS were mainly limited to Europe (15 articles) 29,30,42,55,[57][58][59][60][61][62][63][64][65][66][67] and Asia (nine articles), 14,33,35,38,[68][69][70][71][72] with minimal representation from North America (one article), 73 South America (one article), 74 Africa (one article), 75 and Oceania (one article). 34 The setting of one study was not reported.…”