The Turkish Journal of Pediatrics 2020 , Vol 62 , Num 5
SCN1A mutation spectrum in a cohort of Bulgarian patients with GEFS+ phenotype
Valentina Peycheva 1 ,Nevyana Ivanova 1 ,Kunka Kamenarova 1 ,Margarita Panova 2 ,Iliana Pacheva 2 ,Ivan Ivanov 2 ,Maria Bojidarova 3 ,Genoveva Tacheva 3 ,Dimitar Stamatov 3 ,Ivan Litvinenko 3 ,Dimitrina Hristova 4 ,Daniela Deneva 5 ,Elena Rodopska 5 ,Elena Slavkova 5 ,Iliyana Aleksandrova 5 ,Emil Simeonov 6 ,Petia Dimova 7 ,Veneta Bojinova 5 ,Vanyo Mitev 1 ,Albena Jordanova 1-8 ,Radka Kaneva 1
1 Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria
2 Department of Pediatrics and Medical Genetics, Medical Faculty, Medical University-Plovdiv, Plovdiv, Bulgaria
3 Department of Pediatric Neurology, University Pediatrics Hospital, Medical University- Sofia, Sofia, Bulgaria; Children Neurology Unit
4 Pediatrics Clinic, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria
5 Department of Neurology, University Hospital of Neurology and Psychiatry “St’ Naum”, Clinic of Child Neurology, Medical University-Sofia, Sofia, Bulgaria
6 University Hospital
7 Epilepsy Surgery Center, University Hospital “St. Ivan Rilski”, Medical University-Sofia, Sofia, Bulgaria
8 VIB Department of Molecular Genetics, Molecular Neurogenomics Group, University of Antwerp, Antwerp, Belgium
DOI : 10.24953/turkjped.2020.05.002 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. Keywords : Dravet syndrome, SCN1A mutation, GEFS+, seizures

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