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

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 follow-up, 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.

PDF

___

1.Guerrini R. Dravet syndrome: the main issues. Eur J Paediatr Neurol 2012; 16(Suppl 1): S1-S4.

2.Dravet C, Bureau M, Oguni H, Fukuyama Y, Çokar O.Severe myoclonic epilepsy in infancy (Dravet syndrome). In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P (eds). Epileptic Syndromes in Infancy, Childhood and Adolescence (4th ed). Montrouge: John Libbey Eurotext, 2005; 4: 89-113.

3.Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 2011; 52: 386-392.

4.Marini C, Scheffer I, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; 52(Suppl 2): 24-29.

5.McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 2016; 15: 304-316.

6.Trimmer JS, Rhodes KJ. Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol 2004; 66: 477-519.

7.Suls A, Claeys KG, Goossens D, et al. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum Mutat 2006; 27: 914-920.

8.Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet 2009; 46: 183-191.

9.Kimura K, Sugawara T, Mazaki-Miyazaki E, et al. A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures. Brain Dev 2005; 27: 424-430.

10.Nicita F, Spalice A, Papetti L, et al. Genotype-phenotype correlations in a group of 15 SCN1A-mutated Italian patients with GEFS+ spectrum (seizures plus, classical and borderline severe myoclonic epilepsy of infancy). J Child Neurol 2010; 25: 1369-1376.

11.Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes GH. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 2011; 76: 594-600.

12.Kanai K, Hirose S, Oguni H, et al. Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity. Neurology 2004; 63: 329-334.

13.Kanai K, Yoshida S, Hirose S, et al. Physicochemical property changes of amino acid residues accompany missense mutations in SCN1A affect the epilepsy phenotype severity. J Med Genet 2009; 46: 671-679.

14.Löscher W. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur J Pharmacol 2009; 610: 1-11.

15.Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014; 55: 528-538.

16.Berg A, Berkovic S, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51: 676-685.

17.Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68: 1327-1332.

18.Desmet O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67.

19.Adzhubei A, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7: 248-249.

20.Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11: 361-362.

21.Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015; 31: 2745-2747.

22.Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-423.

23.Yordanova I, Todorov T, Dimova P, et al. One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene. Neurosci Lett 2011; 494: 180-183.

24.Suls A, Velizarova R, Yordanova I, et al. Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene. Neurology 2010; 75: 72-76.

25.Dimova P, Yordanova I, Bojinova V, Jordanova A, Kremenski I. Generalized epilepsy with febrile seizures plus: novel SCN1A mutation. Pediatr Neurol 2010; 42: 137-140.

26.Patino A, Claes R, Lopez-Santiago LF, et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci 2009; 29: 10764-10778.

27.Suls A, Jaehn A, Kecskés A, et al ; EuroEPINOMICS RES Consortium. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet 2013; 93: 967-975.

28.Carvill L, Weckhuysen S, McMahon JM, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 2014; 82: 1245-1253.

29.Claes LR, Deprez L, Suls A, et al. The SCN1A variant database: a novel research and diagnostic tool. Hum Mutat 2009; 30: E904-E920.

30.Meng H, Xu HQ, Yu L, et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat 2015; 36: 573-580.

31.Brigo F, Storti M. Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy. Cochrane Database Syst Rev 2013; 11: CD010483.

32.Cho MJ, Kwon SS, Ko A, et al. Efficacy of stiripentol in Dravet syndrome with or without SCN1A mutations. J Clin Neurol 2018; 14: 22-28.

33.Ishii A, Watkins JC, Chen D, Hirose S, Hammer MF. Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. Epilepsia 2017; 58: 282-290.

34.Sugawara T, Mazaki-Miyazaki E, Fukushima K, et al. Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy. Neurology 2002; 58: 1122-1124.

35.Chen YJ, Shi YW, Xu HQ, et al. Electrophysiological differences between the same pore region mutation in SCN1A and SCN3A. Mol Neurobiol 2015; 51: 1263-1270.

36.Depienne C, Trouillard O, Gourfinkel-An I, et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J Med Genet 2010; 47: 404-410.

37.Guerrini R, Cellini E, Mei D, et al. Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene. Epilepsia 2010; 51: 2474-2477.

38.Goldberg-Stern H, Aharoni S, Afawi Z, et al. Broad phenotypic heterogeneity due to a novel SCN1A mutation in a family with genetic epilepsy with febrile seizures plus. J Child Neurol 2014; 29: 221-226.

39.Xu X, Zhang Y, Sun H, et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev 2014; 36: 676-681.

40.Berkovic S, Harkin L, McMahon JM, et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol 2006; 5: 488-492.

41.Fukuma G, Oguni H, Shirasaka Y, et al. Mutations of neuronal voltage-gated Na+ channel α1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB). Epilepsia 2004; 45: 140-148.

42.Ohmori I, Ouchida M, Ohtsuka Y, Oka E, Shimizu K. Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy. Biochem Biophys Res Commun 2002; 295: 17-23.

43.Sun H, Zhang Y, Liu X, et al. Analysis of SCN1A mutation and parental origin in patients with Dravet syndrome. J Hum Genet 2010; 55: 421-427.

44.Xu X, Yang X, Wu Q, et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutations in children with Dravet syndrome. Hum Mutat 2015; 36: 861-872.

45.Harkin LA, McMahon JM, Iona X, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007; 130: 843-852.

46.Dlugos D, Ferraro T, Buono R. Novel de novo mutation of a conserved SCN1A amino-acid residue (R1596). Pediatr Neurol 2007; 37: 303-305.

47.Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet 2007; 16: 2892-2899.

48.Ohmori I, Ouchida M, Miki T, et al. A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy. Neurobiol Dis 2008; 32: 349-354.

49.Singh NA, Pappas C, Dahle EJ, et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet 2009; 5: e1000649.

50.Campbell IM, Stewart JR, James RA, et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 2014; 95: 345-359.

51.Goldmann JM, Wong WS, Pinelli M, et al. Parent-of-origin-specific signatures of de novo mutations. Nat Genet 2016; 48: 935-939.

52.Francioli L, Polak PP, Koren A, et al. Genome-wide patterns and properties of de novo mutations in humans. Nat Genet 2015; 47: 822-826.

53.Selmer K, Eriksson AS, Brandal K, Egeland T, Tallaksen C, Undlien DE. Parental SCN1A mutation mosaicism in familial Dravet syndrome. Clin Genet 2009; 76: 398-403.