Genetic characteristics of <i>SCN1A</i> mutations in 547 Dravet syndrome_Journal of Epilepsy

Authors：

 TIANXiaojuan ¹ ,  ZHANGYuehua ¹ , YANGXiaoling ¹ , XUXiaojing ² , LIUAijie ¹ , LIUXiaoyan ¹ , YANGZhixian ¹ , WUYe ¹ , JIANGYuwu ¹ , WUXiru ¹

1. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China;
2. Department of Pediatrics, China-Japan Friendship Hospital, Beijing 100029, China;

Corresponding author：

ZHANGYuehua, Email: zhangyhdr@126.com

Keywords：

Dravet syndrome; SCN1A gene; De novo mutation; Inherited mutation; Mosaic

DOI：

10.7507/2096-0247.20160001

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Objective To study SCN1A gene mutations and their inheritance in patients with Dravet syndrome (DS), and to analyze the phenotypes of their family members. Methods Genomic DNA was extracted from peripheral blood samples from DS patients and their parents. SCN1A gene mutations were screened using PCR-DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). Results 547 DS patients were collected, SCN1A gene mutations were identified in 379 patients (69.3%), which included 179 missense mutations (47.2%), 78 nonsense mutations (20.6%), 77 frameshift mutations (20.3%), 37 splice site mutations (9.8%), and 8 cases with SCN1A gene fragment deletions or duplications (2.1%). Of 379 DS patients, the parents of 354 DS patients were further analyzed, the de novo mutations accounted for 92.9%, inherited mutations accounted for 7.1%, and in 5 of the latter families, the SCN1A-positive parent carried a somatic mutations mosaicism. For the 25 parents carrying SCN1A mutations, 1 had DS, 11 had febrile seizures plus, 9 had febrile seizures, whilst 4 were normal. Conclusions The mutation rate of SCN1A in DS patients is high. Most mutations are of missense and truncation mutations (including nonsense mutation and frameshift mutation). Only a few patients have carried fragment deletions or duplications. Most SCN1A mutations are de novo, only a few are inherited from the parents. SCN1A mutations carried by the parents can be in the form of mosaicism. The phenotypes of parents with SCN1A mutations can be severe, mild or normal, and a mosaic transmitting parent always shows mild or normal.

Citation： TIANXiaojuan, ZHANGYuehua, YANGXiaoling, XUXiaojing, LIUAijie, LIUXiaoyan, YANGZhixian, WUYe, JIANGYuwu, WUXiru. Genetic characteristics of SCN1A mutations in 547 Dravet syndrome. Journal of Epilepsy, 2016, 2(1): 3-8. doi: 10.7507/2096-0247.20160001 Copy

1.	Ceulemans B. Overall management of patients with Dravet syndrome. Dev Med Child Neurol, 2011, 53 (Suppl 2): 19-23.
2.	Sakauchi M, Oguni H, Kato I, et al. Mortality in Dravet syndrome: search for risk factors in Japanese patients. Epilepsia, 2011, 52 (Suppl 2): 50-54.
3.	Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. Journal of medical genetics, 2009, 46(3): 183-191.
4.	Mulley J C, Scheffer I E, Petrou S, et al. SCN1A mutation and epilepsy. Human Mutation, 2005, 25(6): 535-542.
5.	Nabbout R, Gennaro E, Dalla BB, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology, 2003, 60(12): 1961-1967.
6.	Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes and epilepsy. Lancet Neurol, 2004, 3(7): 421-430.
7.	Anne T Berg, Samuel F Berkovic, Martin J Brodie, 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(4): 676-685.
8.	Ebach K, Joos HH, Stephani U, et al. SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures. Neuropediatrics, 2005, 36(3): 210-213.
9.	Dimova PS, Yordanova I, Bojinova V, et al. Generalized epilepsy with febrile seizures plus: novel SCN1A mutation. Pediatric Neurology, 2010, 42(2): 137-140.
10.	Mulley JC, Nelson P, Guerrero S, et al. A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology, 2006, 67(6): 1094-1095.
11.	Carla M, Scheffer IE, Rima N, et al. SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia, 2009, 50(7):1670-1678.
12.	Marini C, Scheffer I E, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia, 2011, 52(Suppl 2):24-29.
13.	Patino GA, Claes LR. A functional null mutation of SCN1B in a patient with Dravet syndrome. Journal of Neuroscience, 2009, 29(34): 113-118.
14.	Carvill GL, Sarah W, Mcmahon JM, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
15.	Mulley JC, Hodgson B, Mcmahon JM, et al. Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. Epilepsia, 2013, 54(9): e122-e126.
16.	Depienne C, Trouillard O, Gourfinkelan I, et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. Journal of Medical Genetics, 2010, 47(6): 404-410.
17.	Carla M, Davide M, Cross JH, et al. Mosaic SCN1A mutation in familial severe myoclonic epilepsy of infancy. Epilepsia, 2006, 47(10): 1737-1740.
18.	Elena G, Santorelli FM, Enrico B, et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem.bioph.res.co, 2006, 341(2): 489-493.
19.	Suls A, Velizarova R, Yordanova I, et al. Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene. Neurology, 2010, 75(1): 72-76.
20.	Kalume F. Sudden unexpected death in Dravet syndrome: Respiratory and other physiological dysfunctions. Respiratory Physiology & Neurobiology, 2013, 189(2): 324-328.

1. Ceulemans B. Overall management of patients with Dravet syndrome. Dev Med Child Neurol, 2011, 53 (Suppl 2): 19-23.
2. Sakauchi M, Oguni H, Kato I, et al. Mortality in Dravet syndrome: search for risk factors in Japanese patients. Epilepsia, 2011, 52 (Suppl 2): 50-54.
3. Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. Journal of medical genetics, 2009, 46(3): 183-191.
4. Mulley J C, Scheffer I E, Petrou S, et al. SCN1A mutation and epilepsy. Human Mutation, 2005, 25(6): 535-542.
5. Nabbout R, Gennaro E, Dalla BB, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology, 2003, 60(12): 1961-1967.
6. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes and epilepsy. Lancet Neurol, 2004, 3(7): 421-430.
7. Anne T Berg, Samuel F Berkovic, Martin J Brodie, 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(4): 676-685.
8. Ebach K, Joos HH, Stephani U, et al. SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures. Neuropediatrics, 2005, 36(3): 210-213.
9. Dimova PS, Yordanova I, Bojinova V, et al. Generalized epilepsy with febrile seizures plus: novel SCN1A mutation. Pediatric Neurology, 2010, 42(2): 137-140.
10. Mulley JC, Nelson P, Guerrero S, et al. A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology, 2006, 67(6): 1094-1095.
11. Carla M, Scheffer IE, Rima N, et al. SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia, 2009, 50(7):1670-1678.
12. Marini C, Scheffer I E, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia, 2011, 52(Suppl 2):24-29.
13. Patino GA, Claes LR. A functional null mutation of SCN1B in a patient with Dravet syndrome. Journal of Neuroscience, 2009, 29(34): 113-118.
14. Carvill GL, Sarah W, Mcmahon JM, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
15. Mulley JC, Hodgson B, Mcmahon JM, et al. Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. Epilepsia, 2013, 54(9): e122-e126.
16. Depienne C, Trouillard O, Gourfinkelan I, et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. Journal of Medical Genetics, 2010, 47(6): 404-410.
17. Carla M, Davide M, Cross JH, et al. Mosaic SCN1A mutation in familial severe myoclonic epilepsy of infancy. Epilepsia, 2006, 47(10): 1737-1740.
18. Elena G, Santorelli FM, Enrico B, et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem.bioph.res.co, 2006, 341(2): 489-493.
19. Suls A, Velizarova R, Yordanova I, et al. Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene. Neurology, 2010, 75(1): 72-76.
20. Kalume F. Sudden unexpected death in Dravet syndrome: Respiratory and other physiological dysfunctions. Respiratory Physiology & Neurobiology, 2013, 189(2): 324-328.

Journal of Epilepsy

Genetic characteristics of SCN1A mutations in 547 Dravet syndrome

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