The Genotype and Phenotype Study of <i>PCDH</i>19 gene related epilepsy_Journal of Epilepsy

Authors：

LIU Aijie ¹ , XU Xiaojing ¹ , SUN dan ² , ZENG Qi ¹ , YANG Xiaoling ¹ , YANG Zhixian ¹ , WU Ye ¹ , LIU Xiaoyan ¹ , JIANG Yuwu ¹ , WU Xiru ¹ ,  ZHANG Yuehua ¹

1. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China;
2. Department of Neurology, Wuhan Children's Hospital, Wuhan 430016, China;

Corresponding author：

ZHANG Yuehua, Email: zhangyhdr@126.com

Keywords：

Epilepsy; PCDH19; Mutation; Mosaicism

DOI：

10.7507/2096-0247.20170042

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ObjectiveTo explore the genotype and phenotype of PCDH19 gene related epilepsy.Methods41 probands, including 39 girls and 2 boys collected from pediatric department of the Peking University and Neurology Department of Wuhan Children's Hospital from February 2005 to April 2017, were diagnosed as PCDH19 gene related epilepsy. The clinical features of the probands and affected relatives were retrospectively analyzed. PCDH19 mutations were detected by Sanger sequencing or targeted next generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA).Results40 in 41 probands with PCDH19 mutations were detected by sequencing and one was detected by MLPA.Two male epilepsy patients with mosaic PCDH19 mutations were detected by NGS with the mutant allele fraction of 85% and 33%. Among 39 female probands, 19 were with inherited mutations and 20 were de novo mutations. The penetrance of females with PCDH19 mutation was estimated as 90% (53/59). Twelve hemizygous fathers and one mosaic father were asymptomatic.The clinical phenotypes of female mutation carriers included epilepsy with mental retardation, Dravet syndrome, febrile seizures, or even asymptomatic. The phenotypic heterogeneity was noticed in females with identical mutations even in members from the same family. The median seizure onset age of 46 patients (including 41 probands and 5 affected relatives) were 11 months (range 4~42months).During the course, 87% (40/46) patients experienced generalized tonic clonic seizures (GTCSs) and 69.6% (32/46) experienced focal seizures. Other rare seizures types included myoclonic seizures (6/46), absence seizures (3/46) and atonic seizures (1/46). Seizures in clusters were observed in all patients, fever sensitivity in 80.4% (37/46), and status epilepticusin only three, cognitive impairment in 76% (35/46) and 7 with autistic features.ConclusionMutations in PCDH19 can be inherited or de novo. Most patients are females, rare mosaic males can be affected or asymptomatic. PCDH19 gene related epilepsy shows incomplete penetrance and variable expressivity.Seizures occurring in clusters and sensitive to fever are the major features.

Citation： LIU Aijie, XU Xiaojing, SUN dan, ZENG Qi, YANG Xiaoling, YANG Zhixian, WU Ye, LIU Xiaoyan, JIANG Yuwu, WU Xiru, ZHANG Yuehua. The Genotype and Phenotype Study of PCDH19 gene related epilepsy. Journal of Epilepsy, 2017, 3(4): 283-291. doi: 10.7507/2096-0247.20170042 Copy

1.	Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet, 2008, 40(6): 776-781.
2.	Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet, 2009, 5(2): e1000381.
3.	Terracciano A, Trivisano M, Cusmai R, et al. PCDH19-related epilepsy in two mosaic male patients. Epilepsia, 2016, 57(3): 51-55.
4.	Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant. Am J Med Genet A, 2016, 170(6): 1585-1589.
5.	Fabisiak K, Erickson RP. A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin Genet, 1990, 38(5): 353-358.
6.	Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain, 2008, 131(Pt 4): 918-927.
7.	Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology, 2010, 75(7): 646-653.
8.	Ikeda H, Imai K, Ikeda H, et al. Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy. Epileptic Disord, 2016, 18(1): 26-33.
9.	胡春辉, 王龙飞, 王华.不明原因早发性癫痫脑病62例临床特点及相关基因突变分析.中华实用儿科临床杂志, 2016, 31(5): 371-375.
10.	庄嘉鑫, 林彩梅, 吴小慧, 等.原钙黏蛋白19(PCDH19) 基因突变相关的癫痫性脑病一例.中国小儿急救医学, 2016, 23(3): 211-213.
11.	刘爱杰, 张月华, 许小菁, 等. PCDH19基因突变导致的女性Dravet综合征的基因型和表型特点.中华儿科杂志, 2016, 54(5): 327-331.
12.	Liu A, Xu X, Yang X, et al. The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. Clin Genet, 2017, 91(1): 54-62.
13.	Zhang Y, Kong W, Gao Y, et al. Gene mutation analysis in 253 chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One, 2015, 10(11): e141782.
14.	Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med, 2011, 3(92): 66-92.
15.	Depienne C, Leguern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(4): 627-634.
16.	Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet, 2015, 56(1): 49-56.
17.	Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet, 2010, 47(3): 211-216.
18.	van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. Neurogenetics, 2013, 14(1): 23-34.
19.	Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutation. Epilepsia, 2011, 52(7): 1251-1257.
20.	Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum Mutat, 2011, 32(1): E1959-E1975.
21.	Dimova PS, Kirov A, Todorova A, et al. A novel PCDH19 mutation inherited from an unaffected mother. Pediatr Neurol, 2012, 46(6): 397-400.

1. Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet, 2008, 40(6): 776-781.
2. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet, 2009, 5(2): e1000381.
3. Terracciano A, Trivisano M, Cusmai R, et al. PCDH19-related epilepsy in two mosaic male patients. Epilepsia, 2016, 57(3): 51-55.
4. Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant. Am J Med Genet A, 2016, 170(6): 1585-1589.
5. Fabisiak K, Erickson RP. A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin Genet, 1990, 38(5): 353-358.
6. Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain, 2008, 131(Pt 4): 918-927.
7. Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology, 2010, 75(7): 646-653.
8. Ikeda H, Imai K, Ikeda H, et al. Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy. Epileptic Disord, 2016, 18(1): 26-33.
9. 胡春辉, 王龙飞, 王华.不明原因早发性癫痫脑病62例临床特点及相关基因突变分析.中华实用儿科临床杂志, 2016, 31(5): 371-375.
10. 庄嘉鑫, 林彩梅, 吴小慧, 等.原钙黏蛋白19(PCDH19) 基因突变相关的癫痫性脑病一例.中国小儿急救医学, 2016, 23(3): 211-213.
11. 刘爱杰, 张月华, 许小菁, 等. PCDH19基因突变导致的女性Dravet综合征的基因型和表型特点.中华儿科杂志, 2016, 54(5): 327-331.
12. Liu A, Xu X, Yang X, et al. The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. Clin Genet, 2017, 91(1): 54-62.
13. Zhang Y, Kong W, Gao Y, et al. Gene mutation analysis in 253 chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One, 2015, 10(11): e141782.
14. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med, 2011, 3(92): 66-92.
15. Depienne C, Leguern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(4): 627-634.
16. Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet, 2015, 56(1): 49-56.
17. Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet, 2010, 47(3): 211-216.
18. van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. Neurogenetics, 2013, 14(1): 23-34.
19. Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutation. Epilepsia, 2011, 52(7): 1251-1257.
20. Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum Mutat, 2011, 32(1): E1959-E1975.
21. Dimova PS, Kirov A, Todorova A, et al. A novel PCDH19 mutation inherited from an unaffected mother. Pediatr Neurol, 2012, 46(6): 397-400.

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