Abstract

Background. We aimed to delineate the genotype and phenotype of patients with KCNQ2 mutations from South China.

Methods. Clinical manifestations and characteristics of KCNQ2 mutations of patients from South China were analyzed. Previous patients with mutations detected in this study were reviewed.

Results. Eighteen epilepsy patients with KCNQ2 mutations, including seven self-limited neonatal epilepsy (SeLNE), two self-limited infantile epilepsy (SeLIE) and nine developmental and epileptic encephalopathy (DEE) were enrolled. The age of onset (p=0.006), mutation types (p=0.029), hypertonia (p=0.000), and seizure offset (p=0.029) were different in self-limited epilepsy (SeLE) and DEE. De novo mutations were mainly detected in DEE patients (p=0.026). The mutation position, EEG or the age of onset were not predictive for the seizure or ID/DD outcome in DEE, while the development of patients free of seizures was better than that of patients with seizures (p=0.008). Sodium channel blockers were the most effective anti-seizure medication, while the age of starting sodium channel blockers did not affect the seizure or development offset. We first discovered the seizure recurrence ratio in SeLNE/SeLIE was 23.1% in South China. Four novel mutations (c.790T>C, c.355_363delGAGAAGAG, c.296+2T>G, 20q13.33del) were discovered. Each of eight mutations (c.1918delC, c.1678C>T, c.683A>G, c.833T>C, c.868G>A, c.638G>A, c.997C>T, c.830C>T) only resulted in SeLE or DEE, while heterogeneity was also found. Six patients in this study have enriched the known phenotype caused by the mutations (c.365C>T, c.1A>G, c.683A>G, c.833T>C, c.830C>T, c.1678C>T).

Conclusion. This research has expanded known phenotype and genotype of KCNQ2-related epilepsy, and the different clinical features of SeLE and DEE from South China.

Keywords: KCNQ2, self-limited epilepsy, developmental and epileptic encephalopathy

Supplementary materials
Supplementary Table

How to cite

1.
Cao B, Peng B, Tian Y, et al. Clinical and genetic analysis of 18 patients with KCNQ2 mutations from South China. Turk J Pediatr 2024; 66: 191-204. https://doi.org/10.24953/turkjpediatr.2024.4593

References

  1. Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 1998; 279: 403-406. https://doi.org/10.1126/science.279.5349.403
  2. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998; 18: 25-29. https://doi.org/10.1038/ng0198-25
  3. Borgatti R, Zucca C, Cavallini A, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology 2004; 63: 57-65. https://doi.org/10.1212/01.wnl.0000132979.08394.6d
  4. Soldovieri MV, Miceli F, Bellini G, Coppola G, Pascotto A, Taglialatela M. Correlating the clinical and genetic features of benign familial neonatal seizures (BFNS) with the functional consequences of underlying mutations. Channels (Austin) 2007; 1: 228-233. https://doi.org/10.4161/chan.4823
  5. Nappi P, Miceli F, Soldovieri MV, Ambrosino P, Barrese V, Taglialatela M. Epileptic channelopathies caused by neuronal Kv7 (KCNQ) channel dysfunction. Pflugers Arch 2020; 472: 881-898. https://doi.org/10.1007/s00424-020-02404-2
  6. Kaplan RE, Lacey DJ. Benign familial neonatal-infantile seizures. Am J Med Genet 1983; 16: 595-599. https://doi.org/10.1002/ajmg.1320160417
  7. Miceli F, Soldovieri MV, Joshi N, et al. KCNQ2-Related Disorders. 2010 Apr 27 [Updated 2018 Sep 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2022.
  8. Miceli F, Soldovieri MV, Ambrosino P, et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 2013; 110: 4386-4391. https://doi.org/10.1073/pnas.1216867110
  9. Miceli F, Soldovieri MV, Ambrosino P, et al. Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 2015; 35: 3782-3793. https://doi.org/10.1523/JNEUROSCI.4423-14.2015
  10. Kuersten M, Tacke M, Gerstl L, Hoelz H, Stülpnagel CV, Borggraefe I. Antiepileptic therapy approaches in KCNQ2 related epilepsy: a systematic review. Eur J Med Genet 2020; 63: 103628. https://doi.org/10.1016/j.ejmg.2019.02.001
  11. Goto A, Ishii A, Shibata M, Ihara Y, Cooper EC, Hirose S. Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia 2019; 60: 1870-1880. https://doi.org/10.1111/epi.16314
  12. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 512-521. https://doi.org/10.1111/epi.13709
  13. Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63: 1349-1397. https://doi.org/10.1111/epi.17239
  14. Richards S, Aziz N, Bale S, et al. 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: 405-424. https://doi.org/10.1038/gim.2015.30
  15. Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 2020; 22: 245-257. https://doi.org/10.1038/s41436-019-0686-8
  16. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 2003; 126: 2726-2737. https://doi.org/10.1093/brain/awg286
  17. Lee IC, Chang TM, Liang JS, Li SY. KCNQ2 mutations in childhood nonlesional epilepsy: Variable phenotypes and a novel mutation in a case series. Mol Genet Genomic Med 2019; 7: e00816. https://doi.org/10.1002/mgg3.816
  18. Yuskaitis CJ, Ruzhnikov MRZ, Howell KB, et al. Infantile spasms of unknown cause: predictors of outcome and genotype-phenotype correlation. Pediatr Neurol 2018; 87: 48-56. https://doi.org/10.1016/j.pediatrneurol.2018.04.012
  19. Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 2019; 142: 2303-2318. https://doi.org/10.1093/brain/awz195
  20. Zhang P, Ji X, Gao Z, Mao Y, Chen Q. Analysis of clinical phenotypes and genotypes in 13 patients with KCNQ2-associated epilepsy. Chinese Journal of Neurology 2021; 54: 553-559. https://doi.org/10.3760/cma.j.cn113694-20210104-00006
  21. Richards MC, Heron SE, Spendlove HE, et al. Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet 2004; 41: e35. https://doi.org/10.1136/jmg.2003.013938
  22. Lindy AS, Stosser MB, Butler E, et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 2018; 59: 1062-1071. https://doi.org/10.1111/epi.14074
  23. Grinton BE, Heron SE, Pelekanos JT, et al. Familial neonatal seizures in 36 families: clinical and genetic features correlate with outcome. Epilepsia 2015; 56: 1071-1080. https://doi.org/10.1111/epi.13020
  24. Zeng Q, Yang X, Zhang J, et al. Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort. J Hum Genet 2018; 63: 9-18. https://doi.org/10.1038/s10038-017-0359-x
  25. Fang ZX, Zhang M, Xie LL, et al. KCNQ2 related early-onset epileptic encephalopathies in Chinese children. J Neurol 2019; 266: 2224-2232. https://doi.org/10.1007/s00415-019-09404-y
  26. Ma X, Yang F, Hua Z. Genetic diagnosis of neonatal-onset seizures. Genes Dis 2019; 6: 441-447. https://doi.org/10.1016/j.gendis.2019.02.002
  27. Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012; 71: 15-25. https://doi.org/10.1002/ana.22644
  28. Na JH, Shin S, Yang D, et al. Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy. Brain Dev 2020; 42: 438-448. https://doi.org/10.1016/j.braindev.2020.02.004
  29. Kim HJ, Yang D, Kim SH, et al. Clinical characteristics of KCNQ2 encephalopathy. Brain Dev 2021; 43: 244-250. https://doi.org/10.1016/j.braindev.2020.08.015
  30. de Kovel CG, Brilstra EH, van Kempen MJ, et al. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Mol Genet Genomic Med 2016; 4: 568-580. https://doi.org/10.1002/mgg3.235
  31. Benetou C, Papailiou S, Maritsi D, Anagnostopoulou K, Kontos H, Vartzelis G. A novel de novo KCNQ2 mutation in a child with treatmentresistant early-onset epileptic encephalopathy. Turk J Pediatr 2019; 61: 279-281. https://doi.org/10.24953/turkjped.2019.02.020
  32. Ostrander BEP, Butterfield RJ, Pedersen BS, et al. Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy. NPJ Genom Med 2018; 3: 22. https://doi.org/10.1038/s41525-018-0061-8
  33. Fernández-Marmiesse A, Roca I, Díaz-Flores F, et al. Rare variants in 48 genes account for 42% of cases of epilepsy with or without neurodevelopmental delay in 246 pediatric patients. Front Neurosci 2019; 13: 1135. https://doi.org/10.3389/fnins.2019.01135
  34. Hunter J, Maljevic S, Shankar A, et al. Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy. Neurobiol Dis 2006; 24: 194-201. https://doi.org/10.1016/j.nbd.2006.06.011
  35. Milh M, Boutry-Kryza N, Sutera-Sardo J, et al. Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. Orphanet J Rare Dis 2013; 8: 80. https://doi.org/10.1186/1750-1172-8-80
  36. Kato M, Yamagata T, Kubota M, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013; 54: 1282-1287. https://doi.org/10.1111/epi.12200
  37. Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 2014; 75: 382-394. https://doi.org/10.1002/ana.24080
  38. Schmitt B, Wohlrab G, Sander T, Steinlein OK, Hajnal BL. Neonatal seizures with tonic clonic sequences and poor developmental outcome. Epilepsy Res 2005; 65: 161-168. https://doi.org/10.1016/j.eplepsyres.2005.05.009
  39. Miao P, Feng J, Guo Y, et al. Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients. Clin Genet 2018; 94: 512-520. https://doi.org/10.1111/cge.13441
  40. 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: e0141782. https://doi.org/10.1371/journal.pone.0141782
  41. Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016; 2: e96. https://doi.org/10.1212/NXG.0000000000000096
  42. Charlesworth G, Plagnol V, Holmström KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet 2012; 91: 1041-1050. https://doi.org/10.1016/j.ajhg.2012.10.024
  43. Ko A, Jung DE, Kim SH, et al. The efficacy of ketogenic diet for specific genetic mutation in developmental and epileptic encephalopathy. Front Neurol 2018; 9: 530. https://doi.org/10.3389/fneur.2018.00530
  44. Xiao T, Chen X, Xu Y, et al. Clinical study of 30 novel KCNQ2 variants/deletions in KCNQ2-related disorders. Front Mol Neurosci 2022; 15: 809810. https://doi.org/10.3389/fnmol.2022.809810
  45. Hwang SK, Makita Y, Kurahashi H, Cho YW, Hirose S. Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation. J Hum Genet 2011; 56: 609-612. https://doi.org/10.1038/jhg.2011.69
  46. Steinlein OK, Conrad C, Weidner B. Benign familial neonatal convulsions: always benign? Epilepsy Res 2007; 73: 245-249. https://doi.org/10.1016/j.eplepsyres.2006.10.010
  47. Al Yazidi G, Shevell MI, Srour M. Two novel KCNQ2 mutations in 2 families with benign familial neonatal convulsions. Child Neurol Open 2017; 4: 2329048X17691396. https://doi.org/10.1177/2329048X17691396