Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.
Channelopathies
/ genetics
Child
Child, Preschool
Electroencephalography
Epilepsy
/ genetics
Epilepsy, Benign Neonatal
/ genetics
Female
Genetic Association Studies
High-Throughput Nucleotide Sequencing
Humans
Intellectual Disability
/ genetics
KCNQ2 Potassium Channel
/ genetics
Male
Mutation
/ genetics
Potassium
/ metabolism
KCNQ2
NGS
intellectual disability
phenotype-genotype
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
19
01
2021
received:
07
11
2020
accepted:
11
03
2021
pubmed:
24
3
2021
medline:
2
9
2021
entrez:
23
3
2021
Statut:
ppublish
Résumé
High-throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease-causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra-familial phenotypic variability, although missense variants in the voltage-sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype-phenotype correlations in KCNQ2-related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non-epileptic ID patients.
Identifiants
pubmed: 33754465
doi: 10.1002/ajmg.a.62181
doi:
Substances chimiques
KCNQ2 Potassium Channel
0
KCNQ2 protein, human
0
Potassium
RWP5GA015D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1803-1815Informations de copyright
© 2021 Wiley Periodicals LLC.
Références
Abidi, A., Devaux, J. J., Molinari, F., Alcaraz, G., Michon, F.-X., Sutera-Sardo, J., Becq, H., Lacoste, C., Altuzarra, C., Afenjar, A., Mignot, C., Doummar, D., Isidor, B., Guyen, S. N., Colin, E., de la Vaissière, S., Haye, D., Trauffler, A., Badens, C., … Aniksztejn, L. (2015). A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels. Neurobiology of Disease, 80, 80-92. https://doi.org/10.1016/j.nbd.2015.04.017
Al Yazidi, G., Shevell, M. I., & Srour, M. (2017). Two novel KCNQ2 mutations in 2 families with benign familial neonatal convulsions. Child Neurology Open, 4, 2329048X17691396. https://doi.org/10.1177/2329048X17691396
Alaimo, A., Etxeberria, A., Gómez-Posada, J. C., Gomis-Perez, C., Fernández-Orth, J., Malo, C., & Villarroel, A. (2018). Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants. Channels (Austin, Texas), 12(1), 299-310. https://doi.org/10.1080/19336950.2018.1511512
Alberdi, A., Gomis-Perez, C., Bernardo-Seisdedos, G., Alaimo, A., Malo, C., Aldaregia, J., Lopez-Robles, C., Areso, P., Butz, E., Wahl-Schott, C., & Villarroel, A. (2015). Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation. Journal of Cell Science, 128(21), 4014-4023. https://doi.org/10.1242/jcs.176420
Allen, N. M., Conroy, J., Shahwan, A., Lynch, B., Correa, R. G., Pena, S. D. J., McCreary, D., Magalhães, T. R., Ennis, S., Lynch, S. A., & King, M. D. (2016). Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia, 57(1), e12-e17. https://doi.org/10.1111/epi.13250
Ambrosino, P., Alaimo, A., Bartollino, S., Manocchio, L., De Maria, M., Mosca, I., Gomis-Perez, C., Alberdi, A., Scambia, G., Lesca, G., Villarroel, A., Taglialatela, M., & Soldovieri, M. V. (2015). Epilepsy-causing mutations in Kv7.2 C-terminus affect binding and functional modulation by calmodulin. Biochimica et Biophysica Acta, 1852(9), 1856-1866. https://doi.org/10.1016/j.bbadis.2015.06.012
Amiet, C., Gourfinkel-An, I., Bouzamondo, A., Tordjman, S., Baulac, M., Lechat, P., Mottron, L., & Cohen, D. (2008). Epilepsy in autism is associated with intellectual disability and gender: Evidence from a meta-analysis. Biological Psychiatry, 64(7), 577-582. https://doi.org/10.1016/j.biopsych.2008.04.030
Anazi, S., Maddirevula, S., Faqeih, E., Alsedairy, H., Alzahrani, F., Shamseldin, H. E., Patel, N., Hashem, M., Ibrahim, N., Abdulwahab, F., Ewida, N., Alsaif, H. S., al sharif, H., Alamoudi, W., Kentab, A., Bashiri, F. A., Alnaser, M., AlWadei, A. H., Alfadhel, M., … Alkuraya, F. S. (2017). Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Molecular Psychiatry, 22(4), 615-624. https://doi.org/10.1038/mp.2016.113
Arafat, A., Jing, P., Ma, Y., Pu, M., Nan, G., Fang, H., Chen, C., & Fei, Y. (2017). Unexplained early infantile epileptic encephalopathy in Han Chinese children: Next-generation sequencing and phenotype enriching. Scientific Reports, 7, 46227. https://doi.org/10.1038/srep46227
Begemann, A., Acuña, M. A., Zweier, M., Vincent, M., Steindl, K., Bachmann-Gagescu, R., Hackenberg, A., Abela, L., Plecko, B., Kroell-Seger, J., Baumer, A., Yamakawa, K., Inoue, Y., Asadollahi, R., Sticht, H., Zeilhofer, H. U., & Rauch, A. (2019). Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes. Molecular Medicine (Cambridge, MA), 25(1), 6. https://doi.org/10.1186/s10020-019-0073-6
Brown, D. A., Gähwiler, B. H., Griffith, W. H., & Halliwell, J. V. (1990). Membrane currents in hippocampal neurons. Progress in Brain Research, 83, 141-160. https://doi.org/10.1016/s0079-6123(08)61247-9
Carroll, L. S., Woolf, R., Ibrahim, Y., Williams, H. J., Dwyer, S., Walters, J., Kirov, G., O'Donovan, M. C., & Owen, M. J. (2016). Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation. Psychiatric Genetics, 26(2), 60-65. https://doi.org/10.1097/YPG.0000000000000110
Chen, L., Zhang, Q., Qiu, Y., Li, Z., Chen, Z., Jiang, H., Li, Y., & Yang, H. (2015). Migration of PIP2 lipids on voltage-gated potassium channel surface influences channel deactivation. Scientific Reports, 5, 15079. https://doi.org/10.1038/srep15079
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B., Brunner, H. G., Veltman, J. A., & Vissers, L. E. L. M. (2012). Diagnostic exome sequencing in persons with severe intellectual disability. The New England Journal of Medicine, 367(20), 1921-1929. https://doi.org/10.1056/NEJMoa1206524
Dedek, K., Kunath, B., Kananura, C., Reuner, U., Jentsch, T. J., & Steinlein, O. K. (2001). Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proceedings of the National Academy of Sciences of the United States of America, 98(21), 12272-12277. https://doi.org/10.1073/pnas.211431298
Dedek, K., Fusco, L., Teloy, N., & Steinlein, O. K. (2003). Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Research, 54(1), 21-27. https://doi.org/10.1016/s0920-1211(03)00037-8
Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M. D., Herzog, J., van den Maagdenberg, A. M. J. M., Pusch, M., & Strom, T. M. (2005). Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet (London, England), 366(9483), 371-377. https://doi.org/10.1016/S0140-6736(05)66786-4
Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E. E., Epstein, M. P., Glauser, T., Goldstein, D. B., Han, Y., Heinzen, E. L., Hitomi, Y., Howell, K. B., Johnson, M. R., Kuzniecky, R., Lowenstein, D. H., Lu, Y. F., Madou, M. R., … Winawer, M. R. (2013). De novo mutations in epileptic encephalopathies. Nature, 501(7466), 217-221. https://doi.org/10.1038/nature12439
Firth, H. V., Wright, C. F., & Study, D. D. D. (2011). The deciphering developmental disorders (DDD) study. Developmental Medicine and Child Neurology, 53(8), 702-703. https://doi.org/10.1111/j.1469-8749.2011.04032.x
Gburek-Augustat, J., Beck-Woedl, S., Tzschach, A., Bauer, P., Schoening, M., & Riess, A. (2016). Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome. European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society, 20(4), 661-665. https://doi.org/10.1016/j.ejpn.2016.04.005
Geoffroy, V., Pizot, C., Redin, C., Piton, A., Vasli, N., Stoetzel, C., Blavier, A., Laporte, J., & Muller, J. (2015). VaRank: A simple and powerful tool for ranking genetic variants. PeerJ, 3, e796. https://doi.org/10.7717/peerj.796
Gieldon, L., Mackenroth, L., Kahlert, A.-K., Lemke, J. R., Porrmann, J., Schallner, J., von der Hagen, M., Markus, S., Weidensee, S., Novotna, B., Soerensen, C., Klink, B., Wagner, J., Tzschach, A., Jahn, A., Kuhlee, F., Hackmann, K., Schrock, E., Di Donato, N., & Rump, A. (2018). Diagnostic value of partial exome sequencing in developmental disorders. PLoS One, 13(8), e0201041. https://doi.org/10.1371/journal.pone.0201041
Gomis-Pérez, C., Urrutia, J., Marcé-Grau, A., Malo, C., López-Laso, E., Felipe-Rucián, A., Raspall-Chaure, M., Macaya, A., & Villarroel, A. (2019). Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy. Epilepsia, 60(1), 139-148. https://doi.org/10.1111/epi.14609
Goto, A., Ishii, A., Shibata, M., Ihara, Y., Cooper, E. C., & Hirose, S. (2019). Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia, 60(9), 1870-1880. https://doi.org/10.1111/epi.16314
Gregor, A., Albrecht, B., Bader, I., Bijlsma, E. K., Ekici, A. B., Engels, H., Hackmann, K., Horn, D., Hoyer, J., Klapecki, J., Kohlhase, J., Maystadt, I., Nagl, S., Prott, E., Tinschert, S., Ullmann, R., Wohlleber, E., Woods, G., Reis, A., … Zweier, C. (2011). Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Medical Genetics, 12, 106. https://doi.org/10.1186/1471-2350-12-106
Grinton, B. E., Heron, S. E., Pelekanos, J. T., Zuberi, S. M., Kivity, S., Afawi, Z., Williams, T. C., Casalaz, D. M., Yendle, S., Linder, I., Lev, D., Lerman-Sagie, T., Malone, S., Bassan, H., Goldberg-Stern, H., Stanley, T., Hayman, M., Calvert, S., Korczyn, A. D., Shevell, M., … Berkovic, S. F. (2015). Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome. Epilepsia, 56(7), 1071-1080. https://doi.org/10.1111/epi.13020
Grozeva, D., Carss, K., Spasic-Boskovic, O., Tejada, M.-I., Gecz, J., Shaw, M., Corbett, M., Haan, E., Thompson, E., Friend, K., Hussain, Z., Hackett, A., Field, M., Renieri, A., Stevenson, R., Schwartz, C., Floyd, J. A., Bentham, J., Cosgrove, C., Keavney, B., … Raymond, F. L. (2015). Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Human Mutation, 36(12), 1197-1204. https://doi.org/10.1002/humu.22901
Gürsoy, S., & Erçal, D. (2016). Diagnostic approach to genetic causes of early-onset epileptic encephalopathy. Journal of Child Neurology, 31(4), 523-532. https://doi.org/10.1177/0883073815599262
Hamdan, F. F., Gauthier, J., Dobrzeniecka, S., Lortie, A., Mottron, L., Vanasse, M., D'Anjou, G., Lacaille, J. C., Rouleau, G. A., & Michaud, J. L. (2011). Intellectual disability without epilepsy associated with STXBP1 disruption. European Journal of Human Genetics: EJHG, 19(5), 607-609. https://doi.org/10.1038/ejhg.2010.183
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M. T., Rosenfeld, J. A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., … Michaud, J. L. (2017). High rate of recurrent De novo mutations in developmental and epileptic Encephalopathies. American Journal of Human Genetics, 101(5), 664-685. https://doi.org/10.1016/j.ajhg.2017.09.008
Hewson, S., Puka, K., & Mercimek-Mahmutoglu, S. (2017). Variable expressivity of a likely pathogenic variant in KCNQ2 in a three-generation pedigree presenting with intellectual disability with childhood onset seizures. American Journal of Medical Genetics. Part A, 173(8), 2226-2230. https://doi.org/10.1002/ajmg.a.38281
Karam, S. M., Riegel, M., Segal, S. L., Félix, T. M., Barros, A. J. D., Santos, I. S., Matijasevich, A., Giugliani, R., & Black, M. (2015). Genetic causes of intellectual disability in a birth cohort: A population-based study. American Journal of Medical Genetics. Part A, 167(6), 1204-1214. https://doi.org/10.1002/ajmg.a.37011
Kipnis, P. A., Sullivan, B. J., & Kadam, S. D. (2019). Sex-dependent signaling pathways underlying seizure susceptibility and the role of chloride cotransporters. Cells, 8(5). https://doi.org/10.3390/cells8050448
Kvarnung, M., & Nordgren, A. (2017). Intellectual disability & rare disorders: a diagnostic challenge. Advances in Experimental Medicine and Biology, 1031, 39-54. https://doi.org/10.1007/978-3-319-67144-4_3
Lee, I.-C., Yang, J.-J., & Li, S.-Y. (2017). A KCNQ2 E515D mutation associated with benign familial neonatal seizures and continuous spike and waves during slow-wave sleep syndrome in Taiwan. Journal of the Formosan Medical Association = Taiwan Yi Zhi, 116(9), 711-719. https://doi.org/10.1016/j.jfma.2016.11.009
Lemke, J. R., Riesch, E., Scheurenbrand, T., Schubach, M., Wilhelm, C., Steiner, I., Hansen, J., Courage, C., Gallati, S., Bürki, S., Strozzi, S., Simonetti, B. G., Grunt, S., Steinlin, M., Alber, M., Wolff, M., Klopstock, T., Prott, E. C., Lorenz, R., Spaich, C., … Biskup, S. (2012). Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia, 53(8), 1387-1398. https://doi.org/10.1111/j.1528-1167.2012.03516.x
Mary, L., Piton, A., Schaefer, E., Mattioli, F., Nourisson, E., Feger, C., Redin, C., Barth, M., el Chehadeh, S., Colin, E., Coubes, C., Faivre, L., Flori, E., Geneviève, D., Capri, Y., Perrin, L., Fabre-Teste, J., Timbolschi, D., Verloes, A., … Giurgea, I. (2018). Disease-causing variants in TCF4 are a frequent cause of intellectual disability: Lessons from large-scale sequencing approaches in diagnosis. European Journal of Human Genetics: EJHG, 26(7), 996-1006. https://doi.org/10.1038/s41431-018-0096-4
Maulik, P. K., Mascarenhas, M. N., Mathers, C. D., Dua, T., & Saxena, S. (2011). Prevalence of intellectual disability: A meta-analysis of population-based studies. Research in Developmental Disabilities, 32(2), 419-436. https://doi.org/10.1016/j.ridd.2010.12.018
Miceli, F., Soldovieri, M. V., Ambrosino, P., De Maria, M., Migliore, M., Migliore, R., & Taglialatela, M. (2015). Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 35(9), 3782-3793. https://doi.org/10.1523/JNEUROSCI.4423-14.2015
Miceli, F., Soldovieri, M. V., Hernandez, C. C., Shapiro, M. S., Annunziato, L., & Taglialatela, M. (2008). Gating consequences of charge neutralization of arginine residues in the S4 segment of K(v)7.2, an epilepsy-linked K+ channel subunit. Biophysical Journal, 95(5), 2254-2264. https://doi.org/10.1529/biophysj.107.128371
Miceli, F., Vargas, E., Bezanilla, F., & Taglialatela, M. (2012). Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain. Biophysical Journal, 102(6), 1372-1382. https://doi.org/10.1016/j.bpj.2012.02.004
Millichap, J. J., Park, K. L., Tsuchida, T., Ben-Zeev, B., Carmant, L., Flamini, R., Joshi, N., Levisohn, P. M., Marsh, E., Nangia, S., Narayanan, V., Ortiz-Gonzalez, X. R., Patterson, M. C., Pearl, P. L., Porter, B., Ramsey, K., McGinnis, E. L., Taglialatela, M., Tracy, M., … Cooper, E. C. (2016). KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurology Genetics, 2(5), e96. https://doi.org/10.1212/NXG.0000000000000096
Olson, H. E., Kelly, M., LaCoursiere, C. M., Pinsky, R., Tambunan, D., Shain, C., Ramgopal, S., Takeoka, M., Libenson, M. H., Julich, K., Loddenkemper, T., Marsh, E. D., Segal, D., Koh, S., Salman, M. S., Paciorkowski, A. R., Yang, E., Bergin, A. M., Sheidley, B. R., & Poduri, A. (2017). Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Annals of Neurology, 81(3), 419-429. https://doi.org/10.1002/ana.24883
Petterson, B., Bourke, J., Leonard, H., Jacoby, P., & Bower, C. (2007). Co-occurrence of birth defects and intellectual disability. Paediatric and Perinatal Epidemiology, 21(1), 65-75. https://doi.org/10.1111/j.1365-3016.2007.00774.x
Quartier, A., Poquet, H., Gilbert-Dussardier, B., Rossi, M., Casteleyn, A.-S., Portes, V. d., Feger, C., Nourisson, E., Kuentz, P., Redin, C., Thevenon, J., Mosca-Boidron, A. L., Callier, P., Muller, J., Lesca, G., Huet, F., Geoffroy, V., el Chehadeh, S., Jung, M., … Piton, A. (2017). Intragenic FMR1 disease-causing variants: A significant mutational mechanism leading to fragile-X syndrome. European Journal of Human Genetics: EJHG, 25(4), 423-431. https://doi.org/10.1038/ejhg.2016.204
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., Hempel, M., Horn, D., Hoyer, J., Joset, P., Röpke, A., Moog, U., Riess, A., Thiel, C. T., … Strom, T. M. (2012). Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: An exome sequencing study. Lancet (London, England), 380(9854), 1674-1682. https://doi.org/10.1016/S0140-6736(12)61480-9
Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., & Baulac, S. (2018). Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. The Journal of Clinical Investigation, 128(6), 2452-2458. https://doi.org/10.1172/JCI99384
Salgueiro-Pereira, A. R., Duprat, F., Pousinha, P. A., Loucif, A., Douchamps, V., Regondi, C., Ayrault, M., Eugie, M., Stunault, M. I., Escayg, A., Goutagny, R., Gnatkovsky, V., Frassoni, C., Marie, H., Bethus, I., & Mantegazza, M. (2019). A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies. Neurobiology of Disease, 125, 31-44. https://doi.org/10.1016/j.nbd.2019.01.006
Shellhaas, R. A., Wusthoff, C. J., Tsuchida, T. N., Glass, H. C., Chu, C. J., Massey, S. L., Soul, J. S., Wiwattanadittakun, N., Abend, N. S., Cilio, M. R., & Neonatal Seizure Registry. (2017). Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology, 89(9), 893-899. https://doi.org/10.1212/WNL.0000000000004284
Singh, N. A., Charlier, C., Stauffer, D., DuPont, B. R., Leach, R. J., Melis, R., Ronen, G. M., Bjerre, I., Quattlebaum, T., Murphy, J. V., McHarg, M. L., Gagnon, D., Rosales, T. O., Peiffer, A., Anderson, V. E., & Leppert, M. (1998). A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nature Genetics, 18(1), 25-29. https://doi.org/10.1038/ng0198-25
Stamberger, H., Nikanorova, M., Willemsen, M. H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destrée, A., Dilena, R., Erasmus, C. E., Fannemel, M., … Weckhuysen, S. (2016). STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology, 86(10), 954-962. https://doi.org/10.1212/WNL.0000000000002457
Staněk, D., Laššuthová, P., Štěrbová, K., Vlčková, M., Neupauerová, J., Krůtová, M., & Seeman, P. (2018). Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. Orphanet Journal of Rare Diseases, 13(1), 71. https://doi.org/10.1186/s13023-018-0812-8
Velíšková, J., & Desantis, K. A. (2013). Sex and hormonal influences on seizures and epilepsy. Hormones and Behavior, 63(2), 267-277. https://doi.org/10.1016/j.yhbeh.2012.03.018
Warner, T. A., Shen, W., Huang, X., Liu, Z., Macdonald, R. L., & Kang, J.-Q. (2016). Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy. Human Molecular Genetics, 25(15), 3192-3207. https://doi.org/10.1093/hmg/ddw168
Watanabe, H., Nagata, E., Kosakai, A., Nakamura, M., Yokoyama, M., Tanaka, K., & Sasai, H. (2000). Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. Journal of Neurochemistry, 75(1), 28-33.
Weckhuysen, S., Mandelstam, S., Suls, A., Audenaert, D., Deconinck, T., Claes, L. R. F., Deprez, L., Smets, K., Hristova, D., Yordanova, I., Jordanova, A., Ceulemans, B., Jansen, A., Hasaerts, D., Roelens, F., Lagae, L., Yendle, S., Stanley, T., Heron, S. E., Mulley, J. C., … de Jonghe, P. (2012). KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy. Annals of Neurology, 71(1), 15-25. https://doi.org/10.1002/ana.22644
Weiss, L. A., Escayg, A., Kearney, J. A., Trudeau, M., MacDonald, B. T., Mori, M., Reichert, J., Buxbaum, J. D., & Meisler, M. H. (2003). Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular Psychiatry, 8(2), 186-194. https://doi.org/10.1038/sj.mp.4001241
Zara, F., Specchio, N., Striano, P., Robbiano, A., Gennaro, E., Paravidino, R., Vanni, N., Beccaria, F., Capovilla, G., Bianchi, A., Caffi, L., Cardilli, V., Darra, F., Bernardina, B. D., Fusco, L., Gaggero, R., Giordano, L., Guerrini, R., Incorpora, G., … Minetti, C. (2013). Genetic testing in benign familial epilepsies of the first year of life: Clinical and diagnostic significance. Epilepsia, 54(3), 425-436. https://doi.org/10.1111/epi.12089
Zhou, X., Ma, A., Liu, X., Huang, C., Zhang, Y., Shi, R., Mao, S., Geng, T., & Li, S. (2006). Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2. European Journal of Pediatrics, 165(10), 691-695. https://doi.org/10.1007/s00431-006-0157-5