CHD2 variants are a risk factor for photosensitivity in epilepsy

Elizabeth C Galizia 1, Candace T Myers 2, Costin Leu 3, Carolien G F de Kovel 4, Tatiana Afrikanova 5, Maria Lorena Cordero-Maldonado 5, Teresa G Martins 5, Maxime Jacmin 5, Suzanne Drury 6, V Krishna Chinthapalli 3, Hiltrud Muhle 7, Manuela Pendziwiat 7, Thomas Sander 8, Ann-Kathrin Ruppert 8, Rikke S Møller 9, Holger Thiele 8, Roland Krause 5, Julian Schubert 10, Anna-Elina Lehesjoki 11, Peter Nürnberg 8, Holger Lerche 10; EuroEPINOMICS CoGIE Consortium; Aarno Palotie 12, Antonietta Coppola 13, Salvatore Striano 14, Luigi Del Gaudio 14, Christopher Boustred 6, Amy L Schneider 15, Nicholas Lench 6, Bosanka Jocic-Jakubi 16, Athanasios Covanis 17, Giuseppe Capovilla 18, Pierangelo Veggiotti 19, Marta Piccioli 20, Pasquale Parisi 21, Laura Cantonetti 22, Lynette G Sadleir 23, Saul A Mullen 24, Samuel F Berkovic 15, Ulrich Stephani 7, Ingo Helbig 7, Alexander D Crawford 5, Camila V Esguerra 25, Dorothee G A Kasteleijn-Nolst Trenité 4, Bobby P C Koeleman 26, Heather C Mefford 27, Ingrid E Scheffer 28, Sanjay M Sisodiya 1

Affiliations

01 May 2015

-

doi: 10.1093/brain/awv052

Abstract

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Keywords: eyelid myoclonia with absences; photosensitive; seizure.

Figures

Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity.

Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity.

Figure 1 Schematic of CHD2 illustrating its functional (chromo, DEXDc, DNA-binding and ATP helicase) domains, the location of previously-reported variants and the unique variants in both cases and controls identified in this study.

Figure 1 Schematic of CHD2 illustrating its functional (chromo, DEXDc, DNA-binding and ATP helicase) domains, the location of previously-reported variants and the unique variants in both cases and controls identified in this study.

Figure 2 Representative tectal field recordings of 4-dpf zebrafish larvae. Background fragment of non-treated wild-type control in the dark (A); reaction of a non-injected fish to light ON - movement artefacts (wavy background) and a very short spike were observed (B); response to light ON of the morpholino-injected larvae: significantly more spiking activity is seen (C). The scale is the same for all three fragments. show full caption

Figure 2 Representative tectal field recordings of 4-dpf zebrafish larvae. Background fragment of non-treated wild-type control in the dark (A); reaction of a non-injected fish to light ON - movement artefacts (wavy background) and a very short spike were observed (B); response to light ON of the morpholino-injected larvae: significantly more spiking activity is seen (C). The scale is the same for all three fragments. show full caption

Figure 3 Electrographic activity of zebrafish larvae with chd2 knockdown and light ON stimulus. Zebrafish larvae (4 dpf) were kept in the dark (or darkened environment, if not possible otherwise) for all groups in Danieau’s medium. Tectal field recordings were performed for the first 5 min in the dark and subsequently in light ON state for the following 5 min in morpholino-injected larvae (n = 15) and non-injected larvae (n = 10). A spiking episode, either spontaneous or evoked by light, was defined as a paroxysm of high-frequency (200–500 Hz) activity with the amplitude exceeding three times the background. Average duration of spiking events ± SEM detected per condition is shown in A. Average number of events per fish ± SEM is shown in B. Cumulative duration of spiking activity per fish as seconds ± SEM is shown in C. Cumulative frequency distribution of spiking episodes is shown in D: morpholino-injected larvae show more activity than any of the non-injected controls, and a higher photosensitivity (curve shift to the right in the light compared to the dark recordings). *P < 0.05 and **P < 0.01 Mann-Whitney test. show full caption

Figure 3 Electrographic activity of zebrafish larvae with chd2 knockdown and light ON stimulus. Zebrafish larvae (4 dpf) were kept in the dark (or darkened environment, if not possible otherwise) for all groups in Danieau’s medium. Tectal field recordings were performed for the first 5 min in the dark and subsequently in light ON state for the following 5 min in morpholino-injected larvae (n = 15) and non-injected larvae (n = 10). A spiking episode, either spontaneous or evoked by light, was defined as a paroxysm of high-frequency (200–500 Hz) activity with the amplitude exceeding three times the background. Average duration of spiking events ± SEM detected per condition is shown in A. Average number of events per fish ± SEM is shown in B. Cumulative duration of spiking activity per fish as seconds ± SEM is shown in C. Cumulative frequency distribution of spiking episodes is shown in D: morpholino-injected larvae show more activity than any of the non-injected controls, and a higher photosensitivity (curve shift to the right in the light compared to the dark recordings). *P < 0.05 and **P < 0.01 Mann-Whitney test. show full caption

Similar articles

CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures.

Trivisano M, Striano P, Sartorelli J, Giordano L, Traverso M, Accorsi P, Cappelletti S, Claps DJ, Vigevano F, Zara F, Specchio N.Epilepsy Behav. 2015 Oct;51:53-6. doi: 10.1016/j.yebeh.2015.06.029. Epub 2015 Aug 7.PMID: 26262932

Adult-onset photosensitivity: clinical significance and epilepsy syndromes including idiopathic (possibly genetic) photosensitive occipital epilepsy.

Koutroumanidis M, Tsirka V, Panayiotopoulos C.Epileptic Disord. 2015 Sep;17(3):275-86. doi: 10.1684/epd.2015.0765.PMID: 26293003

De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.

Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A, Djémié T, Afrikanova T, Gormley P, von Spiczak S, Kluger G, Iliescu CM, Talvik T, Talvik I, Meral C, Caglayan HS, Giraldez BG, Serratosa J, Lemke JR, Hoffman-Zacharska D, Szczepanik E, Barisic N, Komarek V, Hjalgrim H, Møller RS, Linnankivi T, Dimova P, Striano P, Zara F, Marini C, Guerrini R, Depienne C, Baulac S, Kuhlenbäumer G, Crawford AD, Lehesjoki AE, de Witte PA, Palotie A, Lerche H, Esguerra CV, De Jonghe P, Helbig I; EuroEPINOMICS RES Consortium.Am J Hum Genet. 2013 Nov 7;93(5):967-75. doi: 10.1016/j.ajhg.2013.09.017. Epub 2013 Oct 24.PMID: 24207121 Free PMC article.

[Photosensitive epilepsies of children].

Rodríguez-Barrionuevo AC, Bauzano-Poley E, Rodríguez Vives MA.Rev Neurol. 2001 Apr 16-30;32(8):768-72.PMID: 11391515 Review. Spanish.

Photosensitivity in idiopathic generalized epilepsies.

Covanis A.Epilepsia. 2005;46 Suppl 9:67-72. doi: 10.1111/j.1528-1167.2005.00315.x.PMID: 16302877 Review.

Cited by

Zebrafish as an Innovative Tool for Epilepsy Modeling: State of the Art and Potential Future Directions.

D'Amora M, Galgani A, Marchese M, Tantussi F, Faraguna U, De Angelis F, Giorgi FS.Int J Mol Sci. 2023 Apr 22;24(9):7702. doi: 10.3390/ijms24097702.PMID: 37175408 Free PMC article. Review.

Genetic and phenotypic spectrum of Chinese patients with epilepsy and photosensitivity.

Niu Y, Gong P, Jiao X, Xu Z, Zhang Y, Yang Z.Front Neurol. 2022 Aug 2;13:907228. doi: 10.3389/fneur.2022.907228. eCollection 2022.PMID: 36034301 Free PMC article.

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders.

Ochenkowska K, Herold A, Samarut É.Front Mol Neurosci. 2022 Jul 6;15:944693. doi: 10.3389/fnmol.2022.944693. eCollection 2022.PMID: 35875659 Free PMC article. Review.

Photo-Dependent Reflex Seizures-A Scoping Review with Proposal of Classification.

Strzelecka J, Mazurkiewicz DW, Skadorwa T, Gąsior JS, Jóźwiak S.J Clin Med. 2022 Jun 29;11(13):3766. doi: 10.3390/jcm11133766.PMID: 35807051 Free PMC article. Review.

Clinical analysis of CHD2 gene mutations in pediatric patients with epilepsy.

Feng W, Fang F, Wang X, Chen C, Lu J, Deng J.Pediatr Investig. 2022 Apr 26;6(2):93-99. doi: 10.1002/ped4.12321. eCollection 2022 Jun.PMID: 35774528 Free PMC article.

KMEL References

https://pubmed.ncbi.nlm.nih.gov/

References

  1.  
    1. Afrikanova T, Serruys A-SK, Buenafe OEM, Clinckers R, Smolders I, de Witte PA, et al. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PloS One. 2013;8:e54166. - PMC - PubMed
  2.  
    1. Capelli LP, Krepischi ACV, Gurgel-Giannetti J, Mendes MF, Rodrigues T, Varela MC, et al. Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency. Eur J Med Genet. 2012;55:132–4. - PubMed
  3.  
    1. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825–30. - PMC - PubMed
  4.  
    1. Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, et al. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord. 2014;6:9. - PMC - PubMed
  5.  
    1. Cnossen WR, te Morsche RHM, Hoischen A, Gilissen C, Chrispijn M, Venselaar H, et al. Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc Natl Acad Sci USA. 2014;111:5343–8. - PMC - PubMed
  6.  
    1. De Kovel CGF, Pinto D, Tauer U, Lorenz S, Muhle H, Leu C, et al. Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis. Epilepsy Res. 2010;89:286–94. - PubMed
  7.  
    1. Dhamija R, Breningstall G, Wong-Kisiel L, Dolan M, Hirsch B, Wirrell E. Microdeletion of chromosome 15q26.1 in a child with intractable generalized epilepsy. Pediatr Neurol. 2011;45:60–2. - PubMed
  8.  
    1. Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De novo mutations in epileptic encephalopathies. Nature 2013; 501: 217–21. - PMC - PubMed
  9.  
    1. French JA, Krauss GL, Kasteleijn D, DiVentura BD, Bagiella E. Effects of marketed antiepileptic drugs and placebo in the human photosensitivity screening protocol. Neurotherapeutics. 2014;11:412–18. - PMC - PubMed
  10.  
    1. Gregory RP, Oates T, Merry RT. Electroencephalogram epileptiform abnormalities in candidates for aircrew training. Electroencephalogr Clin Neurophysiol. 1993;86:75–7. - PubMed
  11.  
    1. Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, et al. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet. 2012;91:293–302. - PMC - PubMed
  12.  
    1. Kasteleijn-Nolst Trenité D, Rubboli G, Hirsch E, Martins da Silva A, Seri S, Wilkins A, et al. Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory. Epilepsia. 2012;53:16–24. - PubMed
  13.  
    1. Kasteleijn-Nolst Trenite D, Silva L, Maureza M. Prevelance of photoparoxysmal EEG responses in normal children and adolescents in Teofile Otoni, Brazil; 2001-2002. Epilepsia. 2003;44(Suppl 8):48. - PubMed
  14.  
    1. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5. - PMC - PubMed
  15.  
    1. Koeleman BPC, de Kovel CGF, Kasteleijn-Nolst Trenité DGA. Photoparoxysmal EEG response and genetic dissection of juvenile myoclonic epilepsy. Epilepsy Behav. 2013;28(Suppl 1):S69–71. - PubMed
  16.  
    1. Kulkarni S, Nagarajan P, Wall J, Donovan DJ, Donell RL, Ligon AH, et al. Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. Am J Med Genet A. 2008;146A:1117–27. - PMC - PubMed
  17.  
    1. Liu JC, Ferreira CG, Yusufzai T. Human CHD2 Is a Chromatin Assembly ATPase Regulated by Its Chromo- and DNA-binding Domains. J Biol Chem. 2015;290:25–34. - PMC - PubMed
  18.  
    1. Lu Y, Waltz S, Stenzel K, Muhle H, Stephani U. Photosensitivity in epileptic syndromes of childhood and adolescence. Epileptic Disord. 2008;10:136–43. - PubMed
  19.  
    1. Lund C, Brodtkorb E, Oye A-M, Røsby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav. 2014;33:18–21. - PubMed
  20.  
    1. Lund C, Brodtkorb E, Røsby O, Rødningen OK, Selmer KK. Copy number variants in adult patients with Lennox-Gastaut syndrome features. Epilepsy Res. 2013;105:110–17. - PubMed
  21.  
    1. Marfella CGA, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN. Mutation of the SNF2 family member Chd2 affects mouse development and survival. J Cell Physiol. 2006;209:162–71. - PubMed
  22.  
    1. Moore HA, Whitmore D. Circadian rhythmicity and light sensitivity of the zebrafish brain. PloS One. 2014;9:e86176. - PMC - PubMed
  23.  
    1. Mullen SA, Carvill GL, Bellows S, Bayly MA, Trucks H, Lal D, et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013;81:1507–14. - PMC - PubMed
  24.  
    1. Newmark ME, Penry JK. Photosensitivity and epilepsy: a review. New York: Raven Press; 1979.
  25.  
    1. Oguni H, Hayashi K, Awaya Y, Fukuyama Y, Osawa M. Severe myoclonic epilepsy in infants–a review based on the Tokyo Women’s Medical University series of 84 cases. Brain Dev. 2001;23:736–48. - PubMed
  26.  
    1. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709. - PMC - PubMed
  27.  
    1. Quirk JA, Fish DR, Smith SJ, Sander JW, Shorvon SD, Allen PJ. Incidence of photosensitive epilepsy: a prospective national study. Electroencephalogr Clin Neurophysiol. 1995;95:260–7. - PubMed
  28.  
    1. Sadleir LG, Vears D, Regan B, Redshaw N, Bleasel A, Scheffer IE. Family studies of individuals with eyelid myoclonia with absences. Epilepsia. 2012;53:2141–8. - PubMed
  29.  
    1. Schuster EF, Stöger R. CHD5 defines a new subfamily of chromodomain-SWI2/SNF2-like helicases. Mamm Genome. 2002;13:117–19. - PubMed
  30.  
    1. So EL, Ruggles KH, Ahmann PA, Olson KA. Prognosis of photoparoxysmal response in nonepileptic patients. Neurology. 1993;43:1719–22. - PubMed
  31.  
    1. Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, et al. 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;93:967–75. - PMC - PubMed
  32.  
    1. Tauer U, Lorenz S, Lenzen KP, Heils A, Muhle H, Gresch M, et al. Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy. Ann Neurol. 2005;57:866–73. - PubMed
  33.  
    1. Taylor I, Berkovic SF, Scheffer IE. Genetics of epilepsy syndromes in families with photosensitivity. Neurology. 2013;80:1322–9. - PubMed
  34.  
    1. Taylor I, Marini C, Johnson MR, Turner S, Berkovic SF, Scheffer IE. Juvenile myoclonic epilepsy and idiopathic photosensitive occipital lobe epilepsy: is there overlap? Brain J Neurol. 2004;127:1878–86. - PubMed
  35.  
    1. Thomas RH, Zhang LM, Carvill GL, Archer JS, Heavin SB, Mandelstam SA, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology. 2015 pii: 10.1212/WNL.0000000000001305. - PMC - PubMed
  36.  
    1. Veredice C, Bianco F, Contaldo I, Orteschi D, Stefanini MC, Battaglia D, et al. Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case. Epilepsia. 2009;50:1810–15. - PubMed
  37.  
    1. Verrotti A, Beccaria F, Fiori F, Montagnini A, Capovilla G. Photosensitivity: epidemiology, genetics, clinical manifestations, assessment, and management. Epileptic Disord Int Epilepsy J Videotape. 2012;14:349–62. - PubMed
  38.  
    1. Wain LV, Sayers I, Soler Artigas M, Portelli MA, Zeggini E, Obeidat M, et al. Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. PLoS Genet. 2014;10:e1004314. - PMC - PubMed
  39.  
    1. Walter WG, Dovey VJ, Shipton H. Analysis of the electrical response of the human cortex to photic stimulation. Nature. 1946;158:540. - PubMed
  40.  
    1. Waltz S, Stephani U. Inheritance of photosensitivity. Neuropediatrics. 2000;31:82–5. - PubMed
  41.  
    1. Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS. Characterization of the CHD family of proteins. Proc Natl Acad Sci USA. 1997;94:11472–7. - PMC - PubMed

Page Navigation