CHD2 variants are a risk factor for photosensitivity in epilepsy

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.

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 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.

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.