CHD2. Few genes have captured our attention over the last two years like CHD2 has. It is a gene that we almost missed, then sat on for more than a year since we didn’t believe it, only to realize in the end that it is a gene for a specific photosensitive epilepsy syndrome that many people had encountered, but that few people had a name for. Here is what you need to know about CHD2 in 2015.
Epilepsy. Many patients with CHD2 mutations have an onset of seizures between age 6 months and 4 years. Affected individuals have multiple seizure types, with a predominance of myoclonic and absence seizures. Other seizure types include drop attacks and rapid onset of multiple seizure types associated with generalized spike-wave on EEG. A seizure type observed in several patients has been called ‘atonic-myoclonic-absence seizure’, and is characterized by a progressive seizure pattern with an abrupt head nod and atonia followed by a myoclonic absence phase and progression to a ‘ratchet-like’ tonic abduction of the upper limbs. Clinical photosensitivity, with seizures triggered by photostimulation such as a flickering light or television, was described in 9 of 12 patients in one study and may be a distinguishing feature for such early-onset epilepsies. CHD2 mutation is also seen in common epilepsies associated with photosensitivity, and in 3 of 36 patients with the most photosensitive epilepsy syndrome, eyelid myoclonia with absences.
Developmental delay. Patients also have developmental delays that are often present prior to onset of seizures. All patients with the epileptic encephalopathy phenotype reported to date have intellectual disability, though the range is from mild to severe, and some patients exhibit autistic features or other challenging behaviors, including aggression. Developmental delay does not always accompany the more common photosensitive epilepsies with CHD2 mutation.
Haploinsufficient. All CHD2 mutations reported to date in epileptic encephalopathies are de novo. Most of the mutations that have been described are truncating mutations. Four missense mutations have been reported, and all are located in one of the highly conserved helicase domains. No clear genotype-phenotype mutations have been reported, though the number of patients described is still small. Mutations associated with eyelid myoclonia with absences, or with the more common photosensitive epilepsies are usually missense.
Chromatin remodeling. CHD2 encodes the chromodomain DNA helicase binding protein 2. CHD2 and additional members of this family of proteins are responsible for remodeling chromatin, which controls the three-dimensional architecture of the genome and gene expression. CHD2 is ubiquitously expressed, and it is not yet known why mutations cause epilepsy and developmental abnormalities. It is likely that haploinsufficiency of CHD2 leads to altered expression of downstream genes that are important for normal brain development and function.
Family page. The CHD2 patient community maintains an active Facebook page that researchers and families can join. The Facebook page is managed by Melanie Brazil, who will introduce you to the community if you would like to join.