Thursday, July 28, 2016

CHD2 mutations

Inspired by a patient.

Trivisano M, Striano P, Sartorelli J, Giordano L, Traverso M, Accorsi P,
Cappelletti S, Claps DJ, Vigevano F, Zara F, Specchio N. CHD2 mutations are a
rare cause of generalized epilepsy with myoclonic-atonic seizures. Epilepsy
Behav. 2015 Oct;51:53-6.

Chromodomain helicase DNA-binding protein 2 (CHD2) gene mutations have been reported in patients with myoclonic-atonic epilepsy (MAE), as well as in patients with Lennox-Gastaut, Dravet, and Jeavons syndromes and other epileptic encephalopathies featuring generalized epilepsy and intellectual disability. The aim of this study was to assess the impact of CHD2 mutations in a series of patients with MAE. Twenty patients affected by MAE were included in the study. We analyzed antecedents, age at onset, seizure semiology and frequency, EEG, treatment, and neuropsychological outcome. We sequenced the CHD2 gene with Sanger technology. We identified a CHD2 frameshift mutation in one patient (c.4256del19). He was a 17-year-old boy with no familial history for epilepsy and normal development before epilepsy onset. Epilepsy onset was at 3years and 5months: he presented with myoclonic-atonic seizures, head drops, myoclonic jerks, and absences. Interictal EEGs revealed slow background activity associated with generalized epileptiform abnormalities and photoparoxysmal response. His seizures were highly responsive to valproic acid, and an attempt to withdraw it led to seizure recurrence. Neuropsychological evaluation revealed moderate intellectual disability. Chromodomain-helicase-DNA-binding protein 2 is not the major gene associated with MAE. Conversely, CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity, which might overlap with MAE, Lennox-Gastaut, Dravet, and Jeavons syndromes.

Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, Ogilvie
CM, Lionel AC, Marshall CR, Vaags AK, Hashemi B, Boisvert K, Mathonnet G, Tihy F,
So J, Scherer SW, Lemyre E, Stavropoulos DJ. CHD2 haploinsufficiency is
associated with developmental delay, intellectual disability, epilepsy and
neurobehavioural problems. J Neurodev Disord. 2014;6(1):9.

The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.
We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.
Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.
The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.

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. 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 Nov 7;93(5):967-75.


Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.


  1. See

    The patient who inspired this post is heterozygous for a novel variant in the CHD2 gene (c.362 G>T,pArg121Leu). This variant was not observed in approximately 6500 individuals of European and African-American ancestry in the NHLB1 exome sequencing project. The R121L variant is a nonconservative amino acid substitution, which is likely to impact secondary protein structure, as these residues differ in polarity, charge, size and/or other properties. The substitution occurred at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to protein structure/function. The report from this study indicates, "The pathogenic role of this missense change would be further supported if it had occurred de novo or cosegregates with the phenotype in the family." Parental testing for the CHD2 variant was recommended.

    Parental testing was done. Alas, the father has the same CHD2 variant.

  2. Thank you for this information. I'm looking for information on a CHD2 variant 4636C7t deletion.