Saturday, March 24, 2018

CHD2 mutations 2

Carvill G, Helbig I, Mefford H. CHD2-Related Neurodevelopmental Disorders. 2015 Dec 10. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from


CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common. To date only 32 individuals with a CHD2-related neurodevelopmental disorder have been reported; thus, better understanding of the phenotypic spectrum of CHD2-related neurodevelopmental disorders is likely to evolve over time.

The diagnosis of a CHD2-related neurodevelopmental disorder is established in a proband with a heterozygous CHD2 single-nucleotide pathogenic variant, small indel (insertion/deletion) pathogenic variant, or a partial- or whole-gene deletion detected on molecular genetic testing.

Treatment of manifestations: Seizures should be managed by an experienced pediatric neurologist. At this time, no specific guidelines regarding choice of specific antiepileptic drugs (AEDs) exist, as the best AED regimen for CHD2-related neurodevelopmental disorders is not yet established. Most patients remain refractory to treatment and require multiple AEDs. Agents/circumstances to avoid: Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, it is recommended that stimuli which may provoke seizures (e.g., intensely flickering lights) be avoided.

CHD2-related neurodevelopmental disorders are inherited in an autosomal dominant manner. To date, all CHD2-related neurodevelopmental disorders have resulted from a de novo pathogenic variant (i.e., no familial occurrences are known). However, because of the possibility of germline mosaicism in a parent, the risk of recurrence is presumed to be greater than in the general population. Prenatal testing for pregnancies presumed to be at increased risk is possible.

Caputo D, Trivisano M, Vigevano F, Fusco L. CHD2-epilepsy: Polygraphic documentation of self-induced seizures due to fixation-off sensitivity. Seizure. 2018 Mar 3;57:8-10.


CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures. Through an accurate Video-EEG polygraphic analysis, we demonstrated that seizures are related to an abnormal increase of epileptiform activity after eye-closure or loss of fixation as observed in the Fixation-Off Sensitivity (FOS) phenomenon. In conclusion our study adds relevant features of the CHD2-epilepsy phenotype and confirms that CHD2 mutations produce a distinctive form of myoclonic epilepsy with visual-sensitive seizures.

Meganathan K, Lewis EMA, Gontarz P, Liu S, Stanley EG, Elefanty AG, Huettner JE, Zhang B, Kroll KL. Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11180-E11189.


Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development.

Lebrun N, Parent P, Gendras J, Billuart P, Poirier K, Bienvenu T. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant. Clin Genet. 2017 Dec;92(6):669-670.


Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder.

Bernardo P, Galletta D, Iasevoli F, D'Ambrosio L, Troisi S, Gennaro E, Zara F, Striano S, de Bartolomeis A, Coppola A. CHD2 mutations: Only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation. Seizure. 2017 Oct;51:186-189.


The chromodomain helicase DNA binding domain 2 ( CHD2 ) gene (OMIM: 602119 ) was originally characterized by Woodage et al. and has been repeatedly reported to play a pivotal role in cerebrocortical development. CHD2 gene mutations was recently described in patients with photosensitive epilepsies, with myoclonic-atonic epilepsy (MAE), Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS) and other forms of epileptic encephalopathies featuring generalized epilepsy with intellectual disability (ID). Furthermore there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders (NDDs) including developmental delay, ID, autism spectrum disorders (ASD), with phenotypic variability among individuals. Here we describe a patient with an unreported de novo CHD2 frameshift mutation presenting with mild facial dysmorphism, infantile epilepsy, ID and severe behavioral disorder. This case expands the clinical spectrum of manifestations associated with CHD2 mutations and supports a multidisciplinary approach for a detailed and careful description of the epilepsy-cognition-behavior complex.

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