HGNC Approved Gene Symbol: CHD2
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38) : 15:92,900,324-93,027,996 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | Developmental and epileptic encephalopathy 94 | 615369 | Autosomal dominant | 3 |
The CHD2 gene encodes a member of the chromodomain helicase DNA-binding (CHD) family of proteins, which are characterized by a chromatin-remodeling domain, termed the chromodomain, and an SNF2-related helicase/ATPase domain. These domains suggest that these proteins function as chromatin remodelers (summary by Carvill et al., 2013).
See CHD1 (602118) for a description of this gene family.
Woodage et al. (1997) characterized the human CHD2 gene. The predicted 1,739-amino acid polypeptide shares 58.6% identity and 69.5% similarity overall with the mouse Chd1 gene product.
Kulkarni et al. (2008) showed that murine Chd2 was expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development.
Using immunofluorescence analysis, Kim et al. (2018) found that Chd2 was widely expressed throughout young adult mouse brain, with strong expression in olfactory bulb, neocortex, hippocampus, and cerebellum. Chd2 expression was limited to mature neurons, interneurons, and oligodendrocytes.
Woodage et al. (1997) mapped the CHD2 gene to chromosome 15q26 by PCR screening of the Genebridge 4 radiation hybrid mapping panel.
Kulkarni et al. (2008) reported a 17-year-old girl with a balanced de novo translocation, t(X;15)(p22.2;q26.1) that disrupted the CHD2 gene. No known or predicted genes were disrupted by the Xp22.2 breakpoint. Clinical features included scoliosis, hirsutism, learning problems, and developmental delay. She also had a high-arched palate, 2-3 syndactyly of the toes, masculinized face, low voice, and mildly elevated serum testosterone. Kulkarni et al. (2008) suggested that haploinsufficiency of CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome (214800), which is caused by mutations in the CHD7 gene (608892).
In a German girl (MS134) with developmental and epileptic encephalopathy-94 (DEE94; 615369), Rauch et al. (2012) identified a de novo heterozygous truncating mutation in the CHD2 gene (602119.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in either parent. The patient had delayed psychomotor development with an IQ of 50-69 and onset of absence seizures at age 5 years. She was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism.
In 6 unrelated patients with DEE94, Carvill et al. (2013) identified 6 different de novo heterozygous mutations in the CHD2 gene (see, e.g., 602119.0002-602119.0006). Four of the mutations were truncating, and 2 were missense substitutions at highly conserved residues. The mutations were found by targeted sequencing of known or candidate genes in 500 individuals with epileptic encephalopathies, and thus accounted for 1.2% of cases. The median age of seizure onset was 18 months (range, 1-3 years), and all patients had myoclonic seizures in addition to variable seizure types, including absence, atonic, tonic, tonic-clonic, febrile, and status epilepticus. Four patients had developmental delay before the onset of seizures, 5 showed developmental regression after the onset of seizures, 3 had photosensitivity, and all had moderate to severe intellectual disability. EEG studies showed multiple abnormalities. At the time of the report, the patients ranged in age from 2.5 to 29 years. There were no apparent genotype/phenotype correlations. Carvill et al. (2013) postulated haploinsufficiency as the disease mechanism. They noted that mutations in the related CHD7 gene (608892) cause developmental abnormalities.
In 3 unrelated patients with DEE94, Suls et al. (2013) identified 3 different de novo heterozygous mutations in the CHD2 gene (602119.0007-602119.0009). The mutations in the first 2 patients were found by whole-exome sequencing of 9 probands with a similar disorder. The third patient was identified by sequencing of the CHD2 gene in 150 probands with epileptic encephalopathy. The patients had onset of seizures associated with fever between the ages of 14 months and 3.5 years. All subsequently developed multiple seizure types, mostly therapy-resistant, that were associated with EEG abnormalities. Two had normal development before the onset of seizures, whereas 1 patient had mildly delayed development before the onset of seizures. All had mild but persistent intellectual and neurologic impairment. Suls et al. (2013) postulated that haploinsufficiency for CHD2 was responsible for the phenotype, and suggested that helicase dysfunction in humans may result in neuronal hyperexcitability in the absence of dysmorphic features.
In a 5-year-old proband with DEE94 and her mildly affected mother, Petersen et al. (2018) identified a heterozygous nonsense mutation in the CHD2 gene (E210X; 602119.0010). The authors noted that this was the first known case of an inherited autosomal dominant pathogenic CHD2 variant in a clinically affected mother and daughter, and emphasized the importance of parental testing before providing recurrence risk estimates.
Kulkarni et al. (2008) found that a mutant mouse with complete Chd2 disruption showed embryonic and perinatal lethality. Chd2 +/- mice showed pronounced lordosis, kyphosis, reduced body fat, postnatal runting, and growth retardation.
Kim et al. (2018) found that Chd2 +/- mice were viable and fertile, but that they had reduced body weight compared with wildtype. Chd2 +/- mice expressed half of the amount of Chd2 protein in brain compared with wildtype and exhibited mild lordokyphosis, but no substantial disruption in cortical cytoarchitecture. Chd2 +/- mice had reduced numbers of GABAergic interneurons, and further analysis demonstrated a role for Chd2 in cell proliferation, terminal differentiation, and maturation of cortical principal neurons and GABAergic interneurons. Chd2 haploinsufficiency disrupted cell proliferation and neurogenesis in developing forebrain and led to broad dysregulation of genes involved in disease-related pathways, neurogenesis, and synapse organization. Chd2 +/- mice had disrupted excitatory and inhibitory synaptic functions in hippocampus and exhibited changes in cortical rhythmogenesis. In addition, Chd2 +/- mice displayed severe deficits in long-term spatial and recognition memory. However, increasing the number of inhibitory interneurons by transplantation in Chd2 +/- mice rescued the deficits in long-term spatial memory, but recognition memory remained impaired.
Suls et al. (2013) found that morpholino knockdown of Chd2 in zebrafish resulted in multiple developmental abnormalities, including pericardial edema, microcephaly, body curvature, absent swim bladder, and stunted growth. Mutant zebrafish larvae also showed abnormal movement patterns, such as twitching and trembling, associated with epileptiform discharges.
In a German girl (MS134) with developmental and epileptic encephalopathy-94 (DEE94; 615369), Rauch et al. (2012) identified a de novo heterozygous 1-bp deletion (c.1809delG) in the CHD2 gene, resulting in a frameshift and premature termination (Thr604LeufsTer19). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in either parent. The patient had delayed psychomotor development with an IQ of 50-69 and onset of absence seizures at age 5 years. She was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism.
In a 17-year-old boy with developmental and epileptic encephalopathy-94 (DEE94; 615369), Carvill et al. (2013) identified a de novo heterozygous frameshift mutation in the CHD2 gene, resulting in premature termination (Glu1412GlyfsTer64) and likely resulting in haploinsufficiency. The patient had onset of atonic seizures at age 1 year and later developed absence seizures, febrile seizures, myoclonic-atonic jerks, and tonic-clonic seizures associated with generalized 3.8-Hz spike-wave abnormalities on EEG. He had mildly delayed development before the onset of seizures, and moderate intellectual disability and autism spectrum disorder later. The clinical diagnosis was 'myoclonic atonic epilepsy.' The mutation was identified by targeted sequencing of candidate genes.
In a 12-year-old girl with developmental and epileptic encephalopathy-94 (DEE94; 615369), Carvill et al. (2013) identified a de novo heterozygous arg121-to-ter (R121X) substitution in the CHD2 gene, likely resulting in haploinsufficiency. The patient had normal development until 1 year of age, when she developed multiple seizure types, including myoclonic jerks, tonic and tonic-clonic seizures, myoclonic absence seizures, and status epilepticus. She showed cognitive regression and severe intellectual disability. EEG showed multiple abnormalities. The mutation was identified by targeted sequencing of candidate genes.
In a 29-year-old woman with developmental and epileptic encephalopathy-94 (DEE94; 615369), Carvill et al. (2013) identified a de novo heterozygous frameshift mutation in the CHD2 gene, resulting in premature termination (Gly491ValfsTer13) and likely resulting in haploinsufficiency. The patient had delayed development and onset of multiple seizure types at age 1 year, including atypical absence, atonic, myoclonic jerks, tonic and tonic-clonic seizures, and status epilepticus associated with multiple EEG abnormalities. She had developmental regression and severe intellectual disability. The mutation was identified by targeted sequencing of candidate genes.
In a 12-year-old boy with developmental and epileptic encephalopathy-94 (DEE94; 615369), Carvill et al. (2013) identified a de novo heterozygous frameshift mutation in the CHD2 gene, resulting in premature termination (Arg1644LyfsTer22) and likely resulting in haploinsufficiency. The patient had normal development until onset of atonic seizures at age 2 years. Other seizure types included myoclonic jerks, tonic-clonic seizures, and status epilepticus associated with multiple EEG abnormalities. Thereafter, he showed developmental regression and had severe intellectual disability. The clinical diagnosis was 'myoclonic atonic epilepsy.' The mutation was identified by targeted sequencing of candidate genes.
In a 15-year-old boy with developmental and epileptic encephalopathy-94 (DEE94; 615369), Carvill et al. (2013) identified a de novo heterozygous trp548-to-arg (W548R) substitution at a highly conserved residue in the SNF2-related helicase domain of CHD2. The patient had delayed development and onset of tonic-clonic seizures at age 3 years. Other seizure types included focal dyscognitive seizures, hemiclonic seizures, and myoclonic jerks associated with multiple EEG abnormalities. He showed developmental regression and moderate intellectual disability. The mutation was identified by targeted sequencing of candidate genes. Functional studies on this missense mutation were not performed.
In a patient with developmental and epileptic encephalopathy (DEE94; 615369), Suls et al. (2013) identified a de novo heterozygous c.4971G-A transition in exon 38 of the CHD2 gene, resulting in a trp1657-to-ter (W1657X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 137) databases. Studies of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay. The patient had normal development until the onset of febrile seizures at age 2 years. She later developed treatment-resistant myoclonic and generalized seizures associated with spike-wave complexes and polyspikes on EEG. She had mild to moderate intellectual disability at age 24 years.
In a patient with developmental and epileptic encephalopathy-94 (DEE94; 615369), Suls et al. (2013) identified a de novo heterozygous A-to-C transversion in the splice acceptor site of exon 16 (c.1810-2A-C). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 137) databases. Studies of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay, but resulted in complex alternative splicing events. The patient showed normal development until the onset of febrile seizures at age 14 months. This was followed by treatment-resistant myoclonic seizures, atypical absence seizures, and generalized tonic-clonic seizures with status epilepticus. At age 6 years, he had mild to moderate intellectual disability, dysarthria, and ataxia.
In a patient with developmental and epileptic encephalopathy-94 (DEE94; 615369), Suls et al. (2013) identified a de novo heterozygous c.1396C-T transition in exon 13 of the CHD2 gene, resulting in an arg466-to-ter (R466X) substitution. The mutation was found by sequencing the CHD2 gene in a cohort of 150 patients with epileptic encephalopathy. The mutation was not present in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 137) databases. Studies of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay. The patient had slightly delayed psychomotor development before the onset of febrile seizures at age 3.5 years. He later developed multiple seizure types and had mild intellectual disability, autism spectrum disorder, attention deficit-hyperactivity disorder, and mild ataxia. Brain MRI showed atrophic changes.
In a 5-year-old proband with developmental and epileptic encephalopathy-94 (DEE94; 615369) and her mildly affected mother, Petersen et al. (2018) identified a heterozygous c.628G-T transversion (c.628G-T, NM_001271) in exon 7 of the CHD2 gene, resulting in a glu210-to-ter (E210X) substitution. The daughter had global developmental delay, first noted at age 12 months, and onset of medically refractory generalized epilepsy at age 13 months. Her mother had generalized tonic-clonic epilepsy with seizure onset at age 5 years, which was well-controlled with medications, and completed high school in mainstream classes without difficulty.
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
Kim, Y., Khoshkhoo, S., Frankowski, J. C., Zhu, B., Abbasi, S., Lee, S., Wu, Y. E., Hunt, R. F. Chd2 is necessary for neural circuit development and long-term memory. Neuron 100: 1180-1193, 2018. [PubMed: 30344048] [Full Text: https://doi.org/10.1016/j.neuron.2018.09.049]
Kulkarni, S., Nagarajan, P., Wall, J., Donovan, D. J., Donell, R. L., Ligon, A. H., Venkatachalam, S., Quade, B. J. Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. Am. J. Med. Genet. 146A: 1117-1127, 2008. [PubMed: 18386809] [Full Text: https://doi.org/10.1002/ajmg.a.32178]
Petersen, A. K., Streff, H., Tokita, M., Bostwick, B. L. The first reported case of an inherited pathogenic CHD2 variant in a clinically affected mother and daughter. Am. J. Med. Genet. 176A: 1667-1669, 2018. [PubMed: 29740950] [Full Text: https://doi.org/10.1002/ajmg.a.38835]
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., and 27 others. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380: 1674-1682, 2012. [PubMed: 23020937] [Full Text: https://doi.org/10.1016/S0140-6736(12)61480-9]
Suls, A., Jaehn, J. A., Kecskes, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djemie, T., Afrikanova, T., Gormley, P., von Spiczak, S., Kluger, G., and 32 others. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am. J. Hum. Genet. 93: 967-975, 2013. [PubMed: 24207121] [Full Text: https://doi.org/10.1016/j.ajhg.2013.09.017]
Woodage, T., Basrai, M. A., Baxevanis, A. D., Hieter, P., Collins, F. S. Characterization of the CHD family of proteins. Proc. Nat. Acad. Sci. 94: 11472-11477, 1997. [PubMed: 9326634] [Full Text: https://doi.org/10.1073/pnas.94.21.11472]