ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23708187 Carvill et al. 2013: Describes six de novo mutations in CHD2, including one nonsense and 3 frameshift mutations, found in unrelated individuals with various epilepsy phenotypes and intellectual disability, ranging from moderate to severe. Two individuals were also described as having autism spectrum disorders (one with a frameshift mutation, one with a missense). The authors concluded that there was no apparent genotype-phenotype correlations between type of mutation, seizure type, or level of neurocognitive impairment.
23020937 Rauch et al. 2012: Describes a single, de novo, heterozygous frameshift mutation found in a German female with intellectual disability and absence seizures. The authors did not see any additional loss of function variants in CHD2 in "roughly 1600 control exomes, [in] a post-hoc test in the 6500 exomes from the Exome Variant Server (version 0.0.14), [or] in 179 low coverage genomes of the 1000 Genomes project."
24207121 Suls et al. (2013) identified three de novo heterozygous variants in CHD2. 1) c.4971G-A (p.W1657X) variant in CHD2 was found in a patient with childhood-onset epileptic encephalopathy (EEOC; 615369). The variant was found by WES and confirmed by Sanger sequencing. The variant was not present in general population databases. The patient had normal development until the onset of febrile seizures at age 2 years. She had mild to moderate intellectual disability at age 24 years. 2) c.1810-2A-C variant in CHD2 was found in a patient with childhood-onset epileptic encephalopathy (EEOC; 615369). 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. At age 6 years, he had mild to moderate intellectual disability, dysarthria, and ataxia. 3) c.1396C-T, p. R466X variant in CHD2 was found in a patient with childhood-onset epileptic encephalopathy (EEOC; 615369) by sequencing the CHD2 gene in a cohort of 150 patients with epileptic encephalopathy. 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.

Haploinsufficiency phenotype comments:

PubMed: 29740950 Petersen et al. (2018) identified a heterozygous variant c.628G-T, p. E210X in CHD2 in a 5 yro proband with childhood-onset epileptic encephalopathy (EEOC; 615369) and her mildly affected mother. 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. PMID:22178256: Capelli et al. (2012) describe a patient with DD, epilepsy, autistic behavior, and dysmorphic facial features with a de novo 511 kb deletion involving only 2 genes (CHD2 and RGMA). This patient data has been submitted to DECIPHER (249888). Of note, Carvill et al. (mentioned in PMID1 above) also mention a previously unreported individual (in Supplementary Figure 3) with photosensitive generalized early-onset epilepsy and ID and a deletion involving only CHD2 and an uncharacterized non-coding RNA (LOC100507217).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

ISCA Database: nssv580871: de novo duplication involving only this gene (hg18: chr15:91245028-91356680) in a patient with multiple congenital anomalies. The laboratory classified this imbalance as uncertain. Further studies of this case would be needed to determine whether an additional copy of the protein is present or whether the duplication disrupts this gene.