Novel Genetic Variants of the CHD2 Gene in cis Position in a Patient with Epileptic Encephalopathy: A Case Report and In Silico Analysis of the Impact of the Variants on the Protein
- 1Research Institute of Medical Genetics, Tomsk National Research Medical Center, Tomsk 634009, Russia
- 2Department of Medical Genetics, Siberian State Medical University, Tomsk 634050, Russia
Abstract
CHD2-related neurodevelopmental disorders are increasingly recognized as a distinct group of epileptic encephalopathies with heterogeneous clinical manifestations. Here, we report a 12-year-old female patient with pharmacoresistant epilepsy, mild cognitive impairment (IQ = 56), and extraneurological features including grade II kyphoscoliosis and planovalgus foot deformity. Video-EEG monitoring revealed a phenotype consistent with Jeavons syndrome, characterized by daily eyelid myoclonia with absences and marked photosensitivity with an eye closure sensitivity (ECS) phenomenon. Molecular genetic testing via whole-exome and Sanger sequencing identified two novel variants in the CHD2 gene (NM_001271.4): c.1634T>G (p.Leu545Arg) and c.3810G>C (p.Leu1270Phe). Long-read nanopore sequencing confirmed their de novo status and cis-positioning on the paternal allele. Structural bioinformatic analysis using AlphaFold3, FoldX/mCSM (v5.0 package), UCSF ChimeraX (v1.10.1), and PyMOL (v3.1.8) demonstrated that both variants individually destabilize the CHD2 protein, with a cumulative destabilizing effect when combined: p.Leu545Arg affects the ATP-binding domain, whereas p.Leu1270Phe disrupts hydrophobic packing within the C-terminal DNA-binding domain. These findings suggest accelerated protein degradation as a potential disease mechanism. Our data support the pathogenicity of these heterozygous cis-variants and implicate CHD2 haploinsufficiency as the leading etiopathogenic mechanism, though distinct domain-specific effects of each substitution may also contribute to the complex molecular synergy observed in this case.
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BibTeX
@article{zuev2026novel,
title = {{Novel Genetic Variants of the CHD2 Gene in cis Position in a Patient with Epileptic Encephalopathy: A Case Report and In Silico Analysis of the Impact of the Variants on the Protein}},
author = {Andrew S. Zuev and Elizaveta A. Fonova and Daria S. Kuznetsova and Vadim A. Stepanov and Nikolay A. Skryabin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209120},
url = {https://www.mdpi.com/1422-0067/27/20/9120},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Novel Genetic Variants of the CHD2 Gene in cis Position in a Patient with Epileptic Encephalopathy: A Case Report and In Silico Analysis of the Impact of the Variants on the Protein
AU - Andrew S. Zuev
AU - Elizaveta A. Fonova
AU - Daria S. Kuznetsova
AU - Vadim A. Stepanov
AU - Nikolay A. Skryabin
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209120
UR - https://www.mdpi.com/1422-0067/27/20/9120
AB - CHD2-related neurodevelopmental disorders are increasingly recognized as a distinct group of epileptic encephalopathies with heterogeneous clinical manifestations. Here, we report a 12-year-old female patient with pharmacoresistant epilepsy, mild cognitive impairment (IQ = 56), and extraneurological features including grade II kyphoscoliosis and planovalgus foot deformity. Video-EEG monitoring revealed a phenotype consistent with Jeavons syndrome, characterized by daily eyelid myoclonia with absences and marked photosensitivity with an eye closure sensitivity (ECS) phenomenon. Molecular genetic testing via whole-exome and Sanger sequencing identified two novel variants in the CHD2 gene (NM_001271.4): c.1634T>G (p.Leu545Arg) and c.3810G>C (p.Leu1270Phe). Long-read nanopore sequencing confirmed their de novo status and cis-positioning on the paternal allele. Structural bioinformatic analysis using AlphaFold3, FoldX/mCSM (v5.0 package), UCSF ChimeraX (v1.10.1), and PyMOL (v3.1.8) demonstrated that both variants individually destabilize the CHD2 protein, with a cumulative destabilizing effect when combined: p.Leu545Arg affects the ATP-binding domain, whereas p.Leu1270Phe disrupts hydrophobic packing within the C-terminal DNA-binding domain. These findings suggest accelerated protein degradation as a potential disease mechanism. Our data support the pathogenicity of these heterozygous cis-variants and implicate CHD2 haploinsufficiency as the leading etiopathogenic mechanism, though distinct domain-specific effects of each substitution may also contribute to the complex molecular synergy observed in this case.
SN - 1422-0067
ER -