CHD2 – Myoclonic-Astatic Epilepsy

CHD2 de novo heterozygous variants have been identified in patients with myoclonic-astatic epilepsy (MAE), featuring generalized myoclonic-atonic seizures (HP:0011170), myoclonus (HP:0001336) and moderate intellectual disability (HP:0002342). A single patient harbored a frameshift c.4257_4276del (p.Ser1420AlafsTer2) (PMID:26262932) and one of 27 MAE probands carried a missense c.1862G>C (p.Arg621Pro) (PMID:31170314). No familial segregation has been documented, indicating sporadic occurrence.

Functional studies support a haploinsufficiency mechanism: Chd2+/- mice exhibit interneuron deficits, aberrant cortical rhythmogenesis and memory impairments mirroring neurodevelopmental phenotypes (PMID:30344048), and human cortical interneuron models show CHD2 haploinsufficiency causes precocious differentiation with altered H3K27ac enrichment (PMID:36115870).

Limited clinical validity is assigned given only two unrelated MAE probands and absent segregation, despite moderate concordant functional data. Additional CHD2 screening in larger MAE cohorts is warranted to refine diagnostic utility.

Key Take-home: CHD2 mutational analysis should be considered in MAE patients as de novo variants and haploinsufficiency contribute to generalized myoclonic-atonic epilepsy.

References

• Epilepsy & behavior • 2015 • CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures. PMID:26262932
• Clinical genetics • 2019 • Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: Is there a major genetic factor? PMID:31170314
• Neuron • 2018 • Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory. PMID:30344048
• Scientific reports • 2022 • Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2. PMID:36115870

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