CHD2 – Lennox-Gastaut Syndrome

De novo frameshift variants in CHD2 have been identified in Lennox–Gastaut syndrome (LGS) cohorts, with two unrelated probands out of 22 mutation-negative patients harboring a c.4173dup (p.Gln1392fs) variant [PMID:24614520]. Sequencing of an additional 17 mutation-negative LGS-like patients yielded no further CHD2 variants, resulting in two pathogenic alleles in independent families [PMID:24614520]. There is no evidence for familial segregation beyond these de novo events, indicating a limited but reproducible genetic contribution of CHD2 haploinsufficiency to LGS.

Mechanistically, CHD2 haploinsufficiency disrupts chromatin remodeling and cortical interneuron development, as Chd2+/- mice exhibit interneuron deficits, aberrant cortical rhythms, and long-term memory impairments that mirror human LGS features [PMID:30344048]. These functional findings align with the clinical spectrum of myoclonus (HP:0001336), cutaneous photosensitivity (HP:0000992), epileptic spasms (HP:0011097), and moderate intellectual disability (HP:0002342), supporting loss-of-function as the primary pathogenic mechanism. Key Take-home: CHD2 de novo haploinsufficiency represents a clinically actionable etiology in a subset of LGS patients.

References

• Epilepsy & Behavior • 2014 • CHD2 mutations in Lennox-Gastaut syndrome. PMID:24614520
• Neuron • 2018 • Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory. PMID:30344048

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