Genotypic and Phenotypic Profile of 50 Cases With Chromatin Remodeling Complexes-Related Neurological Disorders.

AIM: To describe the genotypic and phenotypic profile of chromatin remodeling complex (CRC)-related neurological disorders.

METHODS

We retrospectively analyzed the clinical characteristics and the genetic spectrum of children with variants in CRC genes.

RESULTS

Fifty patients were included. The genotype spectrum involved genes encoding the CHD complex (CHD2, CHD3, CHD4, CHD7, CHD8), the BAF complex (SMARCA2, ARID1B, ARID2, ACTB), and the ISWI complex (BPTF). The predominant phenotypes were global developmental delay/intellectual disability (GDD/ID) (76.0%, 38/50) and epilepsy (64.0%, 32/50). Seventy-five percent of patients with epilepsy had generalized seizures. Sixty-nine percent (20/29) were seizure-free for more than 1 year at the last follow-up (three were lost to follow-up), although 56.3% (18/32) of patients required three or more kinds of antiseizure medications. EEG abnormalities were prevalent (82.2%, 37/45), commonly showing generalized or diffuse interictal discharges (63.6%), slow background activity (59.5%), and slow waves (35.1%). BAF complex variants were significantly associated with GDD/ID, microcephaly, facial dysmorphism, short stature, and slow background activity on EEG, while CHD complex variants were more likely to cause heat-sensitive seizures (FDR < 0.05).

CONCLUSION

CRC-related disorders are primarily caused by variants in the CHD and BAF complexes, with CHD2, ARID1B, and SMARCA2 being the frequently involved genes. The conditions are characterized by GDD/ID and epilepsy, with distinct clinical patterns between the CHD and BAF complexes.