Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell Motility.

Abstract

CYFIP2, essential for actin cytoskeleton regulation, is implicated in early-onset developmental and epileptic encephalopathy (DEE) with neurodevelopmental impairments and variable movement disorders, including occasional dyskinetic crises. We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic crises and to assess its functional impact. Clinical and genetic evaluations were conducted, alongside functional studies using patient-derived fibroblasts. Actin dynamics and cell motility were analyzed with confocal microscopy and live-cell imaging. The patient exhibited DEE, delayed neurodevelopment, refractory seizures, and movement disorders, including dystonia, choreoathetosis, and dyskinetic crises. Functional studies revealed disrupted actin organization, impaired cell motility, and altered protrusive structures. This study confirms CYFIP2 as a cause of dyskinetic crises and underscores its role in cellular dynamics, broadening the phenotypic spectrum of CYFIP2-related disorders. Early genetic diagnosis and further research are essential to developing targeted therapeutic strategies.