Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Progressive myoclonic epilepsy (PME) is a severe neurological disorder.
• KCTD7 gene variants have been linked to PME, but the full spectrum of clinical manifestations and underlying mechanisms remain incompletely understood.

Observation:

• Four individuals from two families with compound heterozygous KCTD7 variants were identified.
• RNA sequencing revealed a novel splicing defect caused by a synonymous variant.
• Patient-derived neuroblastoma cells showed impaired potassium channel regulation.

Findings:

• Patients presented with variable PME phenotypes, including dysautonomia and reduced thalamus, with some lacking typical myoclonic seizures.
• KCTD7 knockout zebrafish exhibited widespread gene expression changes and increased c-fos transcription, suggesting a link to seizure activity.

Implications:

• This research broadens the known clinical spectrum of KCTD7-associated PME.
• A novel zebrafish model is established for further investigation of KCTD7-related epilepsy.
• Findings provide crucial insights into the molecular pathogenesis of KCTD7-associated neurological disorders.