De novo variants of IRF2BPL result in developmental epileptic disorder

• Published in: Orphanet journal of rare diseases 2024-03, Vol.19 (1), p.121-121, Article 121
• Main Authors: Wang, Yong, Ke, Zhongling, Li, Yufen, Qiu, Mingqi, Liu, Jing, Yang, Zuozhen, Wen, Shu, Liang, Mengmeng, Chen, Shan
• Format: Article
• Language: English
• Subjects: Age; Animals; Anticonvulsants; Body length; Care and treatment; Carrier Proteins - genetics; Causes of; Complications and side effects; Convulsions & seizures; Danio rerio; Developmental delay; Dosage and administration; Drug therapy; Electroencephalography; Electrophysiology; Embryos; Epilepsy; Epilepsy - diagnosis; Epilepsy - genetics; Genetic counseling; Genomes; Humans; IRF2BPL; Magnetic resonance imaging; Mutagenesis; Mutation; Neurodevelopment; Neurodevelopmental disorder; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Nuclear Proteins - genetics; Phenotypes; Proteins; Psychological aspects; Seizures; Seizures (Medicine); Variant; Zebrafish; Zebrafish - genetics
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-024-03130-z

Pathogenic variants of the IRF2BPL gene have been reported to cause neurodevelopmental disorders; however, studies focused on IRF2BPL in zebrafish are limited. We reported three probands diagnosed with developmental delay and epilepsy and investigated the role of IRF2BPL in neurodevelopmental disorders in zebrafish. The clinical and genetic characteristics of three patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS) were collected. Three de novo variants (NM_024496.4: c.1171 C > T, p.Arg391Cys; c.1157 C > T, p.Thr386Met; and c.273_307del, p.Ala92Thrfs*29) were detected and classified as pathogenic or likely pathogenic according to ACMG guidelines. Zebrafish crispants with disruption of the ortholog gene irf2bpl demonstrated a reduced body length and spontaneous ictal-like and interictal-like discharges in an electrophysiology study. After their spasms were controlled, they gain some development improvements. We contribute two new pathogenic variants for IRF2BPL related developmental epileptic disorder which provided evidences for genetic counseling. In zebrafish model, we for the first time confirm that disruption of irf2bpl could introduce spontaneous electrographic seizures which mimics key phenotypes in human patients. Our follow-up results suggest that timely cessation of spasmodic seizures can improve the patient's neurodevelopment.