De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy. Issue 2 (15th October 2018)

• Record Type: Journal Article
• Authors: Sega, Annalisa G; Mis, Emily K; Lindstrom, Kristin; Mercimek-Andrews, Saadet; Ji, Weizhen; Cho, Megan T; Juusola, Jane; Konstantino, Monica; Jeffries, Lauren; Khokha, Mustafa K; Lakhani, Saquib Ali
• Is Part Of: Journal of medical genetics. Volume 56:Issue 2(2019)
• Page Start: 113
• Page End: 122
• Publication Date: 2018-10-15
• Subjects: neurod2 -- neuronal differentiation factor -- epileptic encephalopathy -- epilepsy and seizures -- xenopus; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2018-105322
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Early infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies. Objectives: This study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative. Methods: We used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles. Results: We identified novel de novo variants in neuronal differentiation factor 2 ( NEUROD2 ) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients' condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic. Conclusion: This study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.