De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy.
J Med Genet
; 56(2): 113-122, 2019 02.
Article
en En
| MEDLINE
| ID: mdl-30323019
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Espasmos Infantiles
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Neuropéptidos
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
Tipo de estudio:
Etiology_studies
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Prognostic_studies
Límite:
Animals
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
J Med Genet
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos