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Am J Med Genet A
2021 Apr 01;1854:1076-1080. doi: 10.1002/ajmg.a.62064.
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Expansion of NEUROD2 phenotypes to include developmental delay without seizures.
Mis EK
,
Sega AG
,
Signer RH
,
Cartwright T
,
Ji W
,
Martinez-Agosto JA
,
Nelson SF
,
Palmer CGS
,
Lee H
,
Mitzelfelt T
,
Konstantino M
,
Undiagnosed Diseases Network
,
Jeffries L
,
Khokha MK
,
Marco E
,
Martin MG
,
Lakhani SA
.
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De novo heterozygous variants in the brain-specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early-onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro). Functional testing using an in vivo assay of neuronal differentiation in Xenopus laevis tadpoles demonstrated that the patient variant of NEUROD2 displays minimal protein activity, strongly suggesting a loss of function effect. In contrast, a second rare NEUROD2 variant, p.(Ala235Thr), identified in an adolescent with developmental delay but lacking parental studies for inheritance, showed normal in vivo NEUROD2 activity. We thus provide clinical, genetic, and functional evidence that NEUROD2 variants can lead to developmental delay without accompanying early-onset seizures, and demonstrate how functional testing can complement genetic data when determining variant pathogenicity.
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