Expansion of NEUROD2 phenotypes to include developmental delay without seizures

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• De novo heterozygous variants in Neuronal Differentiation Factor 2 (NEUROD2) are linked to early-onset epileptic encephalopathy and developmental delay.
• NEUROD2 is a brain-specific transcription factor crucial for neuronal development.

Observation:

• A novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro), was identified in an adolescent with developmental delay but no seizures.
• Functional testing in Xenopus laevis tadpoles indicated the patient's NEUROD2 variant exhibits minimal protein activity, suggesting a loss-of-function effect.

Findings:

• The patient's NEUROD2 variant demonstrated significantly reduced activity in vivo, supporting its role in developmental delay.
• A second rare NEUROD2 variant, p.(Ala235Thr), showed normal activity, highlighting the importance of specific variant pathogenicity.

Implications:

• NEUROD2 variants can cause developmental delay independently of early-onset seizures.
• In vivo functional assays are valuable tools to complement genetic data in determining variant pathogenicity.
• This study expands the phenotypic spectrum associated with NEUROD2 variants and emphasizes the utility of functional studies in genetic diagnostics.