Comprehensive analysis of the EFNB1 gene c.451G>A(p.Gly151Ser) mutation: structural, functional, and pathogenicity...

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by mutations in the EFNB1 gene, which encodes the ephrin-B1 protein involved in craniofacial and neural development. This study aims to investigate the effects of a de novo heterozygous EFNB1 missense variant c.451G > A (p.Gly151Ser) using in silico methods.

The whole-exome analysis in a child with CFNS harbored a heterozygous missense variant c.451G > A (p.Gly151Ser) in the EFNB1 gene. The clinical data of the child were collected. The child's physical growth and neurodevelopmental progress were followed up within the first year of life. Our study reveals the pathogenicity of the c.451G > A (p.Gly151Ser) mutation in the EFNB1 gene and its impact on protein function through AlphaFold3 Protein Modeling, HADDOCK Protein Docking, and Molecular Dynamics Simulations.

A child with CFNS presented with craniofacial asymmetry, frontal bossing, hypertelorism, and polydactyly. Genetic testing identified the pathogenic variant. Structural modeling revealed altered local topology, increased rigidity, and disruption of hydrophobic interactions at the mutation site. Docking and MD simulations showed that the mutation impaired EFNB1-EPHB2 interactions at the dimer (DIM) interface by reducing stability and binding energy. Conversely, enhanced binding affinity was observed at the tetramer (TET) interface due to strengthened van der Waals and electrostatic interactions. Overall, the mutation destabilized global structure while modulating binding dynamics in an interface-specific manner.

This study highlights the potential pathogenicity of the c.451G > A variant and underscores the need for further research into EFNB1-associated disorders.