Genomic Context Analysis of de Novo STXBP1 Mutations Identifies Evidence of Splice Site DNA-Motif Associated Hotspots

Abstract

Abstract: Mutations withinSTXBP1have been associated with a range of neuro developmental disorder simplicating the pleotropic impact of this gene. Although the frequency of de novo mutations withinSTXBP1for selective cohorts with early onset epileptic encephalopathy is more than 1%, there is no evidence for a hotspot within the gene. In this study, we analyzed the genomic context ofde novo STXBP1mutations to examine whether certain motifs indicated a greater risk of mutation. Through a comprehensive context analysis of 136de novo/rare mutation (SNV/Indels) sites in this gene, strikingly 26.92% of all SNV mutations occurred within 5bp upstream or downstream of a‘GTA’ motif (P,0.0005). This implies a genomic context modulated mutagenesis. Moreover, 51.85% (14 out of 27) of the‘GTA’ mutations are splicing compared to14.70% (20 out of 136) of all reported mutations withinSTXBP1. We also noted that 11 of these 14‘GTA’ associated mutations are de novo in origin. Our analysis provides strong evidence of DNA motif modulated mutagenesis forSTXBP1 de novo splicing mutations.