TY - JOUR
T1 - Genomic context analysis of de novo STXBP1 mutations identifies evidence of splice site DNA-motif associated hotspots
AU - Uddin, Mohammed
AU - Woodbury-Smith, Marc
AU - Chan, Ada J.S.
AU - Albanna, Ammar
AU - Minassian, Berge
AU - Boelman, Cyrus
AU - Scherer, Stephen W.
N1 - Funding Information:
We thank The Centre for Applied Genomics (TCAG), which is funded by Genome Canada and the Ontario Genomics Institute, Canada Foundation for Innovation (CFI), and the Ontario Research Fund of the Government of Ontario. M.W.S. was supported by a Clinical Investigatorship Award from the Canadian Institutes of Health Research’s (CIHR) Institute of Genetics; S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. IRB numbers: Sick-Kids 0019980189 and MBRU-IRB-2017-010.
Publisher Copyright:
© 2018 Uddin et al.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Mutations within STXBP1 have been associated with a range of neurodevelopmental disorders implicating the pleotropic impact of this gene. Although the frequency of de novo mutations within STXBP1 for 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 of de novo STXBP1 mutations to examine whether certain motifs indicated a greater risk of mutation. Through a comprehensive context analysis of 136 de 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 to 14.70% (20 out of 136) of all reported mutations within STXBP1. 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 for STXBP1 de novo splicing mutations.
AB - Mutations within STXBP1 have been associated with a range of neurodevelopmental disorders implicating the pleotropic impact of this gene. Although the frequency of de novo mutations within STXBP1 for 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 of de novo STXBP1 mutations to examine whether certain motifs indicated a greater risk of mutation. Through a comprehensive context analysis of 136 de 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 to 14.70% (20 out of 136) of all reported mutations within STXBP1. 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 for STXBP1 de novo splicing mutations.
KW - DNA motif
KW - Epilepsy encephalopathy
KW - Genome context
KW - Loss of function mutation
KW - Mutant screen report
KW - Mutation etiology
UR - http://www.scopus.com/inward/record.url?scp=85044743815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044743815&partnerID=8YFLogxK
U2 - 10.1534/g3.118.200080
DO - 10.1534/g3.118.200080
M3 - Article
C2 - 29438995
AN - SCOPUS:85044743815
SN - 2160-1836
VL - 8
SP - 1115
EP - 1118
JO - G3: Genes, Genomes, Genetics
JF - G3: Genes, Genomes, Genetics
IS - 4
ER -