title: Rare deleterious variants in GRHL3 are associated with human spina bifida.
abstract: Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.
authors.affiliation: CHU Sainte Justine Research Center and University of Montréal, Montréal, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemay
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.affiliation: CHU Sainte Justine Research Center and University of Montréal, Montréal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Emond
authors.affiliation: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Laurent
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Accogli
authors.affiliation: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.affiliation: CHU Sainte Justine Research Center and University of Montréal, Montréal, Québec, Canada.
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D009436:Neural Tube Defects / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017384:Sequence Deletion / Q000235:genetics; D016135:Spinal Dysraphism / Q000235:genetics* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; D014157:Transcription Factors
keywords: GRHL3; molecular inversion probes; neural tube defects; spina bifida; whole-exome sequencing