Rare deleterious variants in GRHL3 are associated with human spina bifida

• Published in: Human mutation Vol. 38; no. 6; pp. 716 - 724
• Main Authors: Lemay, Philippe, Marco, Patrizia, Emond, Alexandre, Spiegelman, Dan, Dionne‐Laporte, Alexandre, Laurent, Sandra, Merello, Elisa, Accogli, Andrea, Rouleau, Guy A, Capra, Valeria, Kibar, Zoha
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2017
• Subjects: Animal models; Animals; Congenital defects; DNA-Binding Proteins - genetics; Etiology; Female; Gene Expression Regulation; Genetic factors; Genetic Predisposition to Disease; GRHL3; Humans; Male; Mice; molecular inversion probes; Mutation, Missense - genetics; Neural tube defects; Neural Tube Defects - genetics; Neural Tube Defects - physiopathology; Pedigree; Rodents; Sequence Deletion - genetics; Siblings; Spina bifida; Spinal Dysraphism - genetics; Spinal Dysraphism - physiopathology; Splicing; Transcription Factors - genetics; Whole Exome Sequencing; molecular inversion probes; GRHL3; neural tube defects; whole-exome sequencing; spina bifida
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.23214

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. Graphical representation showing previously identified variants associated to Van Der Woude syndrome and nonsyndromic cleft palate on top and spina bifida variants on the bottom. A clustering of highly deleterious variants in the trans‐activation domain of the GRHL3 protein is observed in spina bifida while no variant had previously been identified in this region in the Van Der Woude syndrome or in nonsyndromic cleft palate.