Open AccessWhole exome sequencing identifies novel predisposing genes in neural tube defects
Author(s) -
Lemay Philippe,
De Marco Patrizia,
Traverso Monica,
Merello Elisa,
DionneLaporte Alexandre,
Spiegelman Dan,
Henrion Édouard,
Diallo Ousmane,
Audibert François,
Michaud Jacques L.,
Cama Armando,
Rouleau Guy A.,
Kibar Zoha,
Capra Valeria
Publication year - 2019
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.467
Subject(s) - exome sequencing , neural tube , genetics , candidate gene , gene , exome , biology , methylenetetrahydrofolate reductase , neural tube defect , bioinformatics , computational biology , phenotype , allele , embryo
Background Neural tube defects ( NTD ) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. Methods We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. Results We identified four novel loss‐of‐function variants in three genes, MTHFR , DLC 1, and ITGB 1 , previously associated with NTD . Notably, DLC 1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO 1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD . Conclusion These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next‐generation sequencing in deciphering the genetics of this complex trait.