title: Loss-of-function de novo mutations play an important role in severe human neural tube defects.
abstract: BACKGROUND
  Neural tube defects (NTDs) are very common and severe birth defects that are caused by failure of neural tube closure and that have a complex aetiology. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness and suggest a role for de novo mutations (DNMs) in their aetiology.
  
  
  METHODS
  We used whole-exome sequencing in 43 sporadic cases affected with myelomeningocele or anencephaly and their unaffected parents to identify DNMs in their exomes.
  
  
  RESULTS
  We identified 42 coding DNMs in 25 cases, of which 6 were loss of function (LoF) showing a higher rate of LoF DNM in our cohort compared with control cohorts. Notably, we identified two protein-truncating DNMs in two independent cases in SHROOM3, previously associated with NTDs only in animal models. We have demonstrated a significant enrichment of LoF DNMs in this gene in NTDs compared with the gene specific DNM rate and to the DNM rate estimated from control cohorts. We also identified one nonsense DNM in PAX3 and two potentially causative missense DNMs in GRHL3 and PTPRS.
  
  
  CONCLUSIONS
  Our study demonstrates an important role of LoF DNMs in the development of NTDs and strongly implicates SHROOM3 in its aetiology.
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Philippe
authors: P
authors: Lemay
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Marie-Claude
authors: MC
authors: Guyot
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Élizabeth
authors: É
authors: Tremblay
authors: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Alexandre
authors: A
authors: Dionne-Laporte
authors: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Dan
authors: D
authors: Spiegelman
authors: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Édouard
authors: É
authors: Henrion
authors: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Ousmane
authors: O
authors: Diallo
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Patrizia
authors: P
authors: De Marco
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Elisa
authors: E
authors: Merello
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Christine
authors: C
authors: Massicotte
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Valérie
authors: V
authors: Désilets
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Jacques L
authors: JL
authors: Michaud
authors: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Guy A
authors: GA
authors: Rouleau
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Valeria
authors: V
authors: Capra
authors: CHU Ste-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors: Zoha
authors: Z
authors: Kibar
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; D008840:Microfilament Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C000596976:SHROOM3 protein, human; D014157:Transcription Factors; C516883:PTPRS protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: Complex traits; Developmental; Genetics; Genome-wide