title: Expanding the mutational spectrum associated to neural tube defects: literature revision and description of novel VANGL1 mutations.
abstract: BACKGROUND
  Neural Tube Defects (NTD) are a common class of birth defects that occur in approximately 1 in 1000 live births. Both genetic and nongenetic factors are involved in the etiology of NTD. Planar cell polarity (PCP) genes plays a critical role in neural tube closure in model organisms. Studies in humans have identified nonsynonymous mutations in PCP pathway genes, including the VANGL genes, that may play a role as risk factors for NTD.
  
  
  METHODS
  Here, we present the results of VANGL1 and VANGL2 mutational screening in a series of 53 NTD patients and 27 couples with a previous NTD affected pregnancy.
  
  
  RESULTS
  We identified three heterozygous missense variants in VANGL1, p.Ala187Val, p.Asp389His, and p.Arg517His, that are absent in controls and predicted to be detrimental on the protein function and, thus, we expanded the mutational spectrum of VANGL1 in NTD cases. We did not identify any new variants having an evident pathogenic effect on protein function in VANGL2. Moreover, we reviewed all the rare nonsynonymous or synonymous variants of VANGL1 and VANGL2 found in patients and controls so far published and re-evaluated them for their pathogenic role by in silico prediction tools. Association tests were performed to demonstrate the enrichment of deleterious variants in reviewed cases versus controls from Exome Variant Server (EVS).
  
  
  CONCLUSIONS
  We showed a significant (p = 7.0E-5) association between VANGL1 rare genetic variants, especially missense mutations, and NTDs risk.
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Merello
authors.forename: S
authors.initials: S
authors.lastname: Mascelli
authors.forename: A
authors.initials: A
authors.lastname: Raso
authors.forename: G
authors.initials: G
authors.lastname: Piatelli
authors.forename: A
authors.initials: A
authors.lastname: Consales
authors.forename: A
authors.initials: A
authors.lastname: Cama
authors.forename: Z
authors.initials: Z
authors.lastname: Kibar
authors.forename: V
authors.initials: V
authors.lastname: Capra
authors.forename: Patrizia De
authors.initials: PD
authors.lastname: Marco
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D016764:Cell Polarity / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009436:Neural Tube Defects / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D012196:Review Literature as Topic; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C488287:VANGL1 protein, human; C468513:VANGL2 protein, human
keywords: Neural Tube Defects (NTD); Planar Cell Polarity (PCP) pathway; VANGL1; VANGL2