Genome-wide investigation identifies a rare copy number variant burden associated with human spina bifida

Details

• Alternative Title:
  Genet Med
• Personal Author:
  Wolujewicz, Paul ; Aguiar-Pulido, Vanessa ; AbdelAleem, Alice ; Nair, Vidya ; Thareja, Gaurav ; Suhre, Karsten ; Shaw, Gary M. ; Finnell, Richard H. ; Elemento, Olivier ; Ross, M. Elizabeth
• Description:
  Purpose:
  
  Next generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy number variant (CNV) participation in the genetic architecture underlying SB risk.
  
  Methods:
  
  A high-confidence ensemble approach to whole genome sequences (WGS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case-control cohorts.
  
  Results:
  
  SB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 KB, in both ancestral populations (P=6.75×10-7; P=7.59×10-4). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene-environment interactions that interfere with neurulation, useful for further functional characterization.
  
  Conclusion:
  
  This study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single nucleotide variation toward human SB risk to include structural variation. Since WGS data affords detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.
  
  
• Subjects:
  Article Case-Control Studies DNA Copy Number Variations Genome Genome-Wide Association Study Humans Polymorphism, Single Nucleotide Spinal Dysraphism
• Source:
  Genet Med. 23(7):1211-1218
• Pubmed ID:
  33686259
• Pubmed Central ID:
  PMC8257499
• Document Type:
  Journal Article
• Funding:
  P01 HD067244/HD/NICHD NIH HHSUnited States/ ; T32 HD060600/HD/NICHD NIH HHSUnited States/ ; U01 DD000489/DD/NCBDD CDC HHSUnited States/ ; R01 NS076465/NS/NINDS NIH HHSUnited States/ ; T32 ES027801/ES/NIEHS NIH HHSUnited States/ ; R01 HD081216/HD/NICHD NIH HHSUnited States/
• Volume:
  23
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:157274e9f768dd69d5a08a6a7fc1ea56f3c1929e98fb3f9e3f3c87251062c1e3
• Download URL:
  https://stacks.cdc.gov/view/cdc/107883/cdc_107883_DS1.pdf
• File Type:
  [PDF - 1.40 MB ]