Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida. Academic Article uri icon

Overview

abstract

  • 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 genome sequences (GS) 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 GS data afford 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.

publication date

  • March 8, 2021

Research

keywords

  • DNA Copy Number Variations
  • Spinal Dysraphism

Identity

PubMed Central ID

  • PMC8257499

Scopus Document Identifier

  • 85102334171

Digital Object Identifier (DOI)

  • 10.1038/s41422-018-0061-3

PubMed ID

  • 33686259

Additional Document Info

volume

  • 23

issue

  • 7