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

TitleGenome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida.
Publication TypeJournal Article
Year of Publication2021
AuthorsWolujewicz P, Aguiar-Pulido V, AbdelAleem A, Nair V, Thareja G, Suhre K, Shaw GM, Finnell RH, Elemento O, M Ross E
JournalGenet Med
Date Published2021 Jul

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; P = 7.59 × 10). 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.

Alternate JournalGenet Med
PubMed ID33686259
PubMed Central IDPMC8257499
Grant ListT32HD060600 / / National Institute of Child Health and Human Development /
P01 HD067244 / HD / NICHD NIH HHS / United States
T32 HD060600 / HD / NICHD NIH HHS / United States
U01 DD000489 / DD / NCBDD CDC HHS / United States
R01 NS076465 / NS / NINDS NIH HHS / United States
T32 ES027801 / ES / NIEHS NIH HHS / United States
R01 HD081216 / HD / NICHD NIH HHS / United States