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

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.

Systems Biology Analysis of Human Genomes Points to Key Pathways Conferring Spina Bifida Risk

“…Greater power may be gained from combining gene enrichment by deleterious variants along with damaging structural variation (e.g. CNVs [86]), demanding new computational approaches to accomplish. It is unlikely that a single variant or gene would greatly impact non-syndromic SB risk.…”

“…Genetic studies of the more prevalent structural birth defects like CHD have indicated that, while sequence variants that are common in human populations probably contribute to birth defects, they account for only a small proportion of genetic risk [66], so that genome wide association studies (GWAS) will require thousands of subjects to identify factors. Nevertheless, NTD cases display significant enrichment in rare variants [16, 86], suggesting these changes have greater effect sized and may be identifiable in smaller cohorts, This is the first multicenter SB case-control study to mount a comprehensive, ancestry-matched whole genome sequence (WGS) analysis from a systems biology perspective. This study seeks to identify pathways and biological functions that are disrupted in SB as reflected in their enrichment with genes or regulatory regions harboring rare, likely damaging mutations.…”

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

“…Our genome-wide investigations of exonic sequences established a threshold model of ultra-rare singleton loss of function variant (SloV) burden, replicated in three different populations, that found on average 9 SloVs per individual with SB, compared to 15 SloVs per genome in individuals with anencephaly . We recently reported an initial investigation of SVs through analysis of WGS from two ancestry balanced case-control cohorts (Wolujewicz et al, 2021). The study used a computational ensemble approach to identify copy number variants (CNV) with a MAF < 0.01%, relying on CNVs that met "high confidence" criteria.…”

CIC missense variants contribute to susceptibility for spina bifida

“…A total of 140 case samples with isolated spina bifida (myelomeningocele) which recently reported in our paper (Wolujewicz et al, 2021) were collected from California, USA and Doha, Qatar. Cases with no other anomalies, only minor anomalies or related anomalies were considered isolated.…”