A framework for associating structural variants with cell-specific transcription factors and histone modifications in defect phenotypes

Structural Variations (SVs) naturally occur in healthy human populations and account for more genomic difference than Single Nucleotide Variations (SNVs). However, because of the low prevalence in gene coding regions and the ubiquity in the intergenic regions, determining SV association for defect phenotypes remains challenging. We developed a framework that classifies five categories of SVs using defect associated genes along with cell-specific histone modifications (HM) concurrently with transcription factor binding sites (TFBS). We completed a comprehensive structural variation analysis of 17 family trios consisting of healthy paternal and maternal genomes along with the non-syndromic Orofacial cleft (OFC) child genomes which are publicly available from the Kids First Data Resource Portal. For the integrative analysis, we used ChIP-seq data from Neural Crest and Mesenchymal Stem Cell types from ENCODE along with TFBS taken from JASPAR. We found that the OFC children had elevated regulatory SVs when classified with our framework, aligning with prior studies regarding the complex non-syndromic phenotype. This result supports the use of a defect-specific gene paralog lists integrated with HMs and TFBS to identify plausible SV regions connected to a defect phenotype.