Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall

Abstract

We investigated whether likely pathogenic variants co-segregating with gastroschisis through a family-based approach using bioinformatic analyses were implicated in body wall closure. Gene Ontology (GO)/Panther functional enrichment and protein-protein interaction analysis by String identified several biological networks of highly connected genes in UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, AOX1, NOTCH1, HIST1H2BB, RPS3, THBS1, ADCY9, and FGFR4. SVS–PhoRank identified a dominant model in OR10G4 (also as heterozygous de novo), ITIH3, PLEKHG4B, SLC9A3, ITGA2, AOX1, and ALPP, including a recessive model in UGT1A7, UGT1A6, PER2, PTPRD, and UGT1A3. A heterozygous compound model was observed in CDYL, KDM5A, RASGRP1, MYBPC2, PDE4DIP, F5, OBSCN, and UGT1A. These genes were implicated in pathogenetic pathways involving the following GO related categories: xenobiotic, regulation of metabolic process, regulation of cell adhesion, regulation of gene expression, inflammatory response, regulation of vascular development, keratinization, left-right symmetry, epigenetic, ubiquitination, and regulation of protein synthesis. Multiple background modifiers interacting with disease-relevant pathways may regulate gastroschisis susceptibility. Based in our findings and considering the plausibility of the biological pattern of mechanisms and gene network modeling, we suggest that the gastroschisis developmental process may be the consequence of several well-orchestrated biological and molecular mechanisms which could be interacting with gastroschisis predispositions within the first ten weeks of development.

Database for Gene Variants and Metabolic Networks Implicated in Familial Gastroschisis

“…Second, gene pairs detected in two or more of the PPI including coexpression, protein homology, curated databases, gene neighborhood, or experimentally determined data sets were selected and included in the network modeling using String database 10.5 [11]. A gene-gene pairwise network was constructed using the PPI with a confidence score of 0.4 [6]. These databases include a "hierarchical view" as a structure of the most significant classifications and ontologies of the human genes and E-value statistics (p values of less than 0.05 false discovery rate (FDR)-adjusted) [10,11].…”

“…Candidate gene model generation was based on a three-step process. First, manual curation of genes identified as (a) high impact, (b) segregating among both affected half-sisters and the mother, (c) highly significant functional enrichment, (d) high connectivity/direct PPI, and (e) highest score for dominant, recessive, and heterozygous compound models [6]. Second, gene functional similarity analysis as well as candidate gene prioritization was performed using ToppGene Suite database, which combines an overall score using statistical meta-analysis including p-value (FDR-adjusted) of each annotation of a test gene derived by random sampling from the whole genome [12].…”

“…Gastroschisis represents one of the leading human birth defects affecting~1:2500 live births with an alarming increase in its prevalence [1]. In addition to risk factors such as maternal smoking and young maternal age [1], there is emerging evidence for a genetic component in gastroschisis etiology [2][3][4][5][6]. Heritable factors in gastroschisis were estimated to be 3% adjusted for probands, 4.3% in gastroschisis cases followed by a subsequent affected pregnancy, and overall recurrence risk of 5.7% [3].…”

“…Heritable factors in gastroschisis were estimated to be 3% adjusted for probands, 4.3% in gastroschisis cases followed by a subsequent affected pregnancy, and overall recurrence risk of 5.7% [3]. Moreover, candidate gene analysis has been performed identifying gene variants and pathways related to xenobiotic metabolism, regulation of cell adhesion, regulation of gene expression, inflammatory response, regulation of vascular development, keratinization, left-right symmetry, epigenetic, ubiquitination, and regulation of protein synthesis [4][5][6].…”

“…As a result of this work, gene variants and metabolic networks showing plausibility with gastroschisis from two affected half-sisters, mother, and father of the proband have been described and fully available to scientific communities to review and verify our proposed model [6,7]. Furthermore, our dataset could be useful to enhance the data transparency or reusability for further investigations and can also be utilized for studying and addressing new insights into human biology and molecular mechanisms involved in gastroschisis.…”