Dataset Information

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.

SUBMITTER: Salinas-Torres VM

PROVIDER: S-EPMC6539040 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Salinas-Torres Víctor M VM Gallardo-Blanco Hugo L HL Salinas-Torres Rafael A RA Cerda-Flores Ricardo M RM Lugo-Trampe José J JJ Villarreal-Martínez Daniel Z DZ Martínez de Villarreal Laura E LE

International journal of molecular sciences 20190509 9

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 <i>UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, AOX1, NOTCH1, HIST1H2BB, RPS3, THBS1, ADCY9</i>, and <i>FGFR4</i>. SVS-PhoRank i ...[more]

PMID: 31075877

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Project description:ImportanceSutureless gastroschisis repair offers an alternative to the traditional sutured method and has been associated with decreased intubation time. Published study results are inconsistent regarding the advantages of sutureless closure.ObjectiveTo compare the clinical outcomes of sutureless and sutured gastroschisis repair.Design, setting, and participantsA single-center cohort review was performed of all consecutive patients (n = 97) who underwent gastroschisis repair from February 1, 2007, to April 30, 2017, at the University of California, San Francisco. Patients' medical records were evaluated for clinical characteristics and outcomes. Cases with incomplete data during initial hospitalization were excluded.Main outcomes and measuresLength of hospital stay, time to full enteral feeds, total parenteral nutrition duration, days requiring intravenous analgesia, days intubated, wound infection rate, antibiotic treatment duration, rate of umbilical hernias that required an operation, and readmission rate.ResultsIn total, 97 patients (47 [48%] were female and 50 [52%] were male with a mean [SD] age of 2.8 [2.8] days) underwent gastroschisis repair, of which 7 were excluded for incomplete medical record. Of the 90 patients included in the study, 50 (56%) underwent sutured closure and 40 (44%) underwent sutureless closure. No statistical difference was found between the sutured and sutureless groups in length of hospital stay (mean [SD] days, 43.9 [40.4] vs 36.7 [21.2]; P = .71), time to full enteral feeds (mean [SD] days, 31.4 [20.2] vs 27.9 [17.3]; P = .22), total parenteral nutrition duration (mean [SD] days, 33.5 [29.8] vs 27.4 [18.2]; P = .23), wound infection rates (14 [28%] vs 10 [25%]; P = .81), and readmission rates (5 [10%] vs 7 [18%]; P = .36). The sutureless group, compared with the sutured group, had substantially fewer days receiving antibiotics (mean [SD], 7.2 [6.4] vs 12.4 [13.2]; P = .003), fewer days intubated (mean [SD], 2.8 [3.3] vs 6.8 [1.3]; P = .001), fewer days receiving intravenous analgesia (mean [SD], 4.2 [4.0] vs 7.1 [4.5]; P = .003), and fewer patients that required silo reduction (25 [63%] vs 48 [96%]; P < .001). Sutureless closures, compared with the sutured technique, had considerably more umbilical hernias requiring surgical repair (5 [13%] vs 0; P = .02).Conclusions and relevanceSutureless repair of gastroschisis appears to be associated with a statistically significant reduction in mechanical ventilation duration and pain medication requirements but may increase umbilical hernia risk. Multicenter randomized clinical trials are necessary to determine the true advantages of the sutureless approach.

Project description:BackgroundRecurrence rates after ventral hernia repair vary widely and evidence about risk factors for recurrence are conflicting. There is little evidence for risk factors for long-term recurrence.MethodsPatients who underwent ventral hernia repair at our institution and were captured in the American College of Surgeons-National Surgical Quality Improvement Program database between 2002 and 2015 were included. We reviewed all demographic, procedural, and hernia-specific data.ResultsSix hundred and thirty patients were included for analysis with a median follow-up of 4.9 years (inter-quartile range, 2-7.3 years). By univariate analysis, index hernia repairs were more likely to recur if defect size was ≥4 cm (P = .019), no mesh was used (P = .026), or if the repair was for a recurrent hernia (P = .001). Five-year cumulative incidence of recurrence and reoperation was 24.3% and 16.0%, respectively. Patients with a perioperative surgical site occurrence, which included superficial, deep-incisional, and organ space surgical site infections as well as wound disruption, had a 5-year cumulative incidence of recurrence of 54.9% compared with 22.6% for those without surgical site occurrence. By multivariable analysis, non-primary hernia repair (hazard ratio 1.7, 95% confidence interval 1.2-2.4, P = .005) and any postoperative surgical site occurrence (hazard ratio 1.9, 95% confidence interval 1.1-3.6, P = .02) were the only risk factors predictive of recurrence. Patient body mass index had no independent effect on recurrence.Conclusion1 in 4 patients undergoing an open ventral hernia repair will have a recurrence after 5 years, and this risk is doubled among patients who experience any perioperative surgical site occurrence. After controlling for patient comorbidities, including body mass index, hernia size, and mesh position, the most significant risk factor for recurrence after ventral hernia repair was a non-primary hernia and surgical site occurrence.

Project description:BackgroundGenetic association studies for gastroschisis have highlighted several candidate variants. However, genetic basis in gastroschisis from noninvestigated heritable factors could provide new insights into the human biology for this birth defect. We aim to identify novel gastroschisis susceptibility variants by employing whole exome sequencing (WES) in a Mexican family with recurrence of gastroschisis.MethodsWe employed WES in two affected half-sisters with gastroschisis, mother, and father of the proband. Additionally, functional bioinformatics analysis was based on SVS-PhoRank and Ensembl-Variant Effect Predictor. The latter assessed the potentially deleterious effects (high, moderate, low, or modifier impact) from exome variants based on SIFT, PolyPhen, dbNSFP, Condel, LoFtool, MaxEntScan, and BLOSUM62 algorithms. The analysis was based on the Human Genome annotation, GRCh37/hg19. Candidate genes were prioritized and manually curated based on significant phenotypic relevance (SVS-PhoRank) and functional properties (Ensembl-Variant Effect Predictor). Functional enrichment analysis was performed using ToppGene Suite, including a manual curation of significant Gene Ontology (GO) biological processes from functional similarity analysis of candidate genes.ResultsNo single gene-disrupting variant was identified. Instead, 428 heterozygous variations were identified for which SPATA17, PDE4DIP, CFAP65, ALPP, ZNF717, OR4C3, MAP2K3, TLR8, and UBE2NL were predicted as high impact in both cases, mother, and father of the proband. PLOD1, COL6A3, FGFRL1, HHIP, SGCD, RAPGEF1, PKD1, ZFHX3, BCAS3, EVPL, CEACAM5, and KLK14 were segregated among both cases and mother. Multiple interacting background modifiers may regulate gastroschisis susceptibility. These candidate genes highlight a role for development of blood vessel, circulatory system, muscle structure, epithelium, and epidermis, regulation of cell junction assembly, biological/cell adhesion, detection/response to endogenous stimulus, regulation of cytokine biosynthetic process, response to growth factor, postreplication repair/protein K63-linked ubiquitination, protein-containing complex assembly, and regulation of transcription DNA-templated.ConclusionConsidering the likely gene-disrupting prediction results and similar biological pattern of mechanisms, we propose a joint "multifactorial model" in gastroschisis pathogenesis.

Dataset Information

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

Publications

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

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