Familial occurrence of gastroschisis: a population-based overview on recurrence risk, sex-dependent influence, and geographical distribution

Objectives: Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high-risk multigenerational pedigrees. Methods: We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high-density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome-wide significance thresholds were determined for each pedigree. Results: We identified six pedigrees that contained genome-wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes. Discussion: The genome-wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/genefocused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis. K E Y W O R D Sgastroschisis, genetics, high-risk multigenerational pedigrees

Section: Introductionmentioning

confidence: 99%

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Feldkamp

Krikov

Gardner

et al. 2019

Birth Defects Research

“…Perhaps the chief explanation for an experimental scarcity regarding the biological or molecular mechanism of human ventral body wall development, particularly in gastroschisis, is linked to the assumption that such defect does not have a genetic basis. Recently, we published research suggesting that this phenotype may result from complex gene-gene or gene-environment interactions [1,2,3,4,44,45]. Accordingly, it is possible that several of the above pathogenetic pathways do indeed lead to a disruptive closure of the ventral body wall, as several well-orchestrated biological and molecular mechanisms could be interacting with gastroschisis genetic predisposition within the first ten weeks of human development.…”

Section: Discussionmentioning

confidence: 99%

“…Given the above, it follows that genes involved in the inflammatory response may play a key role for maternal immunological factors and possibly be responsible for susceptibility to genitourinary infections and the association of a change in sex partner with gastroschisis [44,45,67]. Altogether with the genes involved in the regulation of gene expression, epigenetic, regulation of protein synthesis, and ubiquitination, fetal immune development regulating genes may also play a central role in preterm birth and low fetal weight.…”

Section: Discussionmentioning

confidence: 99%

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

Gallardo‐Blanco

et al. 2019

IJMS

Self Cite

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.

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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]. 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].…”

Section: Introductionmentioning

confidence: 99%

Database for Gene Variants and Metabolic Networks Implicated in Familial Gastroschisis

Gallardo‐Blanco

et al. 2019

Data

Self Cite

Gastroschisis is one of the most prevalent human birth defects concerning the ventral body wall development. Recent research has given a better understanding of gastroschisis pathogenesis through the identification of multiple novel pathogenetic pathways implicated in ventral body wall closure. Deciphering the underlying genetic factors segregating among familial gastroschisis allows better detection of novel susceptibility variants than the screening of pooled unrelated cases and controls, whereas bioinformatic-aided analysis can help to address new insights into human biology and molecular mechanisms involved in gastroschisis. Technological advances in DNA sequencing (Next Generation Sequencing), computing power, and machine learning techniques provide opportunities to the scientific communities to assess significant gaps in research and clinical practice. Thus, in an effort to study the role of gene variation in gastroschisis, we employed whole exome sequencing in a Mexican family with recurrence for gastroschisis. Stringent bioinformatic analyses were implemented to identify and predict pathogenetic networks comprised of potential gastroschisis predispositions. This is the first database for gene variants and metabolic networks implicated in familial gastroschisis. The dataset provides information on gastroschisis annotated genes, gene variants, and metabolic networks and constitutes a useful source to enhance further investigations in gastroschisis.