Database for Gene Variants and Metabolic Networks Implicated in Familial Gastroschisis

Abstract

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.

Whole exome sequencing identifies multiple novel candidate genes in familial gastroschisis

“…No pathological DNA variants associated with gastroschisis were detected by CENTOGENE AG ® and LC Sciences ® . A total of 17,354 variants of the two sets of reports provided by CENTOGENE AG ® (3,518 variants) and LC Sciences ® (13,836 variants) were considered (Salinas‐Torres et al, ,b). As to 31 August 2018, according to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), SVS–PhoRank gene ranking (http://wwwgoldenhelix.com), and Ensembl–VEP (Zerbino et al, ), a total of 428 heterozygous DNA variations have been prioritized and manually curated by phenotypic relevance and functional properties (Salinas‐Torres et al, ,b).…”

“…Thus, a combined effect of in silico prediction tools identified 10 high‐impact potential deleterious variants in both cases, mother, and father of the proband (Table ), whereas 12 genetic variants segregating among both cases with gastroschisis and the mother were identified (Table ). Multiple moderate and modifier impact variants segregating within the family were also identified (Salinas‐Torres et al, ,b). Of note, the following variants were also identified as modifier impact variants in addition to being predicted as having a high or moderate deleterious effect: SPATA17 (rs147297747), PDE4DIP (rs61804988), CFAP65 (rs6736922), ALPP (rs13026692), ZNF717 (rs150689808 and rs140982339), MAP2K3 (rs55796947), TLR8 (rs3764880), COL6A3 (rs202092407) , FGFRL1 (rs4647931), RAPGEF1 (rs554713394), PKD1 (rs142888788), ZFHX3 (rs200992486), BCAS3 (rs201061353), EVPL (rs202057945), CEACAM5 (rs998112305).…”

“…With certainty, the underlying mechanism for the defect seems complex and involves several functionally interacting genes for which all possible genetic and nongenetic factors contributing to complex landscape should be considered. In this sense, the multiple factors and gene interactions identified, particularly, background modifiers (Salinas‐Torres et al, ,b), can aggravate or mask the expected phenotype through gain‐ or loss‐of‐function mutations in genes involved in related cellular functions (Hou, Leeuwen, Andrews, & Boone, ). Accordingly, the genetics of complex traits is significant, considering that even minor fluctuations in a modest number of genes or gene pathways with disease‐relevant cells, as well as their direct regulators, may contribute to disease susceptibility, as depicted in the “omnigenic” hypothesis (Boyle, Li, & Pritchard, ).…”

“…Once the sample information from the two sets of reports by CENTOGENE AG ® and LC Sciences ® was obtained, unifying database was set up in order to have a better visualization of the SNVs and INDELs annotated and considered (Salinas‐Torres, Gallardo‐Blanco, Salinas‐Torres, & Martínez de Villarreal, ,b).…”