A clinical-pathogenetic approach on associated anomalies and chromosomal defects supports novel candidate critical regions and genes for gastroschisis.

BACKGROUND: Gastroschisis has been assumed to have a low rate of syndromic and primary malformations. We aimed to systematically review and explore the frequency and type of malformations/chromosomal syndromes and to identify significant biological/genetic roles in gastroschisis.

METHODS: Population-based, gastroschisis-associated anomalies/chromosomal defects published 1950-2018 (PubMed/MEDLINE) were independently searched by two reviewers. Associated anomalies/chromosomal defects and selected clinical characteristics were subdivided and pooled by race, system/region, isolated, and associated cases (descriptive analysis and chi-square test were performed). Critical regions/genes from representative chromosomal syndromes including an enrichment analysis using Gene Ontology Consortium/Panther Classification System databases were explored. Fisher's exact test with False Discovery Rate multiple test correction was performed.

RESULTS: Sixty-eight articles and 18525 cases as a base were identified (prevalence of 17.9 and 3% for associated anomalies/chromosomal defects, respectively). There were 3596 associated anomalies, prevailing those cardiovascular (23.3%) and digestive (20.3%). Co-occurring anomalies were associated with male, female, American Indian, Caucasian, prenatally diagnosed, chromosomal defects, and mortality (P < 0.00001). Gene clusters on 21q22.11 and 21q22.3 (KRTAP), 18q21.33 (SERPINB), 18q22.1 (CDH7, CDH19), 13q12.3 (FLT1), 13q22.1 (KLF5), 13q22.3 (EDNRB), and 13q34 (COL4A1, COL4A2, F7, F10) were significantly related to biological processes: blood pressure regulation and/or vessel integrity, angiogenesis, coagulation, cell-cell and/or cell-matrix adhesion, dermis integrity, and wound healing (P < 0.05).

CONCLUSIONS: Our findings suggest that gastroschisis may result from the interaction of several chromosomal regions in an additive manner as a pool of candidate genes were identified from critical regions supporting a role for vascular disruption, thrombosis, and mesodermal deficiency in the pathogenesis of gastroschisis.