Genetic variants conferring susceptibility to gastroschisis: a phenomenon restricted to the interaction with the environment?

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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

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“…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]. Third, a final manual curation of GO-biological processes and pathways were selected based on their proximity and plausibility to the phenotype, including previous pathways associated to gastroschisis [4,5]. These implemented analyses allowed us to identify and predict pathogenetic networks comprised by potential gastroschisis predispositions [6].…”

Section: Candidate Gene Model Generationmentioning

confidence: 99%

“…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%

“…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%

See 1 more Smart Citation

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.

Delineating septo‐optic dysplasia

Lubinsky

Encha‐Razavi

2022

Birth Defects Research

Background Septo‐optic dysplasia (SOD), once a variable triad of septum pellucidum defects (SPDs), optic nerve hypoplasia (ONH), and hypopituitarism, has had multiple findings added, with uncertain causes, definitions, and limits. Method Literature review. Results SOD is a complex vascular sequence with confounders. Conclusions Proximal anterior cerebral artery trunk disruptions cause overlapping primary effects, giving ONH alone most often, and isolated SPD less. ONH disruptions can spread to pituitary, SPD disruptions to the cerebral cortex, causing schizencephaly and related anomalies. Pituitary defects are rare without ONH, and cortical findings are rare without SPD. Extensions are unidirectional, so isolated pituitary or cortical defects are separate from SOD. Micro‐ an‐ ophthalmia, a suggested ONH variant, is not part of SOD. Disruption by‐products can affect development, causing cognitive and endocrine issues, and structural anomalies such as corpus callosum thinning, ventriculomegaly, and hippocampal and olfactory findings. Limbic extensions may also contribute to the same structural defects as by‐products. Midline CNS developmental anomalies can act as disruptive foci, most likely through vascular variants, but have separate pathogenesis. Relative frequencies of specific pituitary hormone defects change as SOD rates increase. Increasing relative rates of midline CNS developmental defects and cortical anomalies are consistent with rising levels of exogenous exposures sensitizing to midline predispositions.