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

Gallardo‐Blanco

et al. 2019

Data

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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.

Section: Candidate Gene Model Generationmentioning

confidence: 99%

“…. 5 Gene list input for analysis based on Panther and String [10,11]. 6 Based on ToppGene Suite [12].…”

Section: Dataset Characteristics and Formatmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Database for Gene Variants and Metabolic Networks Implicated in Familial Gastroschisis

Gallardo‐Blanco

et al. 2019

Data

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“…Duplicações parciais da parte distal do cromossomo 13q (13q14-qter) são raras e o fenótipo resultante se assemelha ao da trissomia completa 13 (HELALI et al, 1996;JØNCH et al, 2012). As características craniofaciais incluem microcefalia, orelhas baixas, sobrancelhas grossas, cílios longos e enrolados, hipotelorismo, ponte nasal proeminente, palato alto, filtro labial longo e vermelhão fino do lábio superior (JØNCH et al, 2012 que participa da via extrínseca da coagulação sanguínea (O'HARA et al, 1987;SALINAS-TORRES et al, 2018). A deficiência de FVII é um distúrbio de sangramento autossômico recessivo com gravidade variável, dependendo dos níveis e atividade do antígeno de FVII.…”

Section: Introdução E Revisão De Literaturaunclassified

Microrrearranjos cromossômicos em síndromes craniofaciais complexas

Souza¹

A Deus por cuidar de cada detalhe da minha vida, não me deixar desanimar e me carregar no colo nos momentos mais difíceis. Aos meus filhos, Maria Clara e João Gabriel, a melhor parte de mim, por seus sorrisos, beijos e abraços, por compreenderem a importância do meu trabalho e minha ausência em muitos momentos que precisaram de mim. Meu amor infinito. Aos meus pais, Adelone e Irma, pelo amor incondicional e por terem me ensinado valores como a humildade, responsabilidade, ética, respeito, gratidão, persistência e por cuidarem com todo amor dos meus filhos na minha ausência. Aos meus irmãos Ellen, Lilian, Marlon e Marcos, pela presença nos momentos difíceis, pelo apoio e pelas palavras de incentivo.

Whole exome sequencing identifies multiple novel candidate genes in familial gastroschisis

Gallardo‐Blanco

Salinas‐Torres³

et al. 2020

Molec Gen & Gen Med

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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.