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Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

ABSTRACT: Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein-altering de novo coding variants in complex cases (p = 3.3 × 10^-4), especially in genes that are intolerant of loss-of-function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein-altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. Our results suggest significant genetic heterogeneity of EA/TEF and may have implications for the mechanisms of other rare congenital anomalies.

SUBMITTER: Zhong G

PROVIDER: S-EPMC9065433 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.

Project description:The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.

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Minimally invasive management of combined esophageal atresia with tracheoesophageal fistula and duodenal atresia: a comprehensive case report.

Project description:A newborn presented with a rare combination of esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA), which was successfully managed using minimally invasive surgical techniques. The patient was a 1-day-old male for whom passing a feeding tube was infeasible and who had a double bubble sign on radiography. The neonate underwent a thoracoscopic ligation of the tracheoesophageal fistula (TEF) and a laparoscopic duodeno-duodenostomy on the same day, resulting in stabilized vital signs. Ten days after the initial operation, a thoracoscopic esophago-esophagostomy was successfully performed. The patient demonstrated full feeding capability and normal weight gain after the surgeries. The co-occurrence of EA/TEF and DA is a rare and complex anomaly. This case indicates that minimally invasive techniques can effectively manage this condition.

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Risk Factors for Recurrent Tracheoesophageal Fistula After Gross Type C Esophageal Atresia Repair.

Project description:Background: To determine the possible risk factors of recurrent tracheoesophageal fistula (rTEF) after Gross type C esophageal atresia (EA) and tracheoesophageal fistula (TEF) repair. Methods: The medical records of 343 pediatric patients with Gross type C EA/TEF who underwent surgical repair were retrospectively analyzed. The patients were retrospectively divided into two groups according to whether they had rTEF. Univariate and multivariable logistic regression analysis were performed to identify risk factors for rTEF. Results: After the diagnosis of EA/TEF, 343 patients (221 boys) underwent primary repairs after birth. According to the follow-up results (257 patients survived, 42 died, and 43 were lost to follow-up), 259 patients (257 survived and two died after rTEF repair) were included in the analysis. rTEF occurred in 33 patients (33/259, 12.74%), with a median onset time to recurrence of 3.8 (2.2, 8.2) months. Multivariate analysis showed that closing the original TEF with ligation and hospital stay ≥ 28.5 days were significant risk factors of rTEF with OR of 4.083 (1.481, 11.261) and 3.228 (1.431, 7.282). Conclusions: Surgical closure technique of original TEF and the length of initial stay could influence the occurrence of rTEF after Gross type C EA/TEF repair.

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Project description:Kids First:Genomic Analysis of Esophageal Atresia and Tracheoesophageal Fistulas and Associated Congenital Anomalies

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Kids First:Genomic Analysis of Esophageal Atresia and Tracheoesophageal Fistulas and Associated Congenital Anomalies

Project description:Kids First:Genomic Analysis of Esophageal Atresia and Tracheoesophageal Fistulas and Associated Congenital Anomalies

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Simple Technique of Bridging Wide Gap in Esophageal Atresia with Tracheoesophageal Fistula - "Surgical Innovation".

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