Developmental basis of trachea-esophageal birth defects

Edwards, Nicole; Shacham-Silverberg, Vered; Weitz, Leelah; Kingma, Paul S.; Shen, Yufeng; Wells, James M.; Chung, Wendy K.; Zorn, Aaron M.

doi:10.1016/j.ydbio.2021.05.015

Cited by 24 publications

(30 citation statements)

References 149 publications

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“…Esophageal atresia (EA) is a congenital abnormality of the esophagus, co-occurring with tracheoesophageal fistula (TEF) in 70%–90% cases. 1 , 2 The overall worldwide incidence of EA/TEF is 2.4 per 100,000 births. 3 Approximately 55% of individuals with EA/TEF are complex with additional congenital anomalies 3 in the cardiovascular, musculoskeletal, urinary, gastrointestinal, or central nervous system.…”

Section: Introductionmentioning

confidence: 99%

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

Zhong

Ahimaz

Edwards

et al. 2022

Human Genetics and Genomics Advances

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Section: Introductionmentioning

confidence: 99%

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

Zhong

Ahimaz

Edwards

et al. 2022

Human Genetics and Genomics Advances

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“…Also, among the list is RAB37-204 (log2(fold change) = 1.08), an endosomal protein critical for vesicle trafficking regulation. Rab proteins have been previously linked to foregut malformations (Nasr et al 2019; Nam et al 2010; Edwards et al 2021). Among the top differentially expressed transcripts are several non-coding RNAs, including Y-RNA, MEG3 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Directed differentiation of EA/TEF patient-derived induced pluripotent stem cells into esophageal epithelial organoids reveal SOX2 dysregulation at the anterior foregut stage

Raad

David

Sagniez

et al. 2022

Preprint

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A series of well-regulated cellular and molecular events result in the compartmentalization of the anterior foregut into the esophagus and trachea. Disruption of the compartmentalization process leads to esophageal atresia/tracheoesophageal fistula (EA/TEF). Therefore, the objective is to differentiate pluripotent stem cells (PSCs), namely, embryonic stem cells and iPSCs from healthy individuals and iPSCs from EA/TEF type C patients, into mature 3-dimensional esophageal organoids expressing Involucrin, Keratin-4, -13, and p63. CXCR4, SOX17, and GATA4 expression was similar in both patient and healthy endodermal cells. Key transcription factor SOX2 was significantly lower in patient-derived anterior foregut. RNA sequencing revealed critical genes GSTM1 and RAB37 to be significantly lower in patient-derived anterior foregut. Furthermore, we observed an abnormal expression of NKX2.1 in the patient-derived mature esophageal organoids. We therefore hypothesize that a transient dysregulation of SOX2 and the abnormal expression of NKX2.1 in patient-derived cells could be responsible for the abnormal foregut compartmentalization.

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“…These syndromes have autosomal recessive, Xlinked recessive, and autosomal dominant inheritance. However, they have a much lower prevalence compared with that of OA/TOF, and in most of these syndromes, OA/TOF is a variable characteristic that is not frequently present [24,25]. Mutations in DNA repair genes (FANC genes), genes involved in endocytic vesicular trafficking [26,27], the splicing machinery [28], and several transcription factor genes (e.g., SRY (sex determining region Y)-box 2 (SOX2), MYCN Proto-Oncogene, and BHLH Transcription Factor (MYCN)) could explain some of the aetiology of OA/TOF in patients.…”

Section: Genetic Contribution To Oa/tof Aetiologymentioning

confidence: 99%

“…In Table 1, established genes from animal models and human OA/TOF syndromes are depicted alongside their probability of loss of function, probability of intolerance to bi-allelic variation, missense z-score, and synonymous z-scores. This table was modified after [24,25], and a substantial portion of these genes was evaluated in a large cohort of patients with OA-and VACTERL-associated anomalies using a Molecular Inversion Probe Candidate gene screening [32]. Interestingly, Screening VACTERL patients including those with OA/TOF as well as exome and genome sequencing of patients did not result in high de novo rates in these genes [26,27,29,32].…”

Section: The Impact Of De Novo Mutation On Human Disease and Animal Candidate Genesmentioning

confidence: 99%

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Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology

Brosens

Brouwer

Douben

et al. 2021

Genes

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Tracheoesophageal Fistula (TOF) is a congenital anomaly for which the cause is unknown in the majority of patients. OA/TOF is a variable feature in many (often mono-) genetic syndromes. Research using animal models targeting genes involved in candidate pathways often result in tracheoesophageal phenotypes. However, there is limited overlap in the genes implicated by animal models and those found in OA/TOF-related syndromic anomalies. Knowledge on affected pathways in animal models is accumulating, but our understanding on these pathways in patients lags behind. If an affected pathway is associated with both animals and patients, the mechanisms linking the genetic mutation, affected cell types or cellular defect, and the phenotype are often not well understood. The locus heterogeneity and the uncertainty of the exact heritability of OA/TOF results in a relative low diagnostic yield. OA/TOF is a sporadic finding with a low familial recurrence rate. As parents are usually unaffected, de novo dominant mutations seems to be a plausible explanation. The survival rates of patients born with OA/TOF have increased substantially and these patients start families; thus, the detection and a proper interpretation of these dominant inherited pathogenic variants are of great importance for these patients and for our understanding of OA/TOF aetiology.

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Developmental basis of trachea-esophageal birth defects

Cited by 24 publications

References 149 publications

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

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

Directed differentiation of EA/TEF patient-derived induced pluripotent stem cells into esophageal epithelial organoids reveal SOX2 dysregulation at the anterior foregut stage

Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology

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