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

Zhong, Guojie; Ahimaz, Priyanka; Edwards, Nicole; Hagen, Jacob; Fauré, Christophe; Qiao, Li; Kingma, Paul S.; Middlesworth, William; Khlevner, Julie; Fiky, Mahmoud El; Schindel, David T.; Fialkowski, Elizabeth; Kashyap, Adhish; Forlenza, Sophia; Kenny, Alan P.; Zorn, Aaron M.; Shen, Yufeng; Chung, Wendy K.

doi:10.1016/j.xhgg.2022.100107

Cited by 4 publications

(12 citation statements)

References 54 publications

(71 reference statements)

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“…Using genome sequencing, we recently established a cohort of 185 EA/TEF patients who were enriched for potentially damaging and missense de novo heterozygous variants in genes involved in intracellular transport and endocytosis (Zhong et al, 2022). An analysis of known protein-protein interactions from the STRING database (Szklarczyk et al, 2023) revealed that many of the proteins encoded by patient risk genes interact with core recycling endosome trafficking components (Figure 1A), supporting evidence that this pathway has an important role in trachea-esophageal morphogenesis (Nasr et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Damaging variants in these genes all involved in endosome trafficking are suggestive of a pathway-related syndrome, or an endosomeopathy, that may underlie the pathogenesis of EA/TEF. Endosome trafficking may be required in multiple organs to facilitate tissue and cell organization and may underlie why EA/TEF patients with variants in endosome trafficking genes often present with co-morbidities including neurodevelopmental disorders and congenital anomalies in other organs (Zhong et al, 2022). Comorbidities may manifest due to disruptions of endosome trafficking in other fusing and septating organs like the neural tube, palate, urogenital septum, and the heart.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent whole genome sequencing analysis of 185 EA/TEF parent-proband trios, we found an enrichment of potentially damaging de novo variants in genes related to endocytosis and intracellular trafficking (Zhong et al, 2022). This observation was intriguing considering our previous findings in Xenopus and mouse embryos implicating Rab11-mediated epithelial remodeling in trachea-esophageal morphogenesis (Nasr et al, 2019).…”

Section: Introductionmentioning

confidence: 96%

“…Rab11 is a key small GTPase in the recycling endosome pathway that cells use to transport newly synthesized proteins from the Golgi to plasma membrane and to change the composition of specific plasma membrane domains by internalizing receptors and other cell surface proteins 20 . How recycling endosomes regulate foregut epithelial remodeling was unclear, but intriguingly, whole genome sequencing analysis revealed that EA/TEF patients with complex multi-organ phenotypes are enriched for potentially damaging de novo variants in genes related to endocytosis and intracellular trafficking 21 . These two independent observations led us to test the hypothesis that endosome trafficking is a crucial morphogenetic bottleneck in tracheoesophageal separation and to define the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Edwards,

Kashyap,

Warren

et al. 2023

Preprint

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The developmental basis of esophageal atresia and tracheoesophageal fistulas (EA/TEF), life-threatening congenital anomalies where the embryonic foregut fails to properly separate into trachea and esophagus, is poorly understood. Recent genome sequencing reveals that de novo variants in intracellular trafficking genes are enriched in EA/TEF patients, suggesting that these cellular processes regulate foregut morphogenesis. Here we show that mutation of orthologous genes in Xenopus disrupts trachea-esophageal separation like EA/TEF patients. We identify the underlying mechanism showing that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the apical cell surface where opposite sides of the foregut tube fuses forming a transient epithelial bilayer. A partial loss of endosome trafficking or knockdown of the Vangl/Celsr complex disrupts cell polarity and planar cell division. Mutant cells accumulate in the disorganize septum, fail to downregulate cadherin, and do not separate into distinct trachea and esophagus. These data provide new insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Edwards,

Kashyap,

Warren

et al. 2023

Preprint

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“…They also described candidate genes like TCF4 and NRXN1 as having sufficient evidence to support an association with EA/TEF and others like NSD1, PTPN11, and FLNA with insufficient evidence to support association [12]. Another large study by Zhong et al performed whole genome sequencing on 185 trios that included 59 isolated and 126 complex cases and found a significant burden of protein-altering de-novo coding variants in the complex cases although many were classified as VUS [24]. They concluded that the number of risk genes contributing is very large, highlighting the genetic heterogeneity of EA/TEF.…”

Section: Discussionmentioning

confidence: 99%

Esophageal Atresia With or Without Tracheoesophageal Fistula: Comorbidities, Genetic Evaluations, and Neonatal Outcomes

Khattar¹,

Suhrie²

2023

Cureus

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Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) has a reported incidence of 1 in 3500 live births and requires intensive care and surgery. To evaluate the prevalence of a molecularly confirmed genetic etiology of EA/TEF in a level IV neonatal intensive care unit (NICU), focusing on genetic evaluation, diagnostic yield, and clinical outcomes of these neonates. Study designA retrospective cohort study over a period of seven years was performed for all patients admitted with a diagnosis of EA/TEF. Automated data was extracted for demographic information and manual extraction was done to evaluate the frequency of associated anomalies, type of genetic evaluations and diagnoses, and outcomes at NICU discharge. ResultsSixty-eight infants met the inclusion criteria. The majority were male (n=42; 62%), born at >37 weeks' gestation (n=36; 53%), and had EA with distal TEF (n=54; 79%). Most (n=53; 78%) had additional associated congenital anomalies, but only 47 (69%) patients had a genetics evaluation performed and genetic testing was sent for 44 (65%) of those patients. The most common genetic testing performed was chromosomal microarray analysis (n=40; 59%), followed by chromosome analysis (n=11; 16%), and whole exome/genome sequencing (n=7; 10%). Five unique genetic diagnoses including CHARGE Syndrome, Fanconi Syndrome, EFTUD2-related mandibulofacial dysostosis, and two different chromosomal deletion syndromes were made for a total of nine (13%) patients in our cohort. The cohort suffered a high rate of morbidity and mortality during their NICU stay with important differences noted in isolated vs non-isolated EA/TEF. Twelve infants (18%) died prior to NICU discharge. Of those surviving, 40 (71%) infants had a primary repair, 37 (66%) infants required G or GJ feedings at NICU discharge, and eight (14%) patients were discharged on some type of respiratory support. ConclusionIn this high-risk cohort of EA/TEF patients cared for at a quaternary NICU, a majority were non-isolated and had some form of a genetic evaluation, but a minority underwent exome or genome sequencing. Given the high prevalence of associated anomalies, high mortality, and genetic disease prevalence in this cohort, we recommend standardization of phenotyping and genetic evaluation to allow for precision care and appropriate risk stratification.

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Primary cilia are critical for tracheoesophageal septation

Fitzsimons,

Tasouri,

Willaredt

et al. 2023

Developmental Dynamics

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IntroductionPrimary cilia play pivotal roles in the patterning and morphogenesis of a wide variety of organs during mammalian development. Here we examined murine foregut septation in the cobblestone mutant, a hypomorphic allele of the gene encoding the intraflagellar transport protein IFT88, a protein essential for normal cilia function.ResultsWe reveal a crucial role for primary cilia in foregut division, since their dramatic decrease in cilia in both the foregut endoderm and mesenchyme of mutant embryos resulted in a proximal tracheoesophageal septation defects and in the formation of distal tracheo(broncho)esophageal fistulae similar to the most common congenital tracheoesophageal malformations in humans. Interestingly, the dorsoventral patterning determining the dorsal digestive and the ventral respiratory endoderm remained intact, whereas Hedgehog signaling was aberrantly activated.ConclusionsOur results demonstrate the cobblestone mutant to represent one of the very few mouse models that display both correct endodermal dorsoventral specification but defective compartmentalization of the proximal foregut. It stands exemplary for a tracheoesophageal ciliopathy, offering the possibility to elucidate the molecular mechanisms how primary cilia orchestrate the septation process. The plethora of malformations observed in the cobblestone embryo allow for a deeper insight into a putative link between primary cilia and human VATER/VACTERL syndromes.

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

Cited by 4 publications

References 54 publications

Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Esophageal Atresia With or Without Tracheoesophageal Fistula: Comorbidities, Genetic Evaluations, and Neonatal Outcomes

Primary cilia are critical for tracheoesophageal septation

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