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

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 geneti...

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Autores principales: Zhong, Guojie, Ahimaz, Priyanka, Edwards, Nicole A., Hagen, Jacob J., Faure, Christophe, Lu, Qiao, Kingma, Paul, Middlesworth, William, Khlevner, Julie, El Fiky, Mahmoud, Schindel, David, Fialkowski, Elizabeth, Kashyap, Adhish, Forlenza, Sophia, Kenny, Alan P., Zorn, Aaron M., Shen, Yufeng, Chung, Wendy K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065433/
https://www.ncbi.nlm.nih.gov/pubmed/35519826
http://dx.doi.org/10.1016/j.xhgg.2022.100107
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author Zhong, Guojie
Ahimaz, Priyanka
Edwards, Nicole A.
Hagen, Jacob J.
Faure, Christophe
Lu, Qiao
Kingma, Paul
Middlesworth, William
Khlevner, Julie
El Fiky, Mahmoud
Schindel, David
Fialkowski, Elizabeth
Kashyap, Adhish
Forlenza, Sophia
Kenny, Alan P.
Zorn, Aaron M.
Shen, Yufeng
Chung, Wendy K.
author_facet Zhong, Guojie
Ahimaz, Priyanka
Edwards, Nicole A.
Hagen, Jacob J.
Faure, Christophe
Lu, Qiao
Kingma, Paul
Middlesworth, William
Khlevner, Julie
El Fiky, Mahmoud
Schindel, David
Fialkowski, Elizabeth
Kashyap, Adhish
Forlenza, Sophia
Kenny, Alan P.
Zorn, Aaron M.
Shen, Yufeng
Chung, Wendy K.
author_sort Zhong, Guojie
collection PubMed
description 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.
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spelling pubmed-90654332022-05-04 Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas Zhong, Guojie Ahimaz, Priyanka Edwards, Nicole A. Hagen, Jacob J. Faure, Christophe Lu, Qiao Kingma, Paul Middlesworth, William Khlevner, Julie El Fiky, Mahmoud Schindel, David Fialkowski, Elizabeth Kashyap, Adhish Forlenza, Sophia Kenny, Alan P. Zorn, Aaron M. Shen, Yufeng Chung, Wendy K. HGG Adv Article 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. Elsevier 2022-04-16 /pmc/articles/PMC9065433/ /pubmed/35519826 http://dx.doi.org/10.1016/j.xhgg.2022.100107 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Zhong, Guojie
Ahimaz, Priyanka
Edwards, Nicole A.
Hagen, Jacob J.
Faure, Christophe
Lu, Qiao
Kingma, Paul
Middlesworth, William
Khlevner, Julie
El Fiky, Mahmoud
Schindel, David
Fialkowski, Elizabeth
Kashyap, Adhish
Forlenza, Sophia
Kenny, Alan P.
Zorn, Aaron M.
Shen, Yufeng
Chung, Wendy K.
Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title_full Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title_fullStr Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title_full_unstemmed Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title_short Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
title_sort identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065433/
https://www.ncbi.nlm.nih.gov/pubmed/35519826
http://dx.doi.org/10.1016/j.xhgg.2022.100107
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