Identification and validation of novel 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 orde novogenetic 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 novel 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 alteringde novocoding variants in complex cases (p=3.3e-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 alteringde novovariants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis inXenopusand confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. This research may have implications for the mechanisms of other rare congenital anomalies..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 06. Nov. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhong, Guojie [VerfasserIn] |
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| doi: |
10.1101/2021.07.18.21260699 |
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| PPN (Katalog-ID): |
XBI032245165 |
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| 245 | 1 | 0 | |a Identification and validation of novel candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas |
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| 520 | |a Abstract Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare orde novogenetic 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 novel 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 alteringde novocoding variants in complex cases (p=3.3e-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 alteringde novovariants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis inXenopusand confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. This research may have implications for the mechanisms of other rare congenital anomalies. | ||
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| 700 | 1 | |a Edwards, Nicole A. |0 (orcid)0000-0001-6952-2569 |4 aut | |
| 700 | 1 | |a Hagen, Jacob J. |4 aut | |
| 700 | 1 | |a Faure, Christophe |4 aut | |
| 700 | 1 | |a Kingma, Paul |4 aut | |
| 700 | 1 | |a Middlesworth, William |4 aut | |
| 700 | 1 | |a Khlevner, Julie |4 aut | |
| 700 | 1 | |a Fiky, Mahmoud El |4 aut | |
| 700 | 1 | |a Schindel, David |4 aut | |
| 700 | 1 | |a Fialkowski, Elizabeth |4 aut | |
| 700 | 1 | |a Kashyap, Adhish |4 aut | |
| 700 | 1 | |a Forlenza, Sophia |4 aut | |
| 700 | 1 | |a Kenny, Alan P. |4 aut | |
| 700 | 1 | |a Zorn, Aaron M. |4 aut | |
| 700 | 1 | |a Shen, Yufeng |4 aut | |
| 700 | 1 | |a Chung, Wendy K. |4 aut | |
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