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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number100107
JournalHuman Genetics and Genomics Advances
Volume3
Issue number3
DOIs
StatePublished - Jul 14 2022

Keywords

  • aerodigestive
  • congenital anomaly
  • esophageal atresia
  • tracheoesophageal fistula
  • Xenopus

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics(clinical)

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