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

doi:10.1016/j.xhgg.2022.100107

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

HGG Adv. 2022 Apr 16;3(3):100107. doi: 10.1016/j.xhgg.2022.100107. eCollection 2022 Jul 14.

Authors

Guojie Zhong^{1

2}, Priyanka Ahimaz³, Nicole A Edwards⁴, Jacob J Hagen^{1

3}, Christophe Faure⁵, Qiao Lu^{1

3}, Paul Kingma⁶, William Middlesworth⁷, Julie Khlevner⁸, Mahmoud El Fiky⁹, David Schindel¹⁰, Elizabeth Fialkowski¹¹, Adhish Kashyap⁴, Sophia Forlenza^{6

12}, Alan P Kenny^{6

12}, Aaron M Zorn⁴, Yufeng Shen^{1

13}, Wendy K Chung^{3

14}

Affiliations

¹ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
² Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA.
³ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
⁴ Center for Stem Cell & Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA.
⁵ Division of Pediatric Gastroenterology, CHU Sainte-Justine, Montreal, QC, Canada.
⁶ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁷ Division of Pediatric Surgery, Columbia University Irving Medical Center, New York, NY, USA.
⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Irving Medical Center, New York, NY, USA.
⁹ Pediatric Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹⁰ Division of Pediatric Surgery, UT Southwestern School of Medicine Dallas, Texas, USA.
¹¹ Division of Pediatric Surgery, Oregon Health and Science University, Portland, OR, USA.
¹² Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
¹³ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

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.

Keywords: Xenopus; aerodigestive; congenital anomaly; esophageal atresia; tracheoesophageal fistula.

Abstract

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