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HGG Adv 2022 Jul 14;33:100107. doi: 10.1016/j.xhgg.2022.100107.
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Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

Zhong G , Ahimaz P , Edwards NA , Hagen JJ , Faure C , Lu Q , Kingma P , Middlesworth W , Khlevner J , El Fiky M , Schindel D , Fialkowski E , Kashyap A , Forlenza S , Kenny AP , Zorn AM , Shen Y , Chung WK .

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.

PubMed ID: 35519826
Article link: HGG Adv
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: abra add1 amer3 ap1g2 apc2 arhgap17 arhgap21 celsr2 disp1 eftud2 itgb4 itsn1 map4k3 pam pcdh1 ptpn14 rab3gap2 rapgef3 smad6 sox2 tyr
Antibodies: Foxf1 Ab1 Nkx2-1 Ab3 Sox2 Ab4
gRNAs referenced: abra gRNA1 add1 gRNA1 amer3 gRNA1 ap1g2 gRNA1 apc2 gRNA1 arhgap17 gRNA1 arhgap21 gRNA1 celsr2 gRNA1 disp1 gRNA1 eftud2 gRNA1 eftud2 gRNA2 itgb4 gRNA1 itsn1 gRNA2 itsn1 gRNA3 map4k3 gRNA1 pcdh1 gRNA1 ptpn14 gRNA1 rab3gap2 gRNA1 rapgef3 gRNA1 smad6 gRNA1 smad6 gRNA2 sox2 gRNA1 sox2 gRNA3 tyr gRNA17

Disease Ontology terms: esophageal atresia/tracheoesophageal fistula [+]

Article Images: [+] show captions
References [+] :
Abyzov, CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. 2011, Pubmed