Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing



The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e−5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.

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Fig. 1: Genes with LGD or D-mis de novo variants and their relationship with EFTUD2 and SOX2.

Data availability

All likely pathogenic variants are in ClinVar submission number SUB7053346. Accession numbers of submitted variants can be found in Supplemental Table 1.


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We would like to acknowledge the patients and their families who participated in the study and are grateful for their tremendous contribution. We thank Steve Wyles and Sue Paul from EA for adults, as well as the TOFS UK, OARA, Bridging the Gap of EA/TEF and the Canadian EA network organizations for publicizing the study and assisting with recruitment. We are also appreciative for the technical assistance provided by Patricia Lanzano, Jiangyuan Hu, Liyong Deng, Nikita Chintalapudi, and Charles LeDuc from Columbia University and the study team at Cairo University General Hospital. We thank Na Zhu for help with the calculation of background mutation rate. Funding support provided by P01HD093363 (JW, YS, and WKC) and R01GM120609 (YS).

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Correspondence to Yufeng Shen or Wendy K. Chung.

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Wang, J., Ahimaz, P.R., Hashemifar, S. et al. Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing. Eur J Hum Genet (2020).

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