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 inEFTUD2, 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 ofEFTUD2orSOX2(another known EA/TEF gene), much greater than expected by chance (3.34-fold,pvalue = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identifiedAPC2,AMER3, PCDH1,GTF3C1,POLR2B, RAB3GAP2, andITSN1as 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.

Automated summary

This study identified de novo deleterious variants in EA/TEF patients, especially in genes related to EFTUD2 or SOX2. It is estimated that 33% of patients can be attributed to these variants, and further genomic analysis may uncover previously undescribed genetic causes of EA/TEF.