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.

通气消化道的各种畸形统称为食管闭锁/气管食管瘘 (EA/TEF)，构成了一组罕见的先天缺陷，其病因在很大程度上是未知的。以前的研究已经确定了少量罕见的遗传变异导致与 EA/TEF 相关的综合征。我们使用 EA/TEF 对 45 个不相关的单纯性三重奏（先证者和父母）进行了外显子组测序试验研究。13 人分离，32 人分离 EA/TEF；没有人有 EA/TEF 家族史。我们在蛋白质编码区鉴定了新生变异，包括 19 种预测为有害的错义变异 (D-mis) 和 3 种可能的基因破坏 (LGD) 变异。与之前对结构性出生缺陷的研究一致，在病例中有增加新发 D-mis 负担的趋势 (1.p  = 0.003）。EFTUD2中存在移码从头变体，这是一种已知的参与 mRNA 剪接的 EA/TEF 风险基因。引人注目的是，19 个新 D-mis 变体中有 15 个位于EFTUD2或SOX2（另一种已知的 EA/TEF 基因）的假定靶基因中，远大于偶然预期（3.34 倍，p值 = 7.20e） −5). 我们估计 33% 的患者可归因于已知和新基因的新发有害变异。我们确定了APC2、AMER3、PCDH1、GTF3C1、POLR2B、RAB3GAP2和ITSN1作为 EA/TEF 病因学中似是而非的候选基因。我们的结论是，进一步的基因组分析以确定从头变异可能会确定以前未描述的 EA/TEF 遗传原因。