Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Abstract

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life‐threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Esophageal Atresia With or Without Tracheoesophageal Fistula: Comorbidities, Genetic Evaluations, and Neonatal Outcomes

“…The genetic diagnoses in our cohort (CHARGE Syndrome, Fanconi Syndrome, EFTUD2-related mandibulofacial dysostosis) have been reported in the literature to be associated with EA/TEF [4,12]. The diagnosis with an interstitial deletion of 230.8 kb from the long arm of chromosome 7 (7q11.22 which includes partial AUTS2 gene deletion) has been associated with AUTS2 syndrome with intellectual disability, speech, and language delays, dysmorphic facies, and some rare congenital malformations [21] although EA/TEF has not been reported in the literature with this deletion.…”

“…A recent study by Sy et al evaluated clinical exome sequencing results in 67 individuals with EA/TEF+ (EA/TEF associated with other major birth defects) and found a definitive or probable diagnosis in 11/67 (16%). They also described candidate genes like TCF4 and NRXN1 as having sufficient evidence to support an association with EA/TEF and others like NSD1, PTPN11, and FLNA with insufficient evidence to support association [12]. Another large study by Zhong et al performed whole genome sequencing on 185 trios that included 59 isolated and 126 complex cases and found a significant burden of protein-altering de-novo coding variants in the complex cases although many were classified as VUS [24].…”

“…The underlying mechanism leading to EA/TEF largely remains unknown, but numerous genetic pathways and environmental susceptibility factors have been identified [10]. Multiple studies in the literature have identified a variety of genetic mechanisms such as aneuploidies (trisomy 18), chromosomal microdeletion or microduplication syndromes (22q11.2 deletion syndrome), and a variety of single gene disorders (CHD7, SOX2, FANCB, MYCN, TCF4, NRXN1) that lead to the development of EA/TEF [11,12]. Among environmental factors, antenatal exposure to methimazole, alcohol, cigarette smoke, diethylstilbestrol (DES), and maternal diabetes have been implicated but definitive associations remain unproven [10].…”