Models for infantile hypertrophic pyloric stenosis development in patients with esophageal atresia

Abstract

Tel +31 10 70 37643 22 Fax: +31 10 70 44736 23 e.brosens@erasmusmc.nl 24 ORCID ID: https://orcid.org/0000-0001-8235-4010 25 26 Running title: EA and IHPS: proposal for multifactorial hypothesis 27 Summary statement: 30 Instead of one affected gene, the higher incidence of IHPS in EA patients is more likely the result of 31 multiple (epi)genetic and environmental factors together shifting the balance to disease 32 development. 33 2 ABSTRACT 34 Patients born with esophageal atresia (EA) have a 30 times higher prevalence of infantile 35 hypertrophic pyloric stenosis (IHPS). This makes sense from a developmental perspective as both the 36 esophagus and the pyloric sphincter are foregut derived structures. EA and IHPS are variable features 37in several (monogenetic) syndromes. This, and twin and familial studies, indicates a genetic 38 component for both conditions as single entities. We hypothesized that genetic defects, disturbing 39 foregut morphogenesis, are responsible for this combination of malformations. Non-genetic factors 40 could also contribute, as mice exposed to Adriamycin develop EA and in utero diethylstilbestrol 41 exposure is associated with EA. 42We investigated the copy number profiles and protein coding variants of 15 patients with both EA 43 and IHPS. As all parents were unaffected, we first considered dominant (de novo) or recessive 44 inheritance models but could not identify putatively deleterious mutations or recessive variants. We 45 did identify inherited variants in genes either known to be involved in EA or IHPS or important in 46 foregut morphogenesis in all patients. Unfortunately, variant burden analysis did not show a 47 54