RT Journal Article
SR Electronic
T1 Models for infantile hypertrophic pyloric stenosis development in patients with esophageal atresia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 625921
DO 10.1101/625921
A1 Chantal A. ten Kate
A1 Rutger W.W. Brouwer
A1 Yolande van Bever
A1 Vera K. Martens
A1 Tom Brands
A1 Nicole W.G. van Beelen
A1 Alice S. Brooks
A1 Daphne Huigh
A1 Bert J.F.M.M. Eussen
A1 Wilfred F.J. van IJcken
A1 Hanneke IJsselstijn
A1 Dick Tibboel
A1 Rene M.H. Wijnen
A1 Annelies de Klein
A1 Robert M.W. Hofstra
A1 Erwin Brosens
YR 2019
UL http://biorxiv.org/content/early/2019/05/02/625921.abstract
AB Patients born with esophageal atresia (EA) have a 30 times higher prevalence of infantile hypertrophic pyloric stenosis (IHPS). This makes sense from a developmental perspective as both the esophagus and the pyloric sphincter are foregut derived structures. EA and IHPS are variable features in several (monogenetic) syndromes. This, and twin and familial studies, indicates a genetic component for both conditions as single entities. We hypothesized that genetic defects, disturbing foregut morphogenesis, are responsible for this combination of malformations. Non-genetic factors could also contribute, as mice exposed to Adriamycin develop EA and in utero diethylstilbestrol exposure is associated with EA.We investigated the copy number profiles and protein coding variants of 15 patients with both EA and IHPS. As all parents were unaffected, we first considered dominant (de novo) or recessive inheritance models but could not identify putatively deleterious mutations or recessive variants. We did identify inherited variants in genes either known to be involved in EA or IHPS or important in foregut morphogenesis in all patients. Unfortunately, variant burden analysis did not show a significant difference with unaffected controls. However, the IHPS associated risk SNP rs1933683 had a significantly higher incidence (OR 3.29, p=0.009).Although the genetic variation in likely candidate genes as well as the predisposing locus near BARX1 (rs1933683) suggest a genetic component, it does not fully explain the abnormalities seen in these patients. Therefore, we hypothesize that a combination of high impact genetic, mechanical and environmental factors together can shift the balance to abnormal development.Summary statement Instead of one affected gene, the higher incidence of IHPS in EA patients is more likely the result of multiple (epi)genetic and environmental factors together shifting the balance to disease development.