TY - JOUR TI - Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data AU - Jenkins, Mary M. AU - Almli, Lynn M. AU - Pangilinan, Faith AU - Chong, Jessica X. AU - Blue, Elizabeth E. AU - Shapira, Stuart K. AU - White, Janson AU - McGoldrick, Daniel AU - Smith, Joshua D. AU - Mullikin, James C. AU - Bean, Christopher J. AU - Nembhard, Wendy N. AU - Lou, Xiang-Yang AU - Shaw, Gary M. AU - Romitti, Paul A. AU - Keppler-Noreuil, Kim AU - Yazdy, Mahsa M. AU - Kay, Denise M. AU - Carter, Tonia C. AU - Olshan, Andrew F. AU - Moore, Kristin J. AU - Nascone-Yoder, Nanette AU - Finnell, Richard H. AU - Lupo, Philip J. AU - Feldkamp, Marcia L. AU - Nickerson, Deborah A. AU - Bamshad, Michael J. AU - Brody, Lawrence C. AU - Reefhuis, Jennita T2 - BIRTH DEFECTS RESEARCH AB - Abstract Background The National Birth Defects Prevention Study (NBDPS) is a multisite, population‐based, case–control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. Methods To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. Results The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. Conclusions This proof‐of‐principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well‐characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene–environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers. DA - 2019/12/1/ PY - 2019/12/1/ DO - 10.1002/bdr2.1554 VL - 111 IS - 20 SP - 1618-1632 SN - 2472-1727 KW - birth defects KW - gene-environment interaction KW - genetics KW - intestinal atresia KW - sequence analysis ER - TY - JOUR TI - Vangl2 coordinates cell rearrangements during gut elongation AU - Dush, Michael K. AU - Nascone-Yoder, Nanette M. T2 - DEVELOPMENTAL DYNAMICS AB - Abstract Background The embryonic gut tube undergoes extensive lengthening to generate the surface area required for nutrient absorption across the digestive epithelium. In Xenopus , narrowing and elongation of the tube is driven by radial rearrangements of its core of endoderm cells, a process that concomitantly opens the gut lumen and facilitates epithelial morphogenesis. How endoderm rearrangements are properly oriented and coordinated to achieve this complex morphogenetic outcome is unknown. Results We find that, prior to gut elongation, the core Wnt/PCP component Vangl2 becomes enriched at both the anterior and apical aspects of individual endoderm cells. In Vangl2‐depleted guts, the cells remain unpolarized, down‐regulate cell‐cell adhesion proteins, and, consequently, fail to rearrange, leading to a short gut with an occluded lumen and undifferentiated epithelium. In contrast, endoderm cells with ectopic Vangl2 protein acquire abnormal polarity and adhesive contacts. As a result, endoderm cells also fail to rearrange properly and undergo ectopic differentiation, resulting in guts with multiple torturous lumens, irregular epithelial architecture, and variable intestinal topologies. Conclusions Asymmetrical enrichment of Vangl2 in individual gut endoderm cells orients polarity and adhesion during radial rearrangements, coordinating digestive epithelial morphogenesis and lumen formation with gut tube elongation. DA - 2019/7// PY - 2019/7// DO - 10.1002/dvdy.61 VL - 248 IS - 7 SP - 569-582 SN - 1097-0177 KW - Vangl2 KW - endoderm KW - gut KW - Xenopus KW - morphogenesis KW - elongation ER -