How to Cite this Article: Arrington CB, Bleyl SB, Matsunami N, Bowles NE, Leppert TI, Demarest BL, Osborne K, Yoder BA, Byrne JL, Schiffman JD, Null DM, DiGeronimo R, Rollins M, Faix R, Comstock J, Camp NJ, Leppert MF, Yost HJ, Brunelli L. 2012. A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia. Am J Med Genet Part A 158A: 3137–3147.
A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia†
Article first published online: 19 NOV 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 12, pages 3137–3147, December 2012
How to Cite
Arrington, C. B., Bleyl, S. B., Matsunami, N., Bowles, N. E., Leppert, T. I., Demarest, B. L., Osborne, K., Yoder, B. A., Byrne, J. L., Schiffman, J. D., Null, D. M., DiGeronimo, R., Rollins, M., Faix, R., Comstock, J., Camp, N. J., Leppert, M. F., Yost, H. J. and Brunelli, L. (2012), A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia. Am. J. Med. Genet., 158A: 3137–3147. doi: 10.1002/ajmg.a.35664
- Issue published online: 22 NOV 2012
- Article first published online: 19 NOV 2012
- Manuscript Accepted: 21 AUG 2012
- Manuscript Received: 21 MAY 2011
- NICHD. Grant Number: K08HD062638
- American Heart Association. Grant Number: 09BGIA2251076
- University of Utah, VP for Research and Center for Clinical and Translational Science, National Institutes of Health. Grant Numbers: R01CA134674, R21CA152336
- National Center for Research Resources. Grant Numbers: UL1-RR025764, C06-RR11234
- congenital diaphragmatic hernia;
- Utah population database;
- shared segment analysis;
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2–q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH. © 2012 Wiley Periodicals, Inc.