Our overall goal is to identify the genetic causes of diaphragmatic hernia in humans. The diaphragm is a tissue composed of muscle and tendon that separates the chest and abdomen. If the diaphragm does not form normally, a hernia or protrusion of the abdominal contents into the chest can result. Diaphragmatic hernias are common and occur in 1 in 2500 live- and stillbirths. A diaphragmatic hernia is a devastating birth defect, and the mortality and morbidity associated with the hernias is very high. Little is known about the genetic causes of diaphragmatic hernia, and we therefore would like to discover which genes are important in determining which babies is susceptible to developing a hernia. We have used a technique called array comparative genomic hybridization to identify new, small chromosome deletions in patients with diaphragmatic hernias. These deleted regions contain genes that are needed for normal diaphragm development. We would like to develop this research further and use the same technique to continue to screen patients with diaphragmatic hernias for chromosome deletions. We would also like to determine which of the genes in the deleted regions are involved in diaphragm development. To do this, we propose to determine which of the genes from the deleted regions are expressed in the mouse diaphragm, as we hypothesize that the genes expressed in the mouse diaphragm will also be expressed in the human diaphragm. We will then compile a list of candidate genes for diaphragmatic hernias based on gene expression and published data on gene expression and function. We will sequence the candidate genes in a large cohort of patients with diaphragmatic hernias. Our purpose is to detect the genes that cause the hernias to improve patient counseling and to advance our understanding of the pathogenesis of this birth defect. Relevance to Public Health This project is directed at improving our understanding of the genetic causes of a common birth defect, congenital diaphragmatic hernia. An increase in our knowledge about the genes that cause some individuals to be affected and not others will allow us to optimize treatment and management for the families concerned and thus may help to reduce infant mortality and morbidity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD053476-04
Application #
7822813
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Javois, Lorette Claire
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$125,820
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Slavotinek, Anne M; Mehrotra, Pavni; Nazarenko, Irina et al. (2013) Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1. Hum Mol Genet 22:696-703
Nathanson, Jared; Swarr, Daniel T; Singer, Amihood et al. (2013) Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome. Am J Med Genet A 161A:473-8
Slavotinek, Anne M; Chao, Ryan; Vacik, Tomas et al. (2012) VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans. Hum Mutat 33:364-8
Slavotinek, Anne M; Rosenfeld, Jill A; Chao, Ryan et al. (2011) A de novo deletion of CALN1 in a male with a bilateral diaphragmatic defect does not definitely cause this malformation. Am J Med Genet A 155A:1196-201
Slavotinek, Anne M; Baranzini, Sergio E; Schanze, Denny et al. (2011) Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet 48:375-82
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Jimenez, Nelson Lopez; Flannick, Jason; Yahyavi, Mani et al. (2011) Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. BMC Med Genet 12:172
LopezJimenez, Nelson; Gerber, Simon; Popovici, Vlad et al. (2010) Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm. Hum Genet 127:325-36
Zayed, Hatem; Chao, Ryan; Moshrefi, Ali et al. (2010) A maternally inherited chromosome 18q22.1 deletion in a male with late-presenting diaphragmatic hernia and microphthalmia-evaluation of DSEL as a candidate gene for the diaphragmatic defect. Am J Med Genet A 152A:916-23

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