Congenital diaphragmatic hernia (CDH) is a devastating birth defect characterized by incomplete formation of the diaphragm that results in high morbidity and mortality. Identifying the genetic factors leading to isolated CDH is essential for improving outcome and decreasing healthcare costs. Our published data revealed 16 extended families with statistically significant high-penetrance isolated CDH, and five shared chromosomal regions (SCRs) in seven patients from four of these extended families. Two of the five SCRs contain GATA4 and NR2F2, genes previously linked to CDH in mouse models. CDH susceptibility variants could reside in noncoding regions because we did not identify coding variants in these genes. Mapping SCRs in combination with whole-genome sequencing (WGS) will provide a new tool to identify gene variants causing isolated CDH Under the. oversight of board certified medical geneticists, we collected blood DNA samples from >70 patients with isolated CDH and >100 unaffected family members. In preparation for Aim 1, we selected 12 patients from five extended families, and performed WGS on seven of them.
For Aim 2, we selected five individuals from a three-generation high-penetrance family: an unaffected mother and four affected (two siblings, a father and a grandfather), and performed whole-exam sequencing (WES) on all of them. We also have a large collection of 423 sporadic cases (57 trios from Utah, 90 families from Baylor College of Medicine, and 276 trios from Harvard University) which we will screen as a replication cohort in both Aims. The ultimate goal of our research is to identify susceptibility variants for isolated CDH. The central hypothesis of this proposal is that our unique approach, using family-based genetic methods, will identify the molecular causes of isolated CDH.
Aim 1 : Test the hypothesis that isolated CDH susceptibility variants reside within SCRs in 12 patients from five extended families. After SCR analysis and WGS, we will perform WGS analysis, focusing on coding and non-coding variants within SCRs. We will generate a short-list of predicted disease-causing candidates by analyzing our WGS data with the variant annotation, analysis, and search tool (VAAST), pedigree-VAAST and Phevor; three new ab initio disease-gene finders developed by Dr. Mark Yandell at the University of Utah. Candidates will undergo molecular validation, followed by testing for segregation in these families. Once candidate genes are confirmed, we will screen them in our large replication cohort.
Aim 2 : Map variants causing isolated CDH in a three-generation, high-penetrance family. WES data will be analyzed similarly to Aim 1 except for a focus on coding variants. This research program will move the CDH field forward by revealing new DNA variants involved in isolated CDH. In the future, our novel genetic engineering tools aim to accelerate modeling human CDH variants in mice.

Public Health Relevance

Congenital diaphragmatic hernia (CDH) is a severe developmental, mostly isolated defect. CDH has high mortality, with surviving infants suffering significant long-term complications. CDH is a leading cause of healthcare expenditure in the U.S.; estimated to at least $250 million annually. Identification of the molecular causes of isolated CDH, by hopefully allowing the development of new therapeutic strategies, is the first step for improving outcomes and ultimately lowering healthcare costs. We plan to use our recently developed family-based genetic approach in combination with next generation sequencing to identify the genetic susceptibilities of isolated CDH.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Pediatrics Subcommittee (CHHD)
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Javois, Lorette Claire
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Matsunami, Nori; Shanmugam, Hari; Baird, Lisa et al. (2018) Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia. Birth Defects Res 110:610-617