Increased frequency of de novo predicted deleterious variants in non-isolated congenital diaphragmatic hernia. L. Yu1, A. Sawle2, J. Wynn1, G. Aspelund3, C. Stolar4, M. Arkovitz5, D. Potoka6, K. Azarow7, G. Mychaliska8, Y. Shen2, W. Chung1 1) Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; 2) Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; 3) Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA; 4) California Pediatric Surgery Group, Santa Barbara, California 93105 USA; 5) Division of Pediatric Surgery, Tel Hashomer Medical Center, Tel Hashomer, Israel; 6) Department of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; 7) Pediatric Surgery Division, Department of Surgery, Oregon Health Science University, Portland, OR 97239, USA; 8) Section of Pediatric Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USA.

   Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of CDH occurs in association with other anomalies (non-isolated CDH). We hypothesized that de novo variants would account for a significant fraction of sporadic non-isolated CDH since this likely has a significant effect on reproductive fitness. We performed exome sequencing in 36 non-isolated CDH trios to detect rare and de novo variants. We compared the frequency of de novo variants to 340 unaffected controls from the Simons Simplex Collection, and found that CDH patients were more likely to carry deleterious de novo variants (p =0.007, OR = 1.7, 95% CI: 1.14-2.39). 20/36 of our CDH patients carry de novo deleterious variants. After accounting for the frequency of de novo variants in the control population, we estimate that 23% of sporadic non-isolated CDH patients carry CDH associated de novo variants. By investigating the protein-protein interaction network using genes with de novo predicted pathogenic variants and genes that are known to cause abnormal diaphragmatic phenotypes in mice, we found that SIN3A and MYBBP1A form an interacting network with other known CDH genes. We have identified several genes with deleterious de novo variants that fall into common categories of transcription factors and cell migration which have been implicated in the pathogenesis of CDH. These data provide evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants are more common compared to the general population.

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