The incidence of Pentalogy of Cantrell (POC) in humans is estimated at 1-5.5 per 1 million live births. The syndrome is often fatal and includes: 1) a sternum that is not fused associated with a decrease in apoptosis, thus causing the fetus to be born with the heart external to the thoracic wall. 2) herniation of the diaphragm allowing the abdominal organs to protrude into the thoracic cavity. 3) an omphalocele containing abdominal organs due to a weakened abdominal wall, 4) a missing pericardium and 5) structural and valvular defects in the heart including a ventricular septal defect and displacement of the aorta outlet to the right ventricle. Our laboratory has generated mice with a point mutation (R709C) in the non-muscle myosin IIB heavy chain (encoded by Myh10) which mimic the human POC. Generation of the mouse model prompted us to initiate a clinical study in humans in which we conducted whole-exome sequencing to determine a possible genetic etiology for POC. Of the twenty-two probands enrolled in our study to date, one is a fetal case, and the remaining cases range from 1 day to 31 years of age at enrollment. We filtered for rare variants in the exome data that segregated with POC in each family. Two affected individuals from the same family carry a rare variant in the teneurin-4 gene (TENM4) that is highly conserved and predicted to be deleterious; two additional relatives were heterozygous but apparently unaffected, suggesting that the variant exhibits incomplete penetrance for POC. Teneurins are a conserved family of transmembrane proteins that play a role in intercellular signaling as transcriptional activators. When serving as a transmembrane protein the intracellular carboxyl terminal end of the molecule interacts with the actin cytoskeleton. We are currently investigating 6 de novo variants, identified in individuals with POC born to unaffected parents. To interpret the results, we are developing genetic and protein-interaction networks in order to understand the mechanism(s) underlying POC. We hope to increase the likelihood of identifying genetic etiologies for POC through worldwide recruitment of families affected by this rare disorder.

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U.S. National Heart Lung and Blood Inst
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