Using Whole-Exome Sequencing to Identify Genetic Variants in Patients Diagnosed with Pentalogy of Cantrell

Authors

• B MacTaggart
• C Bowen
• M Markowitz
• J Chong
• M Bamshad
• X Ma
• RS Adelstein

Abstract

Pentalogy of Cantrell (POC) is a developmental disorder estimated to occur in 1-5.5 per 1 million live births with a 61% survival rate. The syndrome includes five features: 1) a defect in sternal fusion, resulting in ectopia cordis, 2) a diaphragmatic hernia, 3) a weakened abdominal wall, oresulting in an omphalocele, 4) a missing pericardium, and 5) structural and valvular defects in the heart. Our laboratory has generated mice with a single amino acid substitution (R709C) in the non-muscle myosin IIB heavy chain, which phenocopy the human POC. Generation of the mouse model prompted us to initiate a clinical study in humans in which we conduct whole-exome sequencing of POC patients and their parents to determine a possible genetic etiology for POC. We filtered for rare variants in the exome data that segregated with POC in each family. To date, we have identified one rare single nucleotide variant in the teneurin-4 gene (TENM4), which appears to exhibit incomplete penetrance for POC. We are also currently investigating a number of de novo SNVs identified in POC patients born to unaffected parents. To interpret the results, we performed network level analyses, which indicate a potential common role for the proteins identified involving ubiquitination and cell death. Additionally, we have observed decreased apoptosis at both the developing sternum and valve cushions in our mouse model, supporting a role for an apoptotic pathway in the pathogenicity of POC.

Scientific Focus Area: Genetics and Genomics

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