Studying Pentalogy of Cantrell in Humans and Mice

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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, often resulting in ectopia cordis, 2) a diaphragmatic hernia, allowing the abdominal organs to protrude into the thoracic cavity, 3) a weakened abdominal wall, often resulting in an omphalocele, 4) a missing or defective pericardium, and 5) structural and valvular defects in the heart, including ventricular septal defect and displacement of the aorta outlet to the right ventricle. Our laboratory has generated mice with a single amino acid substitution (R709C) in the non-muscle myosin 2B heavy chain (encoded by the Myh10 gene) which phenocopies human POC. Generation of the mouse model prompted us to initiate a clinical study in humans in which we are conducting whole exome sequencing as well as whole genomic sequencing of POC patients and their parents to determine a possible genetic etiology for POC. During the past year we have added 5 more families to our study. The 29 probands currently in our study range from 1 day to 31 years of age at time of enrollment and exhibit different subsets of the five characteristic features of the disorder. Recently we have initiated whole genome sequencing (WGS) of our samples in collaboration with the CHIRP facility at USUHS. The samples are presently undergoing bioinformatic analysis. WGS has the benefits of providing better coverage of exons, of calling copy number variants (CNVs) and insertions and deletions (indels), and can provide information about non-coding (potentially regulatory) regions around the genes of interest. Preliminary results from WES and WGS indicate some candidate genes of interest, however none of them is recurrent in two or three unrelated families. We are currently testing their biological significance in mouse models using CRISPR genome editing. We are generating two mouse lines. One with a point mutation in the PTPN11 gene, the other with a point mutation in the MTOR gene. Both PTPN11 and MTOR genes have been implicated in regulating cardiac development.