Studying Pentalogy of Cantrell in Humans and Mice

National Heart, Lung, And Blood Institute

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Linked publications & trials

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, 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 genomic 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 WGS indicate some candidate genes with either CNVs or SNPs of interest, 4 of which are recurrent in two or three unrelated families. We are currently confirming these variants and planning to test their biological significance in animal models.