Ebstein anomaly: molecular genetic studies of a canine equivalent

Doctor's Name: 
D. Woodrow Benson, MD
Cincinnati Children's Hospital Medical Center

Ebstein anomaly of the tricuspid valve is a valve malformation present at birth. A genetic cause has been suspected, but human families suitable for molecular genetic studies have not been found. We identified an extended family of Labrador Retrievers in which canine tricuspid valve malformation (CTVM), the canine equivalent of Ebstein anomaly appeared in 4 generations. Affected dogs demonstrate a malformed tricuspid valve including leaflet dysplasia, displacement, tethering and abnormalities of the right ventricular papillary muscles, similar to Ebstein anomaly in humans. In preliminary studies we identified a critical interval on canine chromosome 9 (CFA9), i.e. a region on CFA9 where the CTVM gene is almost certainly located (odds of nearly 3000:1). Comparative genetic maps show that CFA9 contains the same genes as a region of human chromosome 17 (HSA 17). In 2 other Labrador kindreds, the gene causing CTVM is also located on CFA9 suggesting that the valve disease is inherited from a common ancestor. The purpose of this proposal is to identify the CTVM gene, and once identified, we will evaluate the human homolog to determine if mutations cause Ebstein anomaly. The rationale for genetic study of a rare (1:20,000 births) congenital valve malformation such as Ebstein anomaly is based on finding of genes and signal pathways common to development of all four heart valves. Successful completion of the proposed studies will provide unique opportunities for future studies of other valve development and disease.

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