Copy number variation (CNV) syndromes with low penetrance represent a new challenge to understanding and predicting disease manifestation. One such low-penetrance CNV syndrome is Thrombocytopenia-absent radius (TAR) syndrome. Patients with TAR syndrome have low blood platelet counts (thrombocytopenia), which can lead to life-threatening hemorrhage, as well as bilateral absence of both radius bones in the arm, resulting in shortened forearms. A 200-kilobase (kb) deletion on chromosome 1q21.1 is necessary, but not sufficient, to cause TAR syndrome. To develop disease, an unknown, modifying mutation elsewhere in the genome must be present along with the deletion. While the discovery of the 1q21.1 deletion represented a huge step forward in deciphering the etiology of TAR syndrome, diagnostic predictions are still hindered due to the unknown modifier. In addition, the 200-kb deletion removes 11 genes, and there are currently no known genotype-phenotype correlations for TAR syndrome. Attempting to discover modifying mutations in the human genome is a daunting task, requiring whole-exome or whole-genome sequencing of large numbers of affected and unaffected individuals. Mouse models have an advantage because many well-described inbred strains are available to test the effect of genetic background, and genetic resources are available to quickly map and identify modifying mutations. The goal of this proposal is to develop a mouse model for TAR syndrome and then use the model to determine the inheritance pattern of the TAR modifier, through the following aims: 1) delete the syntenic region on mouse chromosome 3, 2A) assay deletion-carrying mice for blood platelet count, loss of radius bones, and heart and renal defects observed in some TAR patients, and 2B) cross the deletion onto inbred strains with known variation in blood platelet count and bone length to determine the inheritance pattern of the TAR modifier. There is clear and substantial variation in both blood platelet count and bone length in mouse, and they are correlated, arguing strongly that the strains we choose will harbor genetic differences and will show phenotypic variation. At the end of this proposal we will be in position to map and identify the TAR modifier, which will have an immediate clinical impact by allowing targeted diagnostic testing and much more precise recurrence risk estimates. Our novel experimental approach can serve as a general model to quickly and efficiently identify genomic variation that is relevant to human disease.

Public Health Relevance

Thrombocytopenia-absent radius (TAR) syndrome is characterized by low blood platelet counts, which can cause life-threatening hemorrhage, and absence of the radius bones in the forearm. TAR is partially caused by a deletion of part of chromosome 1 that removes 11 genes, but an additional, unknown mutation must also occur to cause disease. To better understand the inheritance and cause of TAR syndrome, we propose to make a mouse model carrying the same deletion on several different inbred mouse strains, allowing us to eventually find the unknown mutation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Link, Rebecca P
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Emory University
Schools of Medicine
United States
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