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Research advances in clinical genetics recently uncovered the causative alterations for several rare diseases. Researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) identified a copy number alteration in the alpha tryptase gene in a series of individuals with a complex multi-symptomatic syndrome. 

Familial analysis of severely affected families identified high copy numbers of the alpha tryptase gene in individuals affected with symptoms. These individuals varied in terms of the number of copies gained. Gains of alpha tryptase resulted in a direct increased expression; individuals with more copies of the gene typically experienced more severe symptoms.

Meanwhile, researchers also identified specific sequence mutations that impact the risk for certain diseases including cardiovascular disease and cancer. These findings are striking as the risk associated with these pathogenic variants is irrespective of family history; in the absence of family history, testing of a panel of 56 genes can provide risk information for 24 dominantly inherited diseases. It is suggested that these results can be included as secondary findings in routine testing so that individuals know their risk of developing these diseases into adulthood.

While these studies both illustrate the strength of copy number analysis or sequence variant mutation alone in the clinic, the combination of both data points can be particularly striking. For example, an infant with an extremely complex phenotype of developmental delay and tumor syndrome was evaluated for both copy number and sequence variant alterations.  Clinical exome testing identified several pathogenic mutations that described the tumor syndrome but did not explain the development delay phenotype.  Chromosomal microarray identified a 133kb copy number duplication which explained the developmental delay but not the tumor syndrome.  However, taken together, these results fully explain the patient’s complex phenotype.  

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