There are approximately 7,000 defined rare diseases affecting an estimated 30 million Americans and 350 million people worldwide. The study of rare diseases offers a unique insight into human disease and has been rapidly improved by the advent of next-generation sequencing (NGS) technologies. Greater than 4000 Mendelian phenotypes are now associated with causal genes, as catalogued in On Line Mendelian Inheritance in Man (OMIM). This knowledge, achieved through the high-throughput analysis of genomic data followed by molecular functional studies, has enhanced our understanding of basic biology and of human disease and offers hope for those afflicted with such rare diseases. However, the genetic causes of many Mendelian disorders or traits remain to be discovered. OMIM describes at least 1,500 Mendelian phenotypes of unknown molecular etiology, and another 1,700 that are likely to be Mendelian and remain undiagnosed in affected individuals. The diagnostic, odyssey, as it is called, for these individuals is a cycle of multiple misdiagnoses and often result in no diagnoses, treatments, or interventions. These cases represent the potential to enhance our knowledge of human biology. The Treasure Your Exceptions (TYE) program at Emory University is dedicated to discovering novel mutations in genes causing novel Mendelian disease phenotypes or traits through the use of next-generation sequencing technologies. We currently have 13 families with unique genetic diseases enrolled in the program with widely varying phenotypes. In the past year we have successfully identified a strong candidate variant (p.Y401C) in the DUSP7 gene for a rare case of severe short stature and insulin resistance. Discovery of this variant was achieved through the development of a custom and adaptable computational pipeline for analysis of genomic data. Consequently, additional families in TYE are now able to be analyzed in a similar manner while I follow up on our initial discovery with functional studies to demonstrate causality. Computational analysis of genomic data to identify causal variants for rare diseases followed by proof of causality afford the opportunity to elucidate the genetic etiology of these diseases and related common diseases to aid in developing diagnostic measures and therapeutics, as well as gain insight into basic human biology. Thus, I propose to analyze three TYE families presenting with 1.) a lethal form of Desbuquois-like dysplasia, 2.) hypersomnia, ataxia, and cognitive impairment, and 3.) inherited breast cancer, respectively. Additionally, I propose to determine the functional consequences of the candidate variant on DUSP7.
In Aim 1, I will perform variation detection to identify candidate causal variants for the diseases described above using whole-genome sequencing and genome mapping followed by comprehensive computation analysis using the pipeline I developed.
In Aim 2, I will use an in vitro phosphatase assay and cellular growth assay to determine the functional consequences of the Y401C mutation on DUSP7 function. The premise is to investigate rare genetic variation in the genome, thereby increasing our understanding of how it contributes to rare disease and how genes normally work to maintain normal human function.
Currently there are an estimated 350 million people worldwide affected by one of 6,800 known rare diseases and thousands more affected by unknown rare diseases. With the advancement and decrease in cost of sequencing technologies, studying rare diseases has become increasingly feasible and offers a fortuitous opportunity to resolve the intricacies of human biology that contribute to rare diseases as well as common diseases. Thus, the goal of this project is to strengthen our understanding of basic human biology in the context of human disease via the investigation of rare disorders using whole genome sequencing, variant analysis, and molecular functional studies.