research : disease studies

NHLBI Lung Cohorts Sequencing Project

The major goal of this project is to apply next-generation resequencing to identify disease-causing variants influencing a key set of pediatric and adult lung diseases. The technology we will apply involves massively parallel resequencing of all protein-coding sequences in the human genome (the “exome”).  In the initial discovery stage, we will work with a selected sequencing center to generate a catalogue of rare and common variants from 50-300 individuals selected from each of the tails of the distribution (1400 exomes total) of the major clinical phenotype assessed for each of seven population cohorts in which a comprehensive set of clinical traits have been well characterized.  The phenotypes include: severity of lung disease in cystic fibrosis, time to acquisition of Pseudomonas aeruginosa (Pa) in cystic fibrosis, severity of lung disease in asthma, rate of decline of lung function in chronic obstructive pulmonary disease, severity of pulmonary hypertension and severity of acute lung injury.  The variant catalogues from each tail will be mined by novel bioinformatics approaches to identify high-priority disease-modifying genes and/or causal variants.  This genome-wide resequencing approach presents one of the most important challenges and opportunities in modern genetics. In a second stage, each high priority candidate gene or variant will be evaluated in all individuals in each cohort using conventional methods.  Both stages of the project are projected for completion within 2 years.

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Genetic Analysis of Limb Malformation Disorders

The goal of this project is to investigate the etiology and pathogenesis of congenital contractures. This will be accomplished by characterizing the extent to which genes that encode sarcomeric proteins of fast-twitch myofibers cause contractures in a group of syndromes collectively called the distal arthrogryposes (DAs). Each DA syndrome, of which there are ten (i.e., DA1-DA10), is typified by dominantly inherited non-progressive contractures of the hand, hips, and feet (e.g., clubfoot) — the body areas most commonly affected by isolated contractures. The two most common forms of DA, DA1 and DA2B, are caused by mutations in TPM2 and TNNI2 or TNNT3, respectively, each of which encodes a component of the troponin-tropomyosin complex of fast-twitch myofibers.

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» Congenital Contractures Registry

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Genetic Susceptibility to West Nile Virus

Emerging pathogens have a unique potential to be weaponized as bioterrorism agents because most humans have no immunity to such infections. The human response to these pathogens varies from aborted infection to overwhelming disease and death. This variation is determined by both environmental factors and host genetic factors (i.e. susceptibility alleles). A significant gap in our knowledge is that most of these genetic factors are unknown. Our goal is to identify alleles influencing susceptibility to severe West Nile virus (WNV) disease using a candidate gene approach.

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Genetic Analysis of Heart Defects

Birth defects occur in about 1 in 33 babies. Most birth defects are caused by a complex mix of factors including genetic, environmental and lifestyle factors. For the most part, these factors are not understood and it is rare to see many babies born with the same birth defect. In order to combine efforts and increase the capacity of state programs to carry out research on the etiology of birth defects, the Centers for Disease Control & Prevention established special centers in different regions of the country to collect phenotypic information and biological materials from children with birth defects as well as children without birth defects, and their parents. These centers have nationally recognized expertise in birth defects surveillance and research. All centers work together on the National Birth Defects Prevention Study (NBDPS).

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