Rare Mutations Associated with Respiratory Distress in Infants
Robi D. Mitra, Ph.D.
Center for Pediatric Pulmonary Disease
Interdisciplinary Research Initiative
2/1/2009 - 1/31/2013
Todd Druley, F. Sessions Cole, Aaron Hamvas
Respiratory Distress Syndrome (RDS) is a major health issue in newborns – it affects 1% of all newborns and is the most common cause of death in the first month of life. Premature infants are more likely than term infants to be affected by RDS, which is caused by a deficiency of pulmonary surfactant, a lung-specific phospholipid-protein complex. RDS is highly heritable, but the genetic variants that predispose to this disease are unknown. This project will test the hypothesis that individual combinations of rare, germline mutations in 38 candidate genes, including genes in the surfactant protein and the unfolded protein response pathways, predispose to RDS. To test this hypothesis, “next-generation” DNA sequencing technology will be used to sequence candidate genes in 900 race-matched cases and controls. Genes that are mutated significantly more often in the RDS cohort compared to the control cohort will undergo further validation in a second RDS cohort. Individual gene-gene interactions will be retrospectively correlated to each individual’s hospital course in order to determine if combinations of mutations help explain disease onset or severity. This approach is designed to identify both rare and common mutations that predispose to RDS. However, this study is novel because it tests the hypothesis that multiple rare, deleterious mutations can cumulatively cause a common disease in a population. Such knowledge will ultimately permit mechanism-specific therapeutic interventions. As one of the first studies on rare variants, this work will also give new insight into the genetic basis of common disease.