The Genetic Basis of Morbidity and Mortality in Small for Gestational Age Preterm Infants

PROJECT SUMMARY/ABSTRACT Preterm infants experience high rates of severe morbidity and mortality prior to discharge home. One of the leading factors associated with morbidity and mortality is being born small for gestational age (SGA; less than 10th percentile for gestational age and sex). While many etiologic factors have been identified, including maternal illnesses, infections, and prenatal exposures, these factors explain only a fraction preterm SGA birth. Some genetic disorders have been shown to cause preterm SGA birth. Genetic disorders have also been linked to morbidity and mortality in related populations. My prior research and that of others indicates that genetic disorders likely contribute, but the overall genetic contribution is unknown. In this project, my team and I will define the prevalence of genetic disorders in this population, the contribution of genetic disorders to morbidity and mortality, and identify disorders in novel genes associated with preterm SGA birth. Using similar strategies, I recently determined that congenital renal anomalies are prevalent in preterm infants, and strongly associated with genetic disorders. Work by my mentors showed that a specific class of genetic variants—loss- of-function (LoF) variants in novel genes—contribute to related diseases. I hypothesize that common, rare, and novel genetic disorders contribute to preterm SGA birth, morbidity, and mortality. I will investigate this through three complementary aims: 1) define epidemiologic factors associated with preterm SGA birth, including common genetic disorders, 2) determine the prevalence of rare genetic disorders in preterm SGA infants, and 3) identify novel genes associated with preterm SGA birth. Positive results would inform improved diagnosis and management of this high-risk population and inform new research into molecular pathogenesis. Negative results would inform research into environmental factors, as well as other genetic diagnostic strategies. This project is central to my Career Development Plan, which consists of three Training Goals: 1) epidemiologic research, 2) human genetics research, and 3) academic development. This project will be mentored by world-class experts in human genetics and perinatal medicine: Drs. Ali Gharavi, Anna Penn, and Ronald Wapner. And this project will be conducted at one of the premier research institutions, Columbia University, which supports a regional referral neonatal ICU and the Institute for Genomic Medicine. Aim 1 of this project will be conducted using a robust database containing records from 409,704 preterm infants. And I will be supported by expert advisors in epidemiology, statistics, and genomics. Through the completion of this research and training, I will gain an ideal skillset to become an R01-funded investigator advancing the field of genomic neonatology.