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

项目总结/摘要 早产儿在出院回家前的严重发病率和死亡率很高。之一 与发病率和死亡率相关的主要因素是小于胎龄儿（SGA;小于 胎龄和性别的第10百分位数）。虽然已经确定了许多致病因素，包括 母亲的疾病、感染和产前暴露，这些因素只能解释一小部分SGA早产。 一些遗传性疾病已被证明会导致早产的SGA出生。遗传性疾病也被 与相关人群的发病率和死亡率有关。我和其他人之前的研究表明， 遗传性疾病可能有贡献，但总体遗传贡献是未知的。在这个项目中，我的团队和 我将定义这个人群中遗传疾病的患病率，遗传疾病对 发病率和死亡率，并确定与早产SGA相关的新基因中的疾病。使用类似 策略，我最近确定先天性肾脏异常在早产儿中很普遍，并且强烈 与遗传疾病有关。我的导师们的研究表明，一类特殊的遗传变异--缺失-- 新基因中的功能缺失（LoF）变异导致相关疾病。我假设常见的罕见的 新的遗传疾病导致早产SGA出生、发病率和死亡率。我会调查清楚 三个互补的目标：1）定义与早产SGA相关的流行病学因素，包括 常见遗传性疾病，2）确定早产SGA婴儿中罕见遗传性疾病的患病率，以及 3)鉴定与早产SGA相关新基因。积极的结果将有助于改善诊断 和管理这一高风险人群，并为分子发病机制的新研究提供信息。负 研究结果将为环境因素的研究以及其他遗传诊断策略提供信息。 这个项目是我的职业发展计划的核心，包括三个培训目标：1） 流行病学研究，2）人类遗传学研究和3）学术发展。该项目将 由世界级的人类遗传学和围产期医学专家指导：Ali Gharavi博士，安娜佩恩博士， 罗纳德瓦普纳。这个项目将在最重要的研究机构之一哥伦比亚进行 该大学支持区域转诊新生儿ICU和基因组医学研究所。目标1 该项目将利用一个包含409 704名早产儿记录的强大数据库进行。我 将得到流行病学、统计学和基因组学专家顾问的支持。通过完成这一 研究和培训，我将获得一个理想的技能，成为一个R 01资助的研究人员推进领域， 基因组学

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.