Expanding the utility of prenatal genetic testing

项目总结 先天性异常影响3-4%的怀孕，并导致全球20%-30%的新生儿死亡。产前 对于越来越多的新生儿来说，诊断可以显著改善新生儿的健康和发育 遗传疾病，特别是随着基因治疗等治疗选择的增加，继续增加。非侵入性 产前检测(NIPT)现在广泛用于染色体异常，最近又用于识别 胎儿中的父系遗传/从头开始常染色体显性疾病。此外，越来越多的女性 对羊膜穿刺术或绒毛标本进行完整外显子组测序(WES) 胎儿中的异常是通过超声波来识别的。然而，当前的WES范例缺乏检测能力 隐性单基因疾病的外显子水平CNV和NIPT选择不存在。 隐性疾病构成了超过一半的单基因疾病，而绝大多数已知的单基因疾病 疾病是由单核苷酸多态(SNPs)引起的。虽然大规模的测序工作是 更好地了解SNPs的流行，外显子水平拷贝数变异的全基因组流行(fi) 在很大程度上仍不为人所知。对有限数量的基因的研究表明，小的CNV大致代表 1%的变异，但超过9%的致病变异。 我们正在收集两组临床样本：(1)当结构异常时，母亲-父亲-胎儿三人组 (2)妊娠期间的母血和分娩时的脐带血。使用这些临床 样本，本方案的具体目的是：(1)展示多路外显子捕获的实用性和新颖性 外显子水平CNV检测分析和(2)开发胎儿基因分型分析框架和新型探针 来自母体的无细胞DNA。目标1将在TRIOS中使用CNV算法(McCNV)来识别外显子水平从头开始 变异，增加诊断产量，并理想地识别新的候选基因来理解人类 发展。目的2通过新包含隐性单基因，极大地扩展了NIPT的可能用途 精神错乱。 通过这项研究计划和相关的培训计划，我将获得一套独特的跨学科技能 以一种创新的方式将数据科学和生物统计学与种群遗传学结合在一起，走在了前列 母胎医学。这次培训将为我提供技术、统计和专业技能 我需要成为学术中心的领导者，追求我实践母胎医学的目标 并以内科科学家的身份进行研究。

PROJECT SUMMARY Congenital abnormalities affect 3-4% of pregnancies and cause 20-30% of neonatal deaths worldwide. Prenatal diagnosis can lead to significant improvements in newborn health and development for a growing number of genetic conditions, especially as treatment options, such as gene therapy, continue to increase. Non-invasive prenatal testing (NIPT) is now widely available for chromosomal abnormalities, and more recently, for identifying paternally-inherited/de novo autosomal dominant conditions in the fetus. Additionally, more and more women are being offered whole-exome sequencing (WES) on amniocentesis or chorionic villus samples after structural abnormalities in the fetus are identified on ultrasound. However, current WES paradigms lack the power to detect exon-level CNV and NIPT options for recessive single-gene disorders do not exist. Recessive conditions constitute over half of single-gene disorders, and the vast majority of known single-gene conditions are caused by single-nucleotide polymorphisms (SNPs). While large-scale sequencing efforts are better defining the prevalence of SNPs, the genome-wide prevalence of exon-level copy number variation (CNV) remains largely unknown. Research on a limited number of genes would suggest small CNVs represent roughly 1% of variants, but over 9% of pathogenic variants. We are collecting two cohorts of clinical samples: (1) mother-father-fetus trios when structural abnormalities are found on ultrasound; (2) maternal blood during pregnancy and cord blood at time of delivery. Using these clinical samples, the Specific Aims of this proposal are: (1) Demonstrate multiplexed exome capture utility and novel analysis for exon-level CNV detection and (2) Develop analysis framework and novel probes for fetal genotyping from maternal cell-free DNA. Aim 1 will employ the CNV algorithm (mcCNV) in trios to identify exon-level de novo variation, increasing the diagnostic yield and ideally identifying new candidate genes for understanding human development. Aim 2 greatly expands the possible utility of NIPT with the novel inclusion of recessive single-gene disorders. Through this research proposal and associated training plan, I will gain a unique and interdisciplinary skill-set that combines data science and biostatistics with population genetics in an innovative manner that is at the forefront of maternal-fetal medicine. This training will provide me with the technical, statistical, and professional skills I need to become a leader at an academic center and to pursue my goals of practicing maternal-fetal medicine and research as a physician-scientist.