Expanding the utility of prenatal genetic testing

扩大产前基因检测的用途

• 批准号: 10025575
• 负责人: Dayne Lewis Filer
• 金额: $ 3.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025575
• 关键词: Address; Affect; Algorithms; Alleles; Amniocentesis; Biometry; Blood; Candidate Disease Gene; Child; Chorionic Villi Sampling; Chromosome abnormality; Classification; Clinical; Clinical Data; Clinical Management; Complement; Congenital Abnormality; Copy Number Polymorphism; DNA; Data; Data Analyses; Data Science; Detection; Development; Diagnostic; Disease; Exons; Family; Fathers; Fetal Development; Fetal Research; Fetus; Gene Frequency; Genes; Genetic Diseases; Genotype; Goals; Human Development; Hyperammonemia; Infant Mortality; Inherited; Large-Scale Sequencing; Lead; Maternal-fetal medicine; Mendelian disorder; Methodology; Modality; Modeling; Molecular; Mothers; Neonatal; Neurologic; Newborn Infant; Ornithine carbamoyltransferase deficiency; Pathogenicity; Patients; Phenotype; Physicians; Placenta; Population Genetics; Population Heterogeneity; Postdoctoral Fellow; Pregnancy; Pregnancy Outcome; Pregnant Women; Prenatal Diagnosis; Prevalence; Procedures; Research; Research Proposals; Resolution; Risk; Sampling; Scientist; Single Nucleotide Polymorphism; Specificity; Structural defect; Techniques; Technology; Testing; Time; Training; Trisomy; Ultrasonography; Umbilical Cord Blood; Untranslated RNA; Validation; Variant; Woman; cell free DNA; cohort; cost; cost effective; deep sequencing; design; differential expression; exome; exome sequencing; experimental study; fetal; gene therapy; genetic disorder diagnosis; genetic testing; genome sciences; genome-wide; improved; in utero; in utero diagnosis; innovation; mortality; neonatal death; neonatal health; novel; prenatal; prenatal testing; screening; sex chromosome aneuploidy; simulation; skills; success; transcriptome sequencing; treatment planning

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.

项目概要 先天性畸形影响全球 3-4% 的妊娠，并导致 20-30% 的新生儿死亡。产前 诊断可以使越来越多的新生儿健康和发育得到显着改善 遗传疾病，特别是随着基因治疗等治疗选择的不断增加。非侵入性 产前检测（NIPT）现已广泛用于检测染色体异常，最近还用于识别 胎儿的父系遗传/从头常染色体显性遗传状况。此外，越来越多的女性 正在对羊膜穿刺术或绒毛膜绒毛样本进行结构后的全外显子组测序（WES） 通过超声波可以识别胎儿的异常情况。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 选项不存在。 隐性病症占单基因疾病的一半以上，并且绝大多数已知的单基因疾病 这些病症是由单核苷酸多态性 (SNP) 引起的。虽然大规模测序工作正在 更好地定义 SNP 的流行率，即外显子水平拷贝数变异 (CNV) 的全基因组流行率 仍然很大程度上未知。对有限数量基因的研究表明，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 超声波发现； (2)怀孕期间的母血和分娩时的脐带血。利用这些临床 样本，该提案的具体目标是：（1）展示多重外显子组捕获实用性和新颖性 外显子水平 CNV 检测分析以及 (2) 开发用于胎儿基因分型的分析框架和新型探针 来自母体游离DNA。目标 1 将采用三重奏中的 CNV 算法 (mcCNV) 来从头识别外显子级 变异，提高诊断率并理想地识别新的候选基因以了解人类 发展。目标 2 通过隐性单基因的新颖纳入，极大地扩展了 NIPT 的可能用途 失调。 通过这个研究计划和相关的培训计划，我将获得独特的跨学科技能， 以走在前沿的创新方式将数据科学、生物统计学与群体遗传学相结合 母胎医学。该培训将为我提供技术、统计和专业技能 需要成为学术中心的领导者并追求我实践母胎医学的目标 并作为医师科学家进行研究。