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.

项目摘要 先天性异常会影响3-4％的怀孕，并在全球造成20-30％的新生儿死亡。产前 诊断可以导致新生儿健康和发展的显着改善，以越来越多 遗传条件，尤其是随着基因治疗等治疗选择的继续增加。非侵入性 现在，产前测试（NIPT）可用于染色体异常，最近可用于识别 胎儿中的图案亲属/新的常染色体显性疾病。此外，越来越多的女人 在结构后，在羊膜穿刺术或绒毛膜绒毛样品上提供全外观测序（WES） 胎儿异常在超声上鉴定出来。但是，当前的WES范式缺乏检测的能力 不存在隐性单基因疾病的外显子级CNV和NIPT选项。 隐性状况构成一半以上的单基因疾病，而绝大多数已知的单基因 条件是由单核苷酸多态性（SNP）引起的。而大规模的测序工作是 更好地定义SNP的流行率，即外显子级拷贝数变化（CNV）的全基因组患病率 仍然是未知的。对有限数量的基因的研究表明，小型CNV大致表示 1％的变体，但超过9％的致病变体。 我们正在收集两个临床样本：（1）当结构异常时，母亲 - 父亲三重奏 在超声波上发现； （2）妊娠期间的母血和分娩时的脐带血。使用这些临床 样本，该提案的特定目的是：（1）演示多重外显子组捕获实用程序和新颖 外显子级CNV检测和（2）开发分析框架和胎儿基因分型的新探针的分析 来自无母细胞的DNA。 AIM 1将在Trios中采用CNV算法（MCCNV）来识别外显子级de。 变异，增加诊断产量并理想地识别新的候选基因以理解人类 发展。 AIM 2大大扩展了NIPT的可能实用性，而新颖的包含隐性单基因 疾病。 通过该研究建议和相关培训计划，我将获得一个独特而跨学科的技能， 以创新的方式将数据科学和生物统计学与种群遗传学相结合，这是最前沿的 母亲医学。这项培训将为我提供我的技术，统计和专业技能 需要成为学术中心的领导 并作为身体科学家进行研究。