Expanding the utility of prenatal genetic testing

扩大产前基因检测的用途

• 批准号: 10311978
• 负责人: Dayne Lewis Filer
• 金额: $ 4.08万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311978
• 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; 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; ultrasound

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.

项目总结

项目成果

Pre-capture multiplexing provides additional power to detect copy number variation in exome sequencing.

• DOI: 10.1186/s12859-021-04246-w
• 发表时间: 2021-07-20
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Filer DL;Kuo F;Brandt AT;Tilley CR;Mieczkowski PA;Berg JS;Robasky K;Li Y;Bizon C;Tilson JL;Powell BC;Bost DM;Jeffries CD;Wilhelmsen KC
• 通讯作者: Wilhelmsen KC