Congenital abnormalities affect 3-4% of pregnancies and cause 20-30% of neonatal deaths worldwide. Prenatal diagnosis can lead to signi?cant 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 identi?ed 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 de?ning 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 Speci?c 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.
Congenital abnormalities/serious genetic disorders affect 3% of pregnancies and are the leading cause of infant mortality. Genetic diagnosis during pregnancy offers the promise of better neonatal management, allowing doc- tors to develop the best possible treatment plan before the child is born. This proposal seeks to expand the utility of prenatal genetic testing using novel sequencing and analytic approaches to identify more genetic disorders during pregnancy.