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Principal Investigator: MICHAEL E TALKOWSKI
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $705,513
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
ABSTRACT
Emerging genomic medicine initiatives are poised to impact prenatal and pediatric diagnostics, including
assessment of fetal structural anomalies (FSAs) from amniocentesis and the rapid adoption of non-invasive
prenatal screening (NIPS). Indeed, the rapid decrease in whole-genome sequencing (WGS) costs and the
improved sophistication of analytic genomics methods has brought prenatal screening to a critical inflection point.
Ongoing studies find improved diagnostic yields from WGS and whole exome sequencing (WES) over
conventional karyotype and microarray (CMA); however, the technical, analytical, and interpretative challenges
presented by structural variants (SVs) continue to confound sequence-based diagnostics. The field lacks
standardized methods to interpret SVs from WGS and WES, yet these variants underlie a significant fraction of
prenatal diagnoses, particularly for high risk fetuses with multiple congenital anomalies (MCAs). Our clinical SV
program was initially formed to nucleate expertise in technology and algorithm development, variant
interpretation, maternal-fetal medicine, and large-scale references to explore the impact of high-resolution SV
detection in prenatal diagnostics. This resubmission builds upon the methods, resources, and discoveries from
those studies to establish uniform approaches to jointly discover and interpret SVs, initially from amniocentesis
and ultimately using non-invasive methods. We will focus on MCAs as exemplars of genomic diagnostics in
severe clinical referrals. The discoveries from our initial funding period collectively suggest several critical
advances could transform prenatal screening and genetic diagnostics, and we directly address three major
barriers to these advances in this renewal: (1) Diagnostic yields from WES in FSAs are highly variable due to
inconsistent methods and limited sensitivity to capture SVs. Aim 1 will benchmark diagnostic yields from
WGS in MCA cases using our standardized open-source pipelines. (2) The genes contributing to the most
severe fetal anomalies in humans remain largely unknown, as studies of MCAs have mostly been restricted to
small cohorts and low-resolution CMA methods. Aim 2 will aggregate these severe fetal anomalies and
perform uniform variant detection and joint association analyses of short variants and SVs from WES and
WGS in FSA trios across multiple consortia, which we will compare to population-scale aggregated controls. (3)
NIPS is ultra-low resolution and fails to capture most causal variant classes underlying MCAs. Aim 3 will
benchmark an innovative approach to detect coding mutations and SVs from cffDNA, comparing yields to
current NIPS and amniocentesis as the standard-of-care. Our team will thus leverage complementary expertise,
novel methods, and unique patient resources to advance routine genomic screening in prenatal diagnostics.
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