R01HD105868

Genomics and Functional Dissection of Fetal Brain Abnormalities Using a Prenatal Cohort - Abstract

Fetal brain abnormalities (FBA) are one of the most common prenatal sonographic abnormalities detected and account for approximately 20% of birth defects, posing a substantial burden on the healthcare system. FBA can be isolated or syndromic and exhibit vast phenotypic heterogeneity. The paired approach of prenatal diagnosis, using ultrasound to characterize aberrant phenotypes, along with genetic analysis to determine causal lesions, has improved the ability to accurately counsel families about diagnosis, prognosis, and recurrence risk.

Recently, prenatal exome sequencing (ES) has been applied in cases of lethal or multiple fetal abnormalities to determine a molecular diagnosis that otherwise could not be identified with traditional testing. Our group, along with others using ES, has shown a diagnostic rate of 23.6% in cases of multiple fetal abnormalities, but only 2.6% in isolated FBA abnormalities. This indicates a need to improve diagnostic capabilities for FBA.

We posit that the overabundance of unresolved fetal cases is due to a gap in our understanding of the repertoire of genotypes underlying prenatal FBA and limitations of population genetics to establish causality of rare variants in novel candidate genes. Our team, at the forefront of prenatal genetic diagnostics and in vivo zebrafish modeling of human disease, will overcome the current challenges of diagnosing prenatal FBA. We will intersect exome- and genome-wide variation with a relevant model system (zebrafish).

We hypothesize that we will:
1) Generate initial discoveries directly relevant to human brain development by modeling novel candidate FBA genes in zebrafish; and
2) Improve prenatal diagnosis for FBA using whole genome sequencing (WGS) and deep phenotyping.

To achieve this, we will:
1. Perform bioinformatic analysis of 200+ clinically ascertained fetuses with FBA and their parents using a tiered filtering strategy on already available parent-fetus trio exome data.
2. Perform WGS on 114 prospectively enrolled fetuses and their parents, paired with comprehensive prenatal and postnatal phenotypic data, to further characterize genotype/phenotype of FBA.
3. Establish the relevance of candidate genes to FBA development and determine variant pathogenicity using genome-editing and phenotyping tools in zebrafish.

Our work will expand the understanding of molecular processes governing human brain development, establish a clinical-research hybrid platform readily applicable to FBA and other anatomical defects detectable by fetal imaging, build an animal model of aberrant FBA development with potential for future use in therapeutic target identification. Our immediate results will improve counseling/management of prenatally diagnosed FBA and lead to future work to develop novel therapeutic and preventative strategies for FBA.

University Of North Carolina At Chapel Hill

NOT APPLICABLE

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 06/30/26 to 06/30/27 and the total obligations have increased 401% from $680,066 to $3,407,070.