# Genomics and functional dissection of fetal brain abnormalities using a prenatal cohort

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $680,066

## Abstract

ABSTRACT
Fetal brain abnormalities (FBA) are one of the most common prenatal sonographic abnormality detected and
account for ~20% of birth defects posing a substantial burden on the health care system. FBA can be isolated
or syndromic and have vast phenotypic heterogeneity. The paired approach of prenatal diagnosis using
ultrasound to characterize aberrant phenotypes 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 and others using ES
have shown a diagnostic rate of 23.6% in cases of multiple fetal abnormalities, but only 2.6% in isolated FBA
abnormalities, indicating 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 who is 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. 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 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.

## Key facts

- **NIH application ID:** 10277107
- **Project number:** 1R01HD105868-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Neeta L Vora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $680,066
- **Award type:** 1
- **Project period:** 2021-08-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10277107

## Citation

> US National Institutes of Health, RePORTER application 10277107, Genomics and functional dissection of fetal brain abnormalities using a prenatal cohort (1R01HD105868-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10277107. Licensed CC0.

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