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

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Neeta L Vora
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $633,886
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development

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.

Terms: <0-11 years old><0-4 weeks old><21+ years old><Ablation><Adult><Adult Human><Affect><Age><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Antenatal Diagnosis><Bio-Informatics><Bioinformatics><Biologic Models><Biological Models><Birth Defects><Body System><Brachydanio rerio><Brain><Brain Nervous System><CALL protein><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CamL1 Gene Product><Candidate Disease Gene><Candidate Gene><Cas nuclease technology><Causality><Cell Surface Glycoprotein L1><Child><Child Youth><Children (0-21)><Clinical><Clinical Data><Clinical Research><Clinical Study><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Collaborations><Collection><Complement><Complement Proteins><Complex><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Counseling><Coupled><Danio rerio><Data><Defect><Development><Diagnosis><Diagnostic><Diagnostic tests><Dideoxy Chain Termination DNA Sequencing><Dissection><Echography><Echotomography><Encephalon><Enrollment><Etiology><F11 Glycoprotein><Family><Fetus><Future><Gene Abnormality><Genes><Genetic><Genetic Diseases><Genetic analyses><Genomics><Genotype><Health Care Systems><Healthcare Systems><Heterogeneity><Holoprosencephaly><Human><Hybrids><Image><Infant><Intrauterine Diagnosis><Knowledge><L1 Cell Adhesion Molecule><L1CAM><Larva><Lesion><Life><Link><Live Birth><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medical Ultrasound><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Messenger RNA><Model System><Modeling><Modern Man><Molecular><Molecular Diagnosis><Morbidity><Morbidity - disease rate><Multiple Abnormalities><NGF-Inducible Glycoprotein><NILE Glycoprotein><NILE Protein><NMR Imaging><NMR Tomography><Nerve Growth Factor-Inducible Large External Glycoprotein><Neural Adhesion Molecule L1><Neural Cell Adhesion Molecule L1><Newborn Infant><Newborns><Nuclear Magnetic Resonance Imaging><Operative Procedures><Operative Surgical Procedures><Organ System><Ortholog><Orthologous Gene><Parents><Pathogenicity><Phenotype><Physiologic><Physiological><Population><Population Genetics><Prenatal Diagnosis><Preventative strategy><Prevention strategy><Preventive><Preventive strategy><Process><Prognosis><Prospective cohort><RNA Splicing><Recurrence><Recurrent><Retrospective cohort><Risk><Sanger Sequencing><Site><Splicing><Structure><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Traction><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><United States><Variant><Variation><Work><Zebra Danio><Zebra Fish><Zebrafish><Zeugmatography><adulthood><ages><antepartum diagnosis><bio-informatics tool><bioinformatics tool><brain abnormalities><candidate validation><causation><cohort><complementation><developmental><diagnostic ability><diagnostic capability><diagnostic power><diagnostic tool><diagnostic ultrasound><diagnostic utility><diagnostic value><discover genes><disease causation><enroll><entire genome><exome><exome sequencing><exome-seq><exomes><fetal><fetal diagnosis><full genome><gene discovery><gene testing><gene-based testing><genetic analysis><genetic condition><genetic diagnosis><genetic disorder><genetic disorder diagnosis><genetic testing><genome editing><genome scale><genome sequencing><genome-wide><genomewide><genomic editing><human disease><human model><imaging><improved><in utero><in vivo><in vivo Model><intra-uterine diagnosis><kids><knock-down><knockdown><mRNA><member><model of animal><model of human><monogenic disease><monogenic disorder><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><newborn child><newborn children><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><parent><perinatal period><perinatal phase><phenotypic data><postnatal><prenatal><proband><prospective><protein function><rare allele><rare mutation><rare variant><segregation><single-gene disease><single-gene disorder><sonogram><sonography><sound measurement><stem><surgery><therapeutic target><tool><ultrasound><ultrasound imaging><ultrasound scanning><unborn><whole genome><youngster><zebrafish genome>