# Genomic analysis of microphthalmia, anophthalmia and coloboma

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $462,429

## Abstract

SUMMARY
 Microphthalmia, anophthalmia and coloboma (MAC) are highly important birth defects because of the
lifelong effects of severely reduced vision. MAC can be caused by pathogenic sequence variants and copy number
variants affecting transcription factors and other genes involved in eye development. Patients with MAC typically
undergo genetic testing with microarrays, gene panels and exome sequencing, but a genetic etiology is not
identified for many patients. A complete catalogue of the genomic variation underlying MAC is critical for
optimizing patient care, facilitating future therapies, and providing information to support research into the
developmental biology of eye defects. In this proposal, we will use whole genome sequencing (WGS) and in vitro
and in vivo functional studies to advance our understanding of the genomic architecture of MAC. Our first Aim
involves the use of WGS to obtain complete genomic data, including coding and non-coding sequence variants,
copy number variants and structural cytogenetic variants, in a minimum of 200 patients with MAC and their
biological parents. We will prioritize patients with MAC who have had negative prior genetic testing, multiple
affected family members, consanguineous parents and bilateral eye involvement to increase our changes of
identifying novel variants and genes. This aim will enable us to investigate the full range of genomic variation in
MAC and to determine the contribution of non-coding variation and structural cytogenetic variation to the
genetic etiology of these birth defects. In our second Aim, we will use zebrafish with gene editing and
CRISPR/Cas9 to investigate the effects of loss and gain of function for novel candidate genes for MAC and to
determine the effects of specific sequence variants on eye development. We will comprehensively phenotype
crispant and control larvae and perform RNA-Seq to study alterations in downstream gene expression. We will
also study non-coding variation by performing bioinformatic studies, minigene assays, RT-PCR in patient cells
as appropriate, and dual-color reporter transgenesis assays in zebrafish. Our results will generate comprehensive
data on the genomic variation that can cause MAC and will provide functional validation of novel genes and
variants. This proposal will substantially improve our understanding of eye development, in addition to
generating rich resources for future investigations and collaborations between clinicians, developmental
biologists and eye researchers.

## Key facts

- **NIH application ID:** 10746478
- **Project number:** 7R01EY032976-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Anne M Slavotinek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,429
- **Award type:** 7
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746478

## Citation

> US National Institutes of Health, RePORTER application 10746478, Genomic analysis of microphthalmia, anophthalmia and coloboma (7R01EY032976-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10746478. Licensed CC0.

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