# Genomic duplications in anophthalmia, microphthalmia and coloboma

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $380,000

## Abstract

PROJECT SUMMARY
Microphthalmia, anophthalmia and coloboma (MAC) is a group of severe ocular phenotypes characterized by a
reduction in size or absence of the eye or a gap (hole) involving various ocular structures. The success rate for
identifying a genetic diagnosis for MAC spectrum remains incomplete, making the discovery of novel
mechanisms an important priority. Copy number variations (CNVs) are deletions or duplications of genomic
segments that can be inherited or occur as dominant de novo variants. There is a growing list of developmental
phenotypes associated with CNVs, indicating that dosage imbalance represents an important factor in human
disease. Within this group, the contribution of dosage gain variants remains underappreciated due to many
factors including the involvement of multiple genes necessitating complex functional studies. In this proposal,
we will combine our expertise in MAC and the zebrafish model to reveal novel mechanisms of these
debilitating human phenotypes. We present evidence for the association of dosage gain at two different
genomic regions, 20q11 and 3q29, with isolated and syndromic MAC, with multiple affected families identified
in our cohort for both loci. We will utilize our extensive collection of DNA samples from individuals affected with
MAC to further define the contribution of these and other candidate regions to human disease, as well as to
discover novel disease-causing dosage-sensitive loci. Specifically, we will: 1) identify the driver gene(s) and
pathway(s) involved in phenotypes associated with 20q11 dosage variation by generating and studying dosage
gain/loss models for the zebrafish id1, bcl2l1 and tpx2 genes, identified as top candidates within the region; 2)
reveal driver gene(s) and pathway(s) involved in phenotypes associated with 3q29 dosage variation by
exploring dosage gain/loss models for zebrafish rubcn, dlg1 and/or bdh1 genes, located in the affected human
region; and 3) uncover critical dosage-sensitive regions involved in human MAC spectrum by additional
mapping of previously identified CNVs as well as exploring a large cohort (760 samples from affected
individuals and their relatives) of extensively tested but unexplained MAC families, followed by dissection of
novel candidate regions in zebrafish. The successful completion of this project will identify novel factors in
human ocular development, both genomic regions/genes and affected pathways, and generate robust animal
models of these complex human phenotypes.

## Key facts

- **NIH application ID:** 10538727
- **Project number:** 1R01EY034398-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Elena V Semina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538727

## Citation

> US National Institutes of Health, RePORTER application 10538727, Genomic duplications in anophthalmia, microphthalmia and coloboma (1R01EY034398-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10538727. Licensed CC0.

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