The Genetics of Uveal Coloboma

National Eye Institute

Investigators

Linked publications & trials

Abstract

1. Clinical and Genomic Studies Recruitment of coloboma patients in the Genetics of Uveal Coloboma protocol (13-EI-0049) and the Whole Exome and Whole Genome Sequencing for Genotyping of Inherited and Congenital Eye Conditions protocol (14-EI-0064) continues. As of August 2025, we had enrolled approximately 403 participants (153 affected or likely forme fruste) from 124 families. Note: the grand total of enrollment since 2005 (give or take a couple) is approximately 825 participants representing 228 families. Twenty-six results were returned to 26 participants in the past year. The protocol has been modified recently to include individuals with microphthalmia and anophthalmia--two phenotypes on the same continuum of developmental abnormalities. This change leverages our recently-funded U01 research effort with Drs. Philip Lupo and Laura Mitchell to perform population-based genetic epidemiology for microphthalmia/anophthalmia/coloboma phenotypes (MAC) as part of the Texas Birth Defects Registry. Recruitment numbers have included patients that have been ascertained through the MAGIC protocol. Our protocol "Potential Environmental Causes of Uveal Coloboma" (000366-EI) explores maternal factors and exposures during the first trimester of pregnancy as potential causes of uveal coloboma to correlate exposure data to clinical data from affected children. We have completed administering a questionnaire over the phone about parents' health, lifestyle and habits before and during pregnancy. The questionnaire is adapted from the National Birth Defects Prevention Study (NBDPS) Mother Questionnaire. Furthermore, the study will use existing data from NBDPS and NIH studies, including family data such as eye exam, genetic test results, and family history of coloboma. Data analysis has begun. We have established a secondary research protocol, "Development in Coloboma" (NIH IRB#001949), to retrospectively look at the developmental testing results of our cohort of coloboma patients, the presence/absence of a genetic diagnosis and other systemic manifestations. A manuscript is written. 2. Laboratory Studies A. The RICO mouse model of coloboma The RICO (Retinal & Iris COloboma) mouse arose from the random insertion of a transgene (NSE-VEGF) on chromosome 13 in the C57BL/6 background. Both homozygous and heterozygous mutants developed coloboma. . Long-read sequencing detected approximately fifteen copies of the transgene at the insertion site, an inversion, one duplications and a deletion in a gene desert on chromosome 13. We detect hVEGF in the developing eye. An open question is whether coloboma is caused by this abnormal expression of VEGF and/or disruption of gene expression caused by the genomic rearrangement. Creation of two additional transgenic lines with NSE-VEGF did not result in coloboma, although copy numbers were considerably lower; as such, a dosage-dependent effect cannot be ruled out. We analyzed RNA-Seq experiments to identify changes in gene expression, particularly those surrounding the integration site. A manuscript is currently under review. B. Coloboma candidate gene studies We have continued to identify candidate genes for coloboma, several of which are under scrutiny at present using a combination of in vitro and in vivo studies. We have also identified novel presentations of genes already associated with human disease but for which ocular phenotypes are not well characterized. Exome sequencing identified variants in NR6A1 in a novel syndrome we called Oculo-vertebral-renal syndrome. We have confirmed these results through a combination of zebrafish and cell culture experiments and molecular and bioinformatic modeling. C. CRISPR screening for genes associated with optic fissure closure Using CRISPR/Cas9-mediated genome editing as a screening method, we generated KO zebrafish lines to investigate the roles of candidate genes from developmental gene profiling--combining data from our experiments as well as those from similar studies published since. We are pursuing validating several candidates that have coloboma using standard markers and rescue experiments. D. Downstream effectors of FAT1 Our collaborators and we have reported that biallelic mutations in FAT1 result in a syndromic form of uveal coloboma. We have since sought to identify potential downstream effectors of FAT1 in ocular development. Recent work has focused on the role of the Hippo signaling pathway (YAP/TAZ) and the RERE pathway.