BMPR1B identified as a novel human ocular coloboma gene through cross-species meta-analysis

Abstract

Purpose : Ocular coloboma arises from genetic or environmental perturbations which inhibit optic fissure fusion in early eye development. Despite high genetic heterogeneity, 70-85% of patients remain molecularly undiagnosed. We report BMPR1B as a novel causative gene using cross-species comparative meta-analysis.

Methods : Evolutionary conserved differentially expressed genes were identified through in silico analysis of mouse and zebrafish datasets over time points covering optic fissure closure. In situ hybridization, morpholino bmpr1b gene knockdown and human mRNA rescue experiments were performed in zebrafish to confirm spatiotemporal gene expression and phenotype. We interrogated the UK 100,000 Genomes Project for putative pathogenic variants within a cohort of genetically undiagnosed MAC (microphthalmia/anophthalmia/coloboma) probands.

Results : Nine conserved DEGs between zebrafish and mouse were identified. Expression was shown in the optic fissure, periocular mesenchyme cells or ciliary marginal zone. Knockdown of bmpr1b revealed a coloboma and microphthalmia phenotype. Novel pathogenic variants in BMPR1B were identified in 4 unrelated MAC families. We show BMPR1B rescued the knockdown phenotype, however mRNA carrying the patient-specific variants failed. confirming the loss of function impact of the variants on BMPR1B.

Conclusions : We demonstrate the utility of cross-species meta-analysis to identify novel coloboma disease-causing genes, including BMPR1B. There is potential to increase the diagnostic yield for new and unsolved patients, whilst adding to our understanding of the genetic basis of optic fissure morphogenesis.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022.