Human biallelic deletion involving MAB21L2 regulatory sequences reveals key to structural eye anomalies across species

Anophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We identified two families with variants in or near MAB21L2. The first proband, with microphthalmia and coloboma, had a likely pathogenic missense variant (c.338G>C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, had an ~113.5kb homozygous deletion 19.38kb upstream of MAB21L2. Modelling the deletion led to transient small lens and coloboma in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Conservation analysis identified 15 non-genic conserved elements (CE) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrated one of these (CE14) binds OTX2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulated an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development, and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC. Overall design: Chip-Seq was performed using antibodies raised against the transcription factors OTX2 and SOX2 in Murine stem cells.