Exploring non-coding variants at two loci associated with developmental abnormalities of the macula

The macula is the central part of the retina, densely packed with cone photoreceptors that are required for acute daytime vision in colour. The macular includes the avascular foveal region. Our fovea is a critical late primate innovation. North Carolina Macular Dystrophy (NCMD) is a developmental abnormality of the central retina with a generally non-progressive phenotype, but of variable severity even within families. However it is fairly readily diagnosed by ophthalmologists and was shown to be inherited in a clear Mendelian dominant manner, allowing it to be mapped unequivocally, many years ago, to two distinct loci. Until the advent of whole genome sequencing no gene could be identified. Interestingly non-coding variants have been identified at both loci: on chromosome 6 upstream of PRDM13, and on chromosome 5 between IRX1 and ADAMTS16. The phenotypes caused by variants at both loci are indistinguishable currently. Single nucleotide variants (SNVs) are found near PRDM13 and we have identified two overlapping duplications downstream of IRX1 (PMID 28790370). Although mice do not have a fovea, they are reported to have developing retina cells expressing IRX1 (ganglion cells) and PRDM13 (amacrine cells). Using CRISPR/Cas9 editing, we have created a mouse model of the duplication and are currently exploring in detail the phenotype created. There are many challenges to understanding how disease is caused and how normal development may be perturbed. One intriguing feature is that at both loci ancestral haplotypes are found in multiple families (ie they share the same original mutation(s)). Very recently we have identified additional SNVs not far from the original PRDM13 SNV region in somewhat more severe disease phenotypes, which were however recognized clinically to be related to NCMD.
Piecing together the puzzle of all these findings is the exciting adventure we shall discuss.