High myopia in a consanguineous Bedouin kindred caused by novel RBP3 nonsense mutation

Myopia, the most common human eye disorder, is a leading cause of visual impairment and blindness worldwide. The Bedouin community has high rates of consanguinity and fecundity culminating in an array of inherited diseases, resulting from homozygosity of founder mutations. Two siblings of an Israeli Bedouin kindred presented with apparently autosomal-recessive severe myopia. Genome-wide linkage analysis and homozygosity mapping were undertaken. Whole exome sequencing (WES) was performed for one of the patients. Exome data was analyzed using the Ingenuity Variant Analysis™ software and in-house WES data of 300 controls. Next, the mapping and the WES results were combined, narrowing down a list of few variants possibly associated with the disease. Sanger sequencing and restriction fragment length polymorphism were used to study the variants found for segregation within the family and healthy ethnically-matched controls. Through the above process, we identified a duplication within RBP3 (c.1687dupA, p.T563fs*5 (NM_002900.2)) as the most probable disease-causing variant in the family. RBP3 encodes Retinol-binding protein 3 and has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. Moreover, homozygous nonsense mutations in RBP3 have been associated to high myopia. The novel mutation we identified is a duplication mutation leading to frameshift, premature termination codon and possibly Nonsense-Mediated Decay. These findings confirm the role of RBP3 mutations in causation of myopia and will allow for carrier testing and early pre-implantation genetic diagnosis both within the proband’s family and the larger clan.