Refinement of the MYP3 locus on human chromosome 12 in a German family with Mendelian autosomal dominant high-grade myopia by SNP array mapping

Myopia, or short-sightedness, is the most common form of vision disorder worldwide. Higher levels of myopia, usually defined as an axial eye length of >26 mm or a refractive error of < -5.00 diopters are often designated as ‘pathologic’ myopia, because of the predisposition to develop further eye disorders such as retinal detachment, macular degeneration, cataract, or glaucoma. Many distinct forms of autosomal dominant non-syndromic high-grade myopia are described in humans. While the underlying chromosomal locations and critical disease intervals have been identified and located to physical map positions, the gene defects and causative mutations responsible for autosomal dominant myopia remain elusive to date. Examination of a German six-generation kindred by 10K whole genome chips led to the identification of a 19-cM map segment as being the most likely familial myopia candidate region spanning from chromosomal band 12q14.3 to 12q21.31 (MYP3). In our family, a maximum multi-point LOD score of 3.9 was obtained between rs1373877 and rs717996. The recombination breakpoints in this family and the interval of the originally reported German/Italian family defining the MYP3 locus on chromosome 12 (OMIM 603221, two-point LOD score 3.85 for markers D12S1706 and D12S327 at 12q21-23) allowed us to significantly refine a minimum consensus region. This new composite region is located between microsatellite marker D12S1684 at 75.8 K and SNP_A-1509586 (alias rs717996) at position 82,636,288 bp, and narrows the original 30.1 cM of the MYP3 interval to 6.8 cM. The refined MYP3 interval allowed us to restrict the list of database-indexed genes to 25, several of which are promising MYP3 candidates based on similarities with genes and proteins involved in vision physiology and eye disease. While autosomal dominant high-grade myopia is recognized to be genetically heterogeneous, our results suggest genetic homogeneity of the MYP3-based condition in families that share the same ethnic and geographical background. The future identification of this MYP3 gene may provide insights into the pathophysiology of myopia and eye development.