Genetic linkage study of autosomal recessive high myopia in two inbred, homogenous populations

Abstract

Abstract: : Purpose: Knobloch syndrome is an autosomal recessive (AR) disorder which is associated with collagen 18A1 (COL18A1) gene mutations on chromosome 21q22.3, and is characterized by high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities, and varying degrees of occipital encephalocele (true prolapse to occipital region skin mark). We sought to identify the chromosomal locus of the gene(s) responsible for AR non–syndromic high myopia in two inbred populations, initially by candidate interval screening on chromosome 21. Methods: After clinical evaluation, genomic DNA was genotyped from 34 members of a Hutterite family from South Dakota (9 affected), and 26 members of a Bedouin family from Israel (9 affected). Linkage analysis was performed with 3 COL18A1 flanking polymorphic microsatellite markers (D21S1259, D21S1897, D21S1446), as well as markers covering the rest of chromosome 21 (8 total markers). SimWalk2 software was used for multipoint linkage analysis based on an AR model with a penetrance of 0.9 and a disease allele frequency of 0.001. Results: The average refractive error of affected individuals of the Hutterite family was –6.96 diopters (range = –5.50 to –12.25), and of the Bedouin family was –12.89 diopters (range = –5.25 to –18.00). The highest multipoint lod score for the COL18A1 region was –10.3 for the Hutterite family and –15.4 for the Bedouin family. For all of chromosome 21, the highest multipoint lod score for the Hutterite family was –0.3 and for the Bedouin family was –0.05. Conclusions: Candidate gene linkage analysis demonstrates that the AR high myopia in these two inbred pedigrees is not linked to COL18A1–associated markers, or other regions on chromosome 21. A genome screen to determine the location of the gene(s) responsible for AR high myopia in these two inbred populations is currently underway.

Keywords: myopia • linkage analysis • gene mapping