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Terri L. Young, MD; Samir S. Deeb, PhD; Shawn M. Ronan, MD; Andrew T. Dewan, PhD; Alison B. Alvear, MS; Genaro S. Scavello, BS; Prasuna C. Paluru, MS; Marcia S. Brott, BS; Takaaki Hayashi, PhD; Ann M. Holleschau, BS; Nancy Benegas, MD; Marianne Schwartz, MD; Larry D. Atwood, PhD; William S. Oetting, PhD; Thomas Rosenberg, MD; Arno G. Motulsky, MD; Richard A. King, MD, PhD

Arch Ophthalmol. 2004;122:897-908.

Objective  Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia.

Methods  X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds.

Results  Significant maximum logarithm of odds scores of 3.38 and 3.11 at = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease–affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia.

Conclusions  Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families.

Clinical Relevance  X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

From the Departments of Ophthalmology (Drs Young, Ronan, and King and Mss Alvear and Holleschau) and Genetics (Drs Young, Dewan, Atwood, Oetting, and King, and Ms Brott), University of Minnesota Medical School, Minneapolis; Division of Ophthalmology, The Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia (Dr Young and Mr Scavello and Ms Paluru); Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle (Drs Deeb, Hayashi, and Motulsky); Department of Ophthalmology, Health Partners Inc, Arden Hills, Minn (Dr Benegas); Section of Clinical Genetics, Department of Pediatrics, University Hospital, Rigshospitalet, Copenhagen, Denmark (Dr Schwartz); and National Eye Clinic for the Visually Impaired, Hellerup, Denmark (Dr Rosenberg). The authors have no relevant financial interest in this article.

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