Homozygosity mapping of the Achromatopsia locus in the Pingelapese.

Achromatopsia, or total color blindness (also referred to as "rod monochromacy"), is a severe retinal disorder characterized clinically by an inability to distinguish colors, impaired visual acuity in daylight, photophobia, and nystagmus. Inherited as an autosomal recessive trait, achromatopsia is rare in the general population (1:20,000-1:50,000). Among the Pingelapese people of the Eastern Caroline Islands, however, the disorder occurs at an extremely high frequency, as recounted in Oliver Sacks's popular book The Island of the Colorblind: 4%-10% of this island population have the disorder and approximately 30% carry the gene. This extraordinary enrichment of the disease allele most likely resulted from a sharp reduction in population in the late 18th century, in the aftermath of a typhoon and subsequent geographic and cultural isolation. To obtain insights into the genetic basis of achromatopsia, as well as into the genetic history of this region of Micronesia, a genomewide search for linkage was performed in three Pingelapese kindreds with achromatopsia. A two-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified on 8q21-q22. A maximal multipoint LOD score of 9.5 was observed with marker D8S1707. Homozygosity was seen for three adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease-gene locus that spans a distance of <6.5cM.