A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22

Abstract

Congenital cataract is a clinically and genetically highly heterogeneous eye disorder, with autosomal dominant inheritance being most common. We investigated a large seven-generation family with 74 individuals affected by autosomal dominant congenital cataract (ADCC). The phenotype in this family can be described as "central pouchlike" cataract with sutural opacities, and it differs from the other mapped cataracts. We performed linkage analysis with microsatellite markers in this family and excluded the known candidate genes. A genomewide search revealed linkage to markers on chromosome 15, with a maximum two-point LOD score of 5.98 at straight theta=0 with marker D15S117. Multipoint analysis also gave a maximum LOD score of 5.98 at D15S117. Multipoint and haplotype analysis narrowed the cataract locus to a 10-cM region between markers D15S209 and D15S1036, closely linked to marker D15S117 in q21-q22 region of chromosome 15. This is the first report of a gene for a clinically new type of ADCC at 15q21-22 locus.

Figure 1

Slit-lamp photograph, under direct focal illumination, of an 8-year-old patient showing central pouchlike cataract with sutural opacities. Viewed in three dimensions, the cataract appears as a six-sided central pouch, on which are seen anterior and posterior sutural opacities, with increased prominence at their ends. One limb of the anterior Y suture ends in a dumbbell-shaped opacity, whereas the other two limbs end in knobs. Of the three limbs of the posterior Y suture, one ends in a small dumbbell-shaped opacity, the second ends in a knob, and the third is not visible. At the junction of three limbs of the anterior Y suture, the Y suture itself has split apart. The lens matter surrounding the central pouch also shows generalized opacifications.

Figure 2

Detailed pedigree of CC-51 family with disease segregating in seven generations

Figure 3

Analyzed portion of family CC-51 showing haplotypes for markers on chromosome 15. Sequence of markers is from centromere to telomere. Blackened bars indicate the affected haplotype. Inferred haplotypes are in parentheses. Uninformative markers are indicated by a vertical line in the haplotype bar. Recombination in individuals 008, 033, 049, and 041 places the disease locus between marker D15S209 and D15S1036.

Figure 4

Multipoint linkage analysis of cataract locus with chromosome 15 markers. The X-axis denotes the map of chromosome 15 markers (distance in cM), and the Y-axis indicates the LOD scores. The multipoint LOD score curve shows the highest peak value of 5.978 at locus D15S117, and the curve delimits the position of the disease gene as between markers D15S209 and D15S1036.