Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population.

Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the ar-RP-patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located on 1q31-q32.1, and RP12 (zmax = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of the family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter (zmax = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully.