Leber congenital amaurosis (LCA)(MIM 204000/204100) is a clinically and genetically heterogeneous retinal disorder that occurs in infancy and is accompanied by profound visual loss, nystagmus, poor pupillary reflexes, and either a normal retina or varying degrees of atrophy and pigmentary changes (Leber 1869, 1871; François 1968). The electroretinogram (ERG) is extinguished or severely reduced (Franceschetti 1954). LCA is largely a recessive disease, although autosomal dominant pedigrees have been identified (Sorsby et al. 1960; Heckenlively 1988). To date, three genes for LCA have been identified and sequenced: retinal guanylate cyclase (GUCY2D) on chromosome 17p13; retinal pigment epithelium protein (RPE65) on chromosome 1p31; and cone-rod homeobox (CRX) on chromosome 19q13. 3. One additional locus has been identified on chromosome 14q24 (Stockton et al. 1998). We show evidence for linkage to chromosome 6q11-16 in a multigenerational kindred of Old Order River Brethren. The disease gene maps to a 23-cM interval flanked by DNA polymorphic markers D6S1551 and D6S1694, with a maximum twopoint LOD score of 3.38 (recombination fraction [v] zero) at D6S391. Two candidate genes on chromosome 6 were screened for mutations: gamma aminobutyric acid rho1 and rho2 (GABRR1 and GABRR2) at 6q14-21 (Cutting et al. 1992), and interphotoreceptor matrix proteoglycan (IMPG1) at 6q13-15 (Gehrig et al. 1998).

The incidence of LCA is 3 in 100,000 persons and accounts for 5% of all inherited retinal dystrophies (Perrault et al. 1996). Clinical and genetic heterogeneity have been demonstrated (Wardenburg 1961; Camuzat et al. 1996). The phenotype has been associated with familial juvenile nephronophthisis and cone-shaped epiphyses (Saldino-Mainzer syndrome) and with kidney disease (Senior-Loken syndrome), osteoporosis, metabolic diseases, and neurological abnormalities (Loken et al. 1961; Senior et al. 1961; Dekaban 1969; Mainzer et al. 1970; Ellis et al. 1984).