A LOCUS FOR AUTOSOMAL RECESSIVE CONGENITAL MICROPHTHALMIA MAPS TO CHROMOSOME 14Q32

Congenital microphthalmia (CMIC) (OMIM 309700) may occur in isolation or in association with a variety of systemic malformations. Isolated C MIC may be inherited as an autosomal dominant, an autosomal recessive, or an X-linked trait. On the basis of a whole-genome linkage analysis , we have mapped the first locus for isolated CMIC, in a five-generati on consanguineous family with autosomal recessive inheritance, to chro mosome 14q32. All affected individuals in this family have bilateral C MIC. Linkage analysis gave a maximum two-point LOD score of 3.55 for t he marker D14S65. Surrounding this marker is a region of homozygosity of 7.3 cM, between the markers D14S987 and D14S267, within which the d isease gene is predicted to lie. The genes for several eye-specific tr anscription factors are located on human chromosome 14q and in the syn tenic region of mouse chromosome 12. However, both CHX10 (14q24.3), mu tations of which give rise to CMIC in mouse models, and OTX2 (14q21-22 ) can be excluded as candidates for autosomal recessive congenital mic rophthalmia (arCMIC), since they map outside the critical disease regi on defined by recombination events. This suggests that arCMIC is cause d by defects in a novel developmental gene that may be important or ev en essential in eye development.