Genetic mapping of a novel X-linked recessive colobomatous microphthalmia

Colobomatous microphthalmia is a common ocular malformation with a heterogeneous phenotype. The majority of cases without associated systemic abnormalities have an autosomal dominant inheritance pattern [McKusick, 1990: Mendelian inheritance in man]. A few isolated cases with autosomal recessive transmission have been described [Zlotogora et al., 1994: Am J Med Genet 49:261-262]. To our knowledge, no cases of X-linked colobomatous microphthalmia that are not a part of a syndrome or a multi-system disorder have been reported. In this study, we describe a genetic and clinical evaluation of a large pedigree in which colobomatous microphthalmia is segregating in an X-linked recessive fashion. Based on recombination breakpoint analysis, we have determined that the critical interval exists between markers DXS989 and DXS441, placing the disease locus on the proximal short arm or the proximal long arm of the X chromosome. Using linkage analysis, we obtained two-point lod scores of 2.71 at zero recombination with markers DXS1058, DXS6810, DXS1199, and DXS7132. Overlapping multipoint analysis established a broad maximum from marker DXS1068 to marker DXS7132, a region spanning approximately 28 cM. This study provides evidence for the presence of a new locus for colobomatous microphthalmia.