LINKAGE STUDIES OF A MISSOURI KINDRED WITH AUTOSOMAL-DOMINANT SPONDYLOEPIMETAPHYSEAL DYSPLASIA (SEMD) INDICATE GENETIC-HETEROGENEITY

A four-generation kindred (14 affected and 10 unaffected members) from Missouri, U.S.A. in which spondyloepimetaphyseal dysplasia (SEMD) had been inherited as an autosomal dominant disorder was investigated for linkage to 13 candidate loci: COL2AI, COL9AI, COL9A2, COL9A3, COL10A1 , COL11A1, COL11A2, PSACH, FGFR3, decorin, CRTL1, COMP, and PTHRP. Mut ations of COL2A1, COL9A2, COL10, and FGFR3 have been reported previous ly in the Strudwick type of SEMD, multiple epiphyseal dysplasia type 2 (EDM2), the Schmid type of metaphyseal dysplasia, and in achondroplas ia, respectively, and the pseudoachondroplasia (PSACH) locus has been mapped to chromosome 19p12. In addition, mutations in COL9 and COL11A are associated with murine forms of degenerative joint disease and cho ndroplasia, respectively, The family proved informative for 12 of the 13 loci and was uninformative at the decorin locus, Linkage between th is form of SEMD, designated the Missouri variant, SEMDMO, and the 12 i nformative candidate loci was excluded (LOD scores < -2.00 at theta = 0.005 to 0.15), thereby indicating further genetic heterogeneity in th ese inherited disorders of bone and cartilage development.