A five-base pair deletion in the sedlin gene causes spondyloepiphyseal dysplasia tarda in a six-generation Arkansas kindred

A six-generation kindred from Arkansas with X-linked recessive spondyloepip hyseal dysplasia tarda (SEDT) was investigated by genetic linkage and mutat ion analysis. SEDT had been mapped on the X-chromosome (Xp22.2), and the cl inical and radiographic evolution of this kindred had been published. Linkage analysis proved informative for all five polymorphic markers tested , and DXS987 and DXS16 co-segregated with the Arkansas kindred (peak logari thm of the odds scores, 3.54 and 3.36, respectively). Subsequently, dinucle otide deletion in a new gene designated "sedlin" was reported to cause SEDT in three families. In an affected man and obligate carrier woman in the Ar kansas kindred, we found a 5-bp deletion in exon 5 of sedlin. The defect ca uses a frameshift, resulting in eight missense amino acids and premature te rmination. The 5-bp deletion was then demonstrated to segregate with SEDT i n the four living generations, including eight affected males and nine obli gate carrier females. Furthermore, the deletion was identified in four fema les who potentially were heterozygous carriers far SEDT. The mutation was n ot detected in the two young sons of the consult and (believed to be a carr ier because of her subtle radiographic skeletal changes and then shown to h ave the deletion), but they were too young for x-ray diagnosis. Identification of a defect in sedlin in this SEDT kindred enables carrier d etection and presymptomatic diagnosis and reveals an important role for thi s gene in postnatal endochondral bone formation.