Familial Idiopathic Scoliosis: Evidence of X-Linked Susceptibility Locus

Baltimore, Maryland, USA

Familial idiopathic scoliosis is believed to be a complex genetic disorder in that the expression of the disease state may depend upon multiple distinct factors within a family or a group of families. Previous studies from a number of populations have suggested a Mendelian pattern of inheritance of an autosomal dominant or X-linked type. The current study investigates the existence of loci on the X chromosome for idiopathic scoliosis within a large population of families diagnosed through consistent radiographic criteria. Families with two or more affected individuals identified through evidence of a ten-degree sagittal curvature (Cobb angle) on standing anterioposterior radiographs were selected. Initially, twenty-four polymorphic X-chromosome markers in 14 families were typed and analyzed through model-independent and dependent linkage analysis. Arbitrary models were assumed for X-linked (XLD) and autosomal dominant (AD) modes of inheritance. The likelihood of each family to represent either an XLD or an AD mode of inheritability pattern was calculated using VITESSE. Families were then ranked in a distribution from an upper end (XLD subset) into a lower end (AD subset). From the two-point linkage results, positive LOD scores at 6 of 8 adjacent markers with peaks at recombination fractions between 0.2 and 0.3 were found when looking at the families that ranked in the top 70% of this initial group of families. We now have analyzed genotyping data from 15 X-linked markers for a population of 202 families (1208 individuals). Using model-independent linkage analysis, no significant p-value was obtained for any of the markers when the entire population of families was analyzed. However, when the top 25% of the families ranked as exhibiting an X-linked inheritability pattern were analyzed, a marker in the area of interest, DXS7132, was significant at a p-value of 0.048. These results suggest a locus on the X-chromosome, which may predispose an individual to idiopathic scoliosis. If further evidence of linkage is confirmed through flanking markers within these families, future work will be directed to mutational screening of potential candidate genes within this genomic area.