Positional cloning strategies for idiopathic scoliosis

Idiopathic scoliosis (IS) affects approximately 1-2% of the population and has a heritable component. It is clear that in general IS displays the features of a complex genetic disorder; however families displaying a Mendelian inheritance pattern have been described. Our aim is to identify families segregating rare, highly penetrant loci. In the case described here the disorder appears to cosegregate with a chromosomal rearrangement.

We have studied a family in which a pericentric inversion of chromosome 8 appears to cosegregate with idiopathic scoliosis in three generations. We have used fluorescent in situ hybridization (FISH) to identify cloned DNAs that span the breakpoints on the two arms of the chromosome. These clones allow the recovery of sequence information from the breakpoint region and identification of candidate genes.

We have identified a YAC of 1190kb that spans the p arm breakpoint and from this a cosmid of 35kb that also identifies the break. We have derived DNA sequence information on this region. We have identified a BAC of 150kb that crosses the q arm breakpoint. The complete genomic DNA sequence of this BAC is being analyzed to identify candidate genes and to further localize the precise breakpoint.

We have sublocalized within two small genomic regions the position of a possible locus for idiopathic scoliosis.