EVIDENCE OF SUSCEPTIBILITY LOCI IN GENOME WIDE SEARCHES OF FAMILIAL IDIOPATHIC SCOLIOSIS

1Carol A.Wise, PhD,
1John A. Herring, MD,
1Joseph D. Gillum, BS,
1Howard C. Gunn, BS,
2Mchael Lovett, PhD,
2Anne M. Bowcock, PhD
1Dallas, Texas;
2St. Louis, MO, USA

Familial idiopathic scoliosis is a complex disorder, although some families with a Mendelian pattern of inheritance have been described. In the past few years, positional cloning has been used to successfully identify genes for numerous diseases. We are ascertaining and sampling multiplex kindreds with idiopathic scoliosis and combining stringent diagnostic criteria with conservative methods of genetic analysis to positionally clone genes predisposing to the disease. Probands having clinically relevant idiopathic scoliosis (50° Cobb angle or greater) were identified. Affecteds were confirmed on the basis of a minimum Cobb angle measurement of 15°, made from standing posteroanterior radiographs. We have previously reported results of a genome–wide search in one family (seven affected of 14 total members), in which the severity of the disease ranged from 16° to 94°. Results of that study revealed some evidence for linkage (p<0.05) at loci on chromosomes 6p, distal 10q, and 18q with maximum non–parametric lod (NPL) scores of 1.42 (p=0.020), 1.60 (p=0.019), and 6.33 (p=0.002) respectively. We have now applied similar strategies in the analysis of two additional large kindreds (17 affected in a total of 37 family members). In these families the severity of the disease ranged from 15° to 113°. Genome–wide scans were performed with polymorphic microsatellites at a resolution of 25 cM, and both parametric and nonparametric methods of linkage analysis were applied using a conservative, affecteds–only analysis. Evidence of linkage to distal 10q was also seen in one of these families (p<0.05), and some evidence for linkage to loci on chromosomes 5, 16, and 18 (p<0.05) was obtained in the second family. All potential candidate loci are being genotyped in 10 additional kindreds (including 29 affected members out of 45 individuals sampled.) Once further evidence of linkage is confirmed in additional families, genes from the identified candidate region(s) will be screened for mutations in affected members of linked families. This approach should identify novel genes for idiopathic scoliosis, and provide insights into the etiology of the disease.