Candidate Regions of Chromosome 17 in Familial Idiopathic Scoliosis

Summary: One hundred one families with idiopathic scoliosis segregating in an autosomal dominant inheritance pattern underwent genomic screening and linkage analyses in order to identify candidate regions involved in disease expression. A candidate locus on chromosome 17q11, recently reported within the literature, was identified, however, finemapping was not confirmatory. Analyses of a second subgroup with males having undergone surgery resulted in increased significance and broadening of the region to approximately 20 megabases.

Introduction: Idiopathic scoliosis (IS) is a structural curvature of the spine with underlying genetic determinants. Salehi (2002) revealed a potential locus on chromosome 17 in a single family. In a genomic screen of a large population, we potentially confirm and define this critical region.

Methods: A sample of families with IS (202 families, 1198 individuals) was recruited with IRB approval and underwent a genomic screen and finemapping. Results were analyzed by model-independent linkage analysis (SIBPAL). Following initial analyses, families were then stratified first, according to mode of inheritance, and, second, by additional clinical criteria. Results from a group of autosomal dominant families (101 families; 598 individuals) are reported followed by results from families with a male having undergone surgery (17 families; 120 individuals).

Results: In the initial sample, when the threshold of disease was _10 degrees, analyses revealed significant results at markers d17s975 and d17s2196. In the subgroup of AD families, analyses resulted in confirmation of the data, however, finemapping results showed were not confimatory. Analyses of a second subgroup with males having undergone surgery resulted in increased significance of this region.

Discussion: The current work has significance in the confirmation of a reported genetic locus as meaningful in the etiology of IS. Stratification of subgroups resulted in heightened significance at specific markers demonstrating the heterogeneity of this disorder. Ultimately, the independent association of genetic loci and this disorder will enhance the ability to elucidate prognosis, counsel patients, and guide therapeutic plans.