Abstract
Introduction
Clinical studies have shown distinct differences in later-onset idiopathic scoliosis (IS) between men and women, including curve severity, stiffness, and ease of operative intervention. Therefore, significant scoliosis in men was used as criteria to create a phenotypical subset of families with IS. The goal of this study is to identify genetic determinants that relate specifically to men with a scoliotic curvature of 30° or more.
Methods
We identified 25 families (208 individuals) in which a male was diagnosed with 30° or more IS curvature in adolescence. 123 individuals were affected (48 male; 75 female), and 85 were unaffected (45 male; 40 female). Initially, a genomic screen was done with a modified CHLC (version 9) marker set. After initial linkage analyses, the group underwent finemapping with a custom single-nucleotide polymorphism (SNP) panel and ABI Taqman methodology on an ABI 377 platform. The initial genome-wide screen and subsequent analyses were analysed by model-independent linkage analysis with SIBPAL (SAGE, version 5).
Results
Genomic screen analyses revealed significant results (=two adjacent STRP markers p<0·005) on chromosome 22 spanning approximately 13 Mb. Subsequent finemapping SNPs were statistically significant in single and multipoint analyses; rs8140312 (-log(p)=8·0 and 2·29, respectively) and rs240597 (-log(p)=5·96 and 1·76; figure). Significant SNPs lie mainly in the introns of the LARGE gene, which is integral to the development and maintenance of skeletal muscle, and SFI1 gene, which is responsible for the integrity of the chromosomal centromere complex.
Conclusions
A subset of families was identified within a cohort of familial idiopathic scoliosis (FIS) families that contained male patients with severe scoliosis, facilitating the study of genetic determinants. Data show a highly significant correlation with a locus containing the LARGE and SFI1 genes on chromosome 22. Future goals include association and sequencing analyses of this region. FIS is a complex genetic disorder. Use of clinical criteria may help to decrease the heterogeneity of any one study population, and enhance the successful identification of specific genes that bring about this disorder. The identification of a genetic locus is of major clinical and therapeutic interest and might improve understanding of spinal growth and stability.
