Abstract
Introduction: Adolescent idiopathic scoliosis (AIS) is described as a sex-influenced autosomal dominantly inherited disorder with females more often affected than males, and operative ratio of 7F:1M (Child et al. 1999). Two AIS loci have been reported on chromosome 17p11 (Salehi et al. 2002) and chromosome 19p13.3 (Chan et al. 2002) in the Italian and Chinese populations, respectively. Three other susceptibility AIS loci on chromosome 6q, distal 10q and 18q (Wise et al. 2000), and more recently primary candidate regions on chromosomes 6, 9, 16, and 17 (Miller et al, 2005) have also been reported.
Purpose: o perform a genome scan for suitable UK multiplex families and identify new genetic loci for AIS.
Method: NA samples from 208 subjects (134 affected, 17 reduced penetrance members and 79 normal) from 25 multi-generation British families with confirmed diagnosis of AIS were selected from our AIS family database, and genotyped for 410 polymorphic markers from the entire genome, spaced at 10 cM intervals. Genotypic data were exported into Cyrillic to construct the most likely inherited haplotypes for each chromosome and in each family. Two–point LOD scores were calculated using MLINK initially for the entire genotypic data, and again for the affected meioses only, followed by GENEHUNTER for multipoint linkage analysis for each family.
Results: Overall, 170 560 genotypes were obtained and analysed. DNA samples from 250 subjects from the 25 families are currently available for further genotyping and saturation mapping. Our AIS families show absence of linkage to the X chromosome as well as previously reported AIS loci, except for chromosome 9q and 17q as reported by Miller et al. (2005). Preliminary inspection of inherited haplotypes indicates that a number of these families may be segregating with several new AIS loci with LOD scores ranging from 1.0 – 3.63 for various DNA markers on 15 different chromosomes. Linkage evaluation and comprehensive saturation mapping of the two loci with the highest LOD scores of 3.63 and 4.08 for chromosomes 9q and 17q respectively were conducted and these regions were successfully refined. Candidate genes are currently being screened.
Conclusion: Preliminary evidence already indicates genetic heterogeneity of AIS. Candidate genes from the highest LOD score regions are at present being screened.
Correspondence should be addressed to Jeremy C T Fairbank at The Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX7 7LD, UK
