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Purpose: To perform a genome scan for suitable UK multiplex families and identify new genetic loci for AIS.

Method: DNA 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. 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 – 3.6 for various DNA markers on 15 different chromosomes (1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 16, 17, 20, 21), and absence of linkage to the X chromosome. Linkage evaluation and comprehensive saturation mapping of the 2 loci with the highest LOD scores 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 two highest LOD score loci are at present being screened.

Correspondence should be addressed to: Sue Woodward, Secreteriat, Britspine, Vale Clinic, Hensol Park, Vale of Glamorgan, CF72 8JY Wales.