Abstract
Introduction: AIS is described as a sex-influenced auto-somal dominantly inherited disorder with females more often affected than males (operative ratio 7F:1M) 1. Two AIS loci have been reported on chromosomes 17p112 and 19p13.33 in the Italian and Chinese populations, respectively. Other susceptibility AIS loci on chromosomes 6p, distal 10q and 18p4, and more recently to chromosomes 6, 9, 16, and 175, and 19p136 have also been reported, in the American population.
Purpose: To perform a genome scan for suitable UK multi-generation families and identify new genetic loci for AIS.
Method: DNA samples from 208 subjects (116 affected members) from 25 British families with confirmed diagnosis of AIS were selected from our family database, and genotyped for 410 polymorphic markers from the entire genome, spaced at ~10 cM intervals. Using Cyrillic, most likely inherited haplotypes were constructed for each chromosome and family. Statistical analyses were calculated using MLINK and GENEHUNTER, initially for the entire genotypic data, and again for affected meioses only.
Results: 170,560 genotypes were obtained and analysed. Our AIS families show no linkage to the X chromosome. Preliminary inspection of inherited haplotypes indicates a number of families may be segregating with several new AIS loci with LOD scores from 1.0–3.64 for markers on 15 different chromosomes. Linkage analysis and saturation mapping of the 2 highest LOD score regions on chromosomes 9q34 and 17q25 were conducted. These regions were successfully refined and candidate genes are 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: Dr Caroline Goldberg, The Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin 12, Ireland.
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