Genetic models for linkage analysis of ataxia-telangiectasia

Ataxia-telangiectasia (AT) is a multifaceted autosomal recessive disorder, inherited as a single gene in each family, presumably due to a defective DNA processing protein such as a recombinase, endonuclease or even a regulatory DNA-binding protein. We are attempting to identify the chromosomal location of the AT gene(s) by performing linkage analyses on a variety of genetic models. At least five AT complementation groups have been defined. This genetic heterogeneity complicates linkage analysis. Model I assumes that the complementation genes are clustered into a single genomic region and, therefore, lod scores of linkage data from all families can be added. Model II assumes that the AT complementation genes are dispersed throughout the genome and the lod scores cannot be added. This model necessitates assigning the complementation group of every family that is included in the linkage analyses and reduces the number of families in each data base. Model III utilizes heterozygote identification to follow the AT gene (in a Group A pedigree of 61 members) as a dominant trait, thereby increasing the amount of linkage information that can be derived from that family. Model IV will focus only on consanguineous offspring of first-cousin marriages, seeking to identify the location of the AT gene(s) by the increased degree of homozygosity of genetic markers in close proximity. This model has several advantages, including that much smaller numbers of patients are required. Model V assumes that a subset of our patients will carry deletions and can be used to confirm the relationship of a candidate gene to the AT phenotype. Progress: Models I and II have been used to survey 7% and 2% of the genome, respectively. (An additional 5% of the genome can be added for exclusion of the X chromosome on clinical grounds). Model III is intended to survey the entire genome. Our initial studies have surveyed approximately 30% of the genome. Several areas of increased lod scores have been identified and are under further investigation.