Genetic linkage studies in antithrombin‐deficient kindreds using a highly polymorphic trinucleotide short tandem repeat (str) within the human antithrombin gene

PCR amplification and analysis of short tandem repeats (STR) have provided a useful tool for genetic linkage studies and for the diagnosis of genetic disorders. We have recently identified a novel trinucleotide STR, (ATT).(TAA), in the fifth intron of the human antithrombin gene (AT3) located on chromosome 1q23. PCR amplification, cloning, and sequence analysis revealed this AT3-STR to be highly polymorphic with repeat units ranging in size from (ATT)5 to (ATT)18. Ten distinct alleles were found in 81 unrelated Caucasian individuals (162 alleles) with an observed heterozygosity of 81%. Genetic linkage studies using the AT3-STR in two previously described antithrombin (AT)-deficient kindreds, AT-Hamilton (Ala 382 Thr) and AT-Amiens (Arg 47 Cys), demonstrate, in a given kindred, that a specific AT3-STR polymorphism is strongly associated with a particular AT mutation. Thus, this highly polymorphic AT3-STR should be very useful in performing linkage studies in AT-deficient kindreds as well as in investigating other chromosome 1-related genetic disorders.