Diagnosis of ataxia telangiectasia with the glycophorin A somatic mutation assay.

There are no widely applied definitive laboratory tests for the diagnosis of ataxia telangiectasia (AT). We, and others, have previously reported significantly elevated levels of in vivo somatic mutation in blood samples from known AT patients, observations that might form the basis for a useful prospective laboratory test for confirmation of a clinical diagnosis of AT. In the present case, a 4 1/2-year-old black female was suspected of having AT based on ataxic gait and chronic upper respiratory infections. Blood work-up showed low IgG2 and elevated alpha-fetoprotein (AFP), consistent with the AT phenotype. Her peripheral blood karyotype was normal, however, with no spontaneous breakage observed among 100 solid stained metaphases. Lymphocytes from AT patients often show elevated levels of chromosome rearrangement, especially at sites of immunoglobulin and T-cell receptor genes. Therefore, a blood sample was analyzed with the glycophorin A (GPA) in vivo somatic mutation assay. The GPA assay detects and quantifies the phenotypically variant erythrocytes resulting from loss of heterozygosity for the MN blood group. The patient had a 10-fold increased frequency of variant erythrocytes with a phenotype consistent with simple loss of the N allele, which is characteristic of AT. In addition, the variant cell distribution for this patient showed three other, more qualitative hallmarks of AT: a normal frequency of allele loss and duplication events, a unique ridge of cells of intermediate phenotype between the normal and mutant peaks, and evidence of similar ongoing mutational loss of the M allele. Together with clinical data, these distinctive qualitative and quantitative features of the GPA assay allow for a diagnosis of AT with a projected accuracy of 95%. Therefore, we suggest that the GPA assay, which can be performed on < 1 ml of blood and completed in less than a day, be considered as a confirmatory laboratory test for a clinical diagnosis of AT.