Genetic testing for ataxia-telangiectasia. • 634

The recent isolation and sequencing of the gene responsible for ataxia telangiectasia, ATM, has facilitated new insights into how genetic testing should be designed. The ATM gene is composed of 9168 nucleotides and 66 exons. Over 200 mutations have been identified in affected individuals. Most mutations (71%) result in protein truncations. Early reports describe changes in mRNA only; genomic mutations are still being characterized. Exon skipping in mRNA is frequently observed. However, even when the same exon is skipped in mRNA from two patients, the underlying genomic mutations may differ. Most patients who are not the offspring of a consanguineous mating are compound heterozygotes, i.e., they carry two distinct mutations. Most mutations are unique and they are distributed across the entire gene. For prenatal testing, in families with a prior affected child in whom the mutations remain unidentified, DNA haplotyping of all members of the immediate family is still the most efficient approach. If one mutation has been identified in the family, haplotyping can be circumvented if that mutation is found to be unambiguously absent in the fetal DNA sample. In extended families or ethnic populations in whom the founder effect mutation has been identified, rapid assays are being developed that can be performed on large numbers of individuals. These assays also allow accurate diagnosis of heterozygotes and screening of cancer prone populations. Rapid assays are presently available for Amish, Moroccan Jews, Norwegian (detects 60% of Norwegian patients) Costa Rican (65%), Polish (30%), and Italian (10%). Heterozygote identification for individuals without a prior affected relative is still problematic and will most likely require an automated approach to genetic testing.