Confirming a diagnosis
When a clinical diagnosis of AT has been made or there is a strong clinical indication of AT, genetic confirmation of this should be obtained by identifying the ATM mutations present.
In the United Kingdom, the diagnosis of AT is confirmed by genetic testing looking for “pathogenic” or “likely pathogenic” variants in both copies of the ATM gene. This is either done by testing a large panel of genes known to cause ataxia in childhood or by testing of the ATM gene only.
Genetic Testing is now completed by The National Genomic Testing Service, through a Network of 7 Genomic Laboratory Hubs (GLHS) in England. (There will be a different system in Scotland, Wales and N Ireland). The process is started with a referral from the GP, Consultant or Local Genetics Service.
As a more general screen for Ataxia-Telangiectasia, as part of the diagnostic process, the following tests can be carried out:
- A chromosomal radiosensitivity analysis is carried out on the blood lymphocytes as sensitivity to ionising radiation is a characteristic of AT.
- A lymphoblastoid cell line (LCL) is also made from the blood sample and a western blot carried out to look for loss of ATM protein.
- If these two tests indicate the likelihood of AT, the patient’s ATM gene is sequenced in order to identify both mutations.
- If the western blot reveals some residual ATM protein activity, as the result of e.g. a missense or leaky splice-site mutation, an activity assay is also carried out to determine whether the ATM protein has some activity. There is a strong phenotype-genotype correlation in AT and patients with some residual AT kinase activity generally have a milder clinical picture. However, as is made clear repeatedly on this website, AT is a condition which varies considerably from individual to individual and it is not always possible to know the precise effects of a pathogenic or likely pathogenic variant in the ATM gene. This means that it is not possible to draw firm conclusions about how this condition will progress for any one person.
All these tests are preferred. For example, some patients have no measurable increase in chromosomal radiosensitivity; however, the western blot shows up a greatly reduced level of ATM protein. This is because the ATM present has some activity that is effective in reducing chromosome damage. Similarly, some AT patients have normal levels of ATM protein on a western blot, but the radiosensitivity assay will indicate a lot of chromosome damage. This is because the mutant ATM protein expressed has no kinase activity.