Technical Aspects of Presymptomatic Gene Testing

Screening for some genes can be very fast, such as in cystic fibrosis, where mutations in most segments of the gene are easily identified. Some larger genes, such as the dystrophin gene in Duchenne muscular dystrophy (DMD) or the BRCA2 gene in familial breast cancer, take much longer, partly due to their size and partly because no common mutation exists that allows easy screening in particular populations.

Often an affected person's blood needs to be tested to be absolutely sure of the exact mutation present in a family. This may be difficult if a boy with DMD has died before female relatives are aware of the diagnosis and seek genetic testing, or in familial breast cancer if the index relative is deceased. Testing of pathological material such as retained biopsy tissues is possible in some cases, but long storage in fixed materials makes this technically difficult and freshly extracted DNA is usually best (for instance, from blood or a cheek swab).

Negative or normal results often mean that although the person is not at high risk, their risk falls back to the population risk of a new mutation or the population risk of the somatic incidence of the disease. In DMD, non mutation carrier females have a 1 in 3,000 chance of a new sporadic case of the condition – this is a low risk that will not usually deter couples from having a child.

Non carriers of a breast cancer mutation still have a risk of breast cancer similar to the population risk (1 in 11 in the UK and US). This is sufficiently high to ensure that they still need to participate in a national breast screening program (such as that in the UK, where every woman is invited for mammographic screening every 3 years after 50 years of age until 65 years, with extension to 70 years recently approved).

Such programs are controversial, although the evidence suggests that programs that are well established have better detection and survival rates. Because patients with a known family mutation who test negative for that mutation are at lower risk than their relatives, continuing breast screening at an early age is not necessary. It is prudent to make sure that patients in this situation do not go away with the thought that their normal gene test has left them with a zero risk of breast cancer, but rather with a risk close to 10% (albeit much lower that the BRCA1 gene carriers risk of up to 80%).

Unfortunately, not all patients with a family history of disease are able to have a mutation identified, either because of limitations in gene screening or because the genes themselves have not yet been identified. For example, in the case of a familial breast cancer history, screening should be carried out for the appropriate duration and can be discontinued if a gene is subsequently identified in the family, and the patient tests negative for that gene.

Most regional genetic centers have established protocols for testing common genetic disorders, especially late-onset diseases. In the UK, services are organized into regional centers within the National Health Service. Often patients can only have a genetic test if they see a geneticist, because of the complexities described above.

Not all centers have laboratories that screen all the currently available genetic tests – a recent review of genetic testing within the UK has started a process of organizing laboratories to provide UK-wide availability of certain tests within specific labs. This seems a sensible approach to rationalize the service as demands and gene discoveries continually increase.

Costs for common genetic tests such as cystic fibrosis and DMD are low, as mutations are easily detectible. In the case of cystic fibrosis, a common mutation, ΔF508, is present in 70%–80% of cases. In large genes such as BRCA1 and BRCA2 where no common mutations exist (except in the Ashkenazi Jewish populations and some countries in which there are a substantial number of founder mutations), searching has to be done by sequencing the entire gene. This can be very time consuming in small hospital laboratories, and may take months or even years.

In the UK, high throughput sequencing facilities are slowly being introduced into clinical practice. Current commercial laboratories can screen and sequence the entire BRCA1 and BRCA2 genes in 3–4 weeks, at a cost of around $3,000. Costs for specific mutation analysis in smaller hospital laboratories are much lower, but reflect the longer time scale, and range from around $200 to $500 for specific mutations or screening of smaller genes. Universities or other academic institutions will often have a research program that can identify mutations more easily in complex or large genes, but these still need to be confirmed in an accredited service laboratory before the results can be given to patients.

In the USA, genetic testing is not as cohesive, but individual laboratories may offer a wider range of genetic tests locally. Genetic counseling is widely accessible in both the UK and the USA.