A genetic test consists of looking for a variation or anomaly in the DNA, the carrier molecule for genetic information. These tests study:
- Either a small part of the genes: a single gene, or a relevant gene panel, depending on the symptoms present in the context of a disease for example,
- Or all the coding DNA: the exome, which represents less than 2% of the genome,
- Or the whole genome.
For us, at Imagine Institute, like for all genetic doctors and counselors in France, it is in the context of medicine and genetic research that these tests are carried out.
In the face of an assumed disease of genetic origin, tests have a diagnostic quality above all, often putting an end to several months or years of uncertainty in looking for the cause of a child’s or adult’s symptoms, often in the context of a rare disease. A positive genetic test is also of huge interest to establish a parallel between patients in other cases, therefore forming homogenous groups, ready for basic or clinical research studies, even therapeutic research projects. A third major interest of genetic tests is to lay the foundation for sound genetic advice for families affected, by identifying genetic alterations for which the parental origin allows the risk of recurrence of the disease to be calculated in the family for some, or on the contrary, for which the accidental nature (new alteration) makes it largely possible to reinsure the whole family.
When is a genetic test carried out?
In some fields of medicine, like the genetics of cancers, beyond diagnosis and genetic counseling, the genetic analysis of the tumor can help identify prognostic factors, therapeutic targets, even therapeutic adaptations. It is this idea in particular that has allowed the concept of “precision” medicine to be developed, which is the treatment of a person being adapted not only for his/her type of cancer but also for genomic variations of the tumor, variations that have been acquired during the malignancy or which, for some, are constitutional, meaning inherited or related to genetic damage.
Finally, in other cases, in individuals free of any symptoms, genetic tests can be carried out:
- In a person who is part of a family at risk of having a genetic disease because of a past history (asymptomatic testing when the risk is major, close to 100%, or predisposition test when the risks are less),
- In a person of such a family, free of disease, but at risk of having children with a genetic disease (heterozygosity test or conductor),
- On an embryo or a fetus at risk of having a specific genetic disease (prenatal or preimplantation diagnosis),
- Even in people in the general population, with no symptoms or any connection to a person with a genetic disease, to look for risk factors making them susceptible to a genetic disease, either rare or common. But this could be, in my opinion, a dangerous shift from diagnosis to screening, and from genetic medicine to eugenics.
In which cases are tests authorized in France today?
The French legal framework authorizes:
- Diagnostic tests in a child or adult who is presenting with symptoms, to name the disease and as a result, adapt the medical care.
- Predictive tests of a specific disease to look for a genetic predisposition in a person who is part of an “at risk” family. For example, in families where several cases of breast and ovarian cancer have been detected and especially if they occur early, a search for BRCA1 and BRCA2 gene mutations, but now also 10 other genes, can be offered. The test looks at a person who has had breast cancer to find out if she is a carrier of a mutation in one of these genes. This research in the “index case” can be long or difficult to interpret because the nature of the mutation can be very varied.
Whatever the field concerned, if a genetic predisposition has been detected and measures of care, prevention, even genetic counseling can be taken, the test can then be offered to the relatives at risk. This raises the question of giving information to the family; bioethics laws of 2004 and 2011 retained that the person in which the predisposition has been identified had to contact members of her family herself, either directly but with the help of a letter from the geneticist summarizing the issues of a genetic test, or indirectly by asking the geneticist to do it for her.
- Prenatal and preimplantation genetic diagnosis for couples where one of the parents or one of the children already has a genetic disease of a particular severity. Prenatal diagnosis aims to determine in utero if the fetus has the disease in question. Preimplantation tests are performed in vitro to transplant an embryo that does not have the specific disease that they have looked for.
- Finally, heterozygosity tests: some “recessive” genetic diseases only develop when both versions of the same gene - the one inherited from the mother and the one inherited from the father - are mutated. This is particularly the case for cystic fibrosis and sickle cell anemia. If both parents are “carriers” of the mutated gene, even though they do not suffer from it themselves (they are called heterozygotes), they have a 1 in 4 risk that each of their children will have a disease, which has never manifested in the family.
By using this last concept, we could consider that genetic tests can be offered to couples free of disease, seeking to know if they are both heterozygotes for the same gene and therefore at risk of passing on a disease. This is the reason why “preconception” tests were created, which are offered if one member of the couple is known to have a higher risk than that of the general population, for example as a relative of a person suffering, or even for people who are part of a genetic isolate, meaning from a population in which the frequency of heterozygotes for a particular gene is higher (for example in population groups of African origin for sickle cell anemia).
What are the future challenges, particularly with the acceleration of sequencing possibilities?
Genetic tests have the benefit of exceptional progress with regards to automated DNA sequencing. High-throughput sequencing can be broken down into three dimensions
- Analysis of a gene panel: After exome sequencing, targeted analysis on a gene panel related to the supposed or presupposed disease depending on the patient’s symptoms is carried out. Panels include genes for which the alterations are known to be responsible for the pathology in question. They evolve with new discoveries of genes.
- Exome: This technique takes into account all 22,000 genes in a person.
- Sequencing of the whole genome: this last possibility is still quite far from clinical applications.
Even if it makes it easier to carry out some genetic tests, high-throughput sequencing does not resolve the issue of interpreting these results. Our genome has about 6 billion nucleotides, elements making up our DNA.
Overall, there are few differences between two individuals, around 0.01%, which still represents 3 million different nucleotides. These genome variations, called variants, can be pathogenic, neutral or have an unknown meaning to date.
The challenge of genetics is determining their meaning to, among other things, identify those which have clinical relevance. There is still a long way to go before being able to understand everything, and even more so since epigenetics, which studies how genes are expressed and makes the connection with the environment, has now come into play in genetics.