The new genetic tests: let’s take stock

From full fetal DNA screening to couple compatibility testing, there are many options for future parents today. But when are these investigations really appropriate?

The most advanced diagnostic clinics offer future and aspiring mothers a variety of genetic tests, prenatal or preconceptional, more or less invasive. What information do they give? What is their degree of reliability? And how much do they cost? Here is a “guide” for orientation.

From molecular karyotype to genetic amnio and villus

These genetic tests are invasive tests, involving the taking of a sample of amniotic fluid or chorionic villi cells, as for traditional amniocentesis or villocentesi. If performed by an experienced operator in a good facility, the risk of accidental termination of pregnancy resulting from collection is extremely low, less than 0.5%. Amniotic fluid collection is usually done between week 16 and 18, villuscentesis between week 10 and 13. In traditional amniocentesis and villocentesi, the collected fetal cells are cultured and examined under a microscope to detect any macroscopic chromosome alterations, such as trisomy, i.e. the presence of three copies of a chromosome instead of the normal two. In this way, over a period of 15-20 days, it is possible to diagnose with almost absolute certainty certain chromosomal diseases: Down’s syndrome (trisomy 21), Edwards’ syndrome (trisomy 18), Patau’s syndrome (trisomy 13) and alterations of the X chromosome. Molecular examination of the karyotype is faster: it does not require cell culture. The fetal chromosomes are examined with a technique known as CGH array, which in 2-3 days allows to highlight, with almost absolute certainty, not only any macroscopic alterations, such as trisomies, but also the so-called micro-deletions, ie the small alterations of the karyotype that can lead to other rarer diseases, such as Prader-Willi syndrome or Cri-du-chat disease. The molecular examination of the karyotype can be associated with the analysis of fetal DNA: the progress in DNA sequencing today allows to analyze hundreds of genes and identify variants associated with many diseases. Future parents can ask for research into the most common genetic diseases, such as cystic fibrosis and congenital deafness, or the analysis of a larger number of genes. The cost of the examination varies accordingly, from 600-700 euros for a molecular karyotype amniocentesis to over 1,000 euros for genetic screening.

When are they really recommended?

The National Health Service offers traditional amnio and villocentesi free of charge to waiting women who have performed the recommended screening, i.e. bitest and nuchal translucency, and have been found to be at greater risk of chromosomal diseases, and genetic investigations targeted at women who, due to their personal or family history, are considered at risk of transmitting a specific genetic defect.

On the other hand, the search for potentially pathogenic genetic variants without specific risk factors is not recommended by the Italian Society of Medical Genetics. “In cases where the family history is negative, there are no chronic maternal diseases, taking drugs or toxic substances and there is no consanguinity between the spouses, the probability that the unborn child is affected by a disease due to a genetic defect is less than 1%,” notes Faustina Lalatta, medical geneticist at the Ospedale Maggiore Policlinico in Milan and consultant to ASM, the Italian Association for the Study of Malformations.

“In addition, the list of variants included in the research includes some that certainly determine known pathologies with a strong clinical impact and others with unpredictable consequences. There are cases in which the outcome of the examination is not possible to determine whether the fetus is a healthy carrier or affected by the disease and, even if it was affected, it is not possible to define the severity of the clinical picture, because the same mutation is expressed differently from one individual to another and the symptoms may be so blurred as to make it difficult to talk about disease. The couple only learns that there is the mutation: it is a situation that generates anxiety without offering the tools to get out of it”.

NIPT or fetal DNA examination in maternal blood

This is one of the most interesting and promising novelties of recent years among genetic tests: the possibility of examining fetal DNA without the need to take amniotic fluid or chorionic villi cells, therefore without invasive interventions, thus eliminating even the slightest risk of accidental termination of pregnancy. The test is based on the fact that small amounts of fetal genetic material cross the placental barrier during pregnancy and circulate in the maternal blood. With current techniques it is possible to isolate this DNA from a woman’s blood sample and analyse it. This is why this test is known by the acronym NIPT, i.e. Non-invasive Prenatal Test.

The information that can be obtained from the examination of fetal DNA from maternal blood is part of that obtained with the molecular karyotype and the screening of fetal DNA from amnio or villocentesi: the identification of any macroscopic chromosomal abnormalities, such as trisomies, chromosomal microdeletions and the search for some specific genetic diseases, the most common, such as cystic fibrosis and congenital deafness. At present, it is not possible to analyse the entire genetic heritage of the fetus with this technique. Furthermore, the test is not applicable in the case of a twin pregnancy, because there is no way to distinguish the DNA of both fetuses.

The results of the test are considered extremely reliable: the probability of a false positive or false negative is 1%. However, they do not yet guarantee the same diagnostic certainty as amnio or villocentesi. Therefore, the test is not considered diagnostic, but screening: if the result reveals an anomaly, it would therefore be necessary to perform the traditional invasive test to confirm the diagnosis.

The search for fetal DNA in maternal blood can be carried out as early as the tenth week of waiting. The cost varies from 600 to over 1,000 euros depending on the information sought. It is not reimbursed by the National Health Service, which instead recommends and offers free screening to all future mothers based on ultrasound examination of nuchal and bitest blood translucency, which, despite being burdened by a higher percentage of false positives and negatives, is cheaper. In the event of a high risk highlighted by the fetal DNA test or by translucency and bitest, amniocentesis for confirmation of diagnosis is the responsibility of the National Health Service.

Genetic test of compatibility of partners

It is a brand new test, still offered by a few diagnostic centers and is carried out before conception, on blood samples of the two partners who want a child. It serves to predict the risk of aspiring parents passing on to their children a hereditary disease of which they are unconsciously healthy carriers. The analysis of the complete sequence of her and his DNA allows to identify any alterations of individual genes that, combined at the time of conception, could give rise to a disease. In case of positivity, the solution offered is to proceed with assisted fertilization, subject the embryos obtained to a pre-implantation examination and, then, implant only those healthy.

Each of us is a healthy and unconscious carrier of genetic pathologies, from 3 to 5 known diseases. If two partners accidentally find themselves having the same mutated gene, the probability that they have a sick child is 25%. The examination, aimed at finding specific pathological mutations, is recommended and offered free of charge to couples who have a family history of hereditary diseases or who have had sick children or pregnancies with fetuses carrying hereditary diseases in the past, on the recommendation of a geneticist medical specialist who has evaluated the history of aspiring parents.

A very expensive examination: who really needs it

In the absence of precedents or factors of greater risk, does it make sense to do the genetic compatibility test, considering that the cost, entirely borne by the couple, is higher than 1,000 euros? “Each of us has about 22,000 genes,” observes Giovanni Porta, a geneticist at the University of Insubria and a consultant to the Association for the Study of Malformations. “The probability that two people taken at random will present a pathogenic mutation in the same gene is extremely low. It is nothing, but it is very, very low. Some recessive monogenic diseases are more frequent than others. For example, one in 25 people is a healthy carrier of cystic fibrosis, one in 35-50 is a healthy carrier of spinal muscular atrophy and one in 80 is a carrier of congenital deafness. In some areas of Sardinia and Sicily, one in 10 people is a healthy carrier of Mediterranean anaemia. For this very reason, there are cases of manifest disease in the families of healthy carriers of these diseases. In the absence of family history or other major risk factors, the probability of transmitting a recessive monogenic disease to a child is minimal and does not justify such an expensive examination. It must be said, then, that this test is not able to assess the risk of genetic or chromosomal alterations that may occur spontaneously during conception and that are the most numerous.

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