PGT – Preimplantation Genetic Test

PGT – PREIMPLANTATION GENETIC TEST

GENERA is the leading Italian group for the analysis and diagnosis of genetic diseases and chromosomal pathologies in embryos obtained during an in vitro fertilization cycle.

The procedure used is called Preimplantation Genetic Test (PGT).

Below are the most common questions to better understand how PGT techniques are aimed at achieving a common goal: obtaining a birth.

WHAT IS PREIMPLANTATION GENETIC TESTING FOR MONOGENIC DISEASES, PGT-M?

The preimplantation genetic test for monogenic diseases (PGT-M) is an analysis designed to identify and transfer, among the embryos produced in an IVF cycle, those not affected by a hereditary transmitted disease, in couples at high reproductive risk.

Are there any risks for embryos that are subject to pre-implantation genetic testing for monogenic diseases?

PGT-M is an absolutely safe procedure for the embryo that precedes its implantation into the uterus and allows the presence of hereditary diseases to be identified at a very early stage of development, when the embryo is still at the blastocyst stage, i.e. 5-7 days after fertilization. At this stage the blastocyst has already differentiated into embryonic (internal cell mass, ICM) and extraembryonic (Trophoblast, TE). The biopsy of a few cells of the trophoblast (<5% of its biomass) has been shown to be safe and does not compromise the embryo’s development and implantation capabilities.

What is the goal of PGT-M?

The objective is to prevent the conception of a child specifically and solely affected by the pathology from which the two components of the couple are affected/healthy carriers.

A preliminary work-up is necessary in order to build specific molecular probes necessary for the analysis.

What are the only diseases that can be diagnosed with PGT-M?

Cystic fibrosis, thalassemia, spinal muscular atrophy, myotonic dystrophy, neurofibromatosis, Duchenne-Becker muscular dystrophy, hemophilia A or B, X-Fragile syndrome, are just some of the more than thousands of genetic diseases that, according to the World Health Organization (WHO), can be diagnosed with Preimplantation Genetic Testing.

Over 95% of these pathologies do not have a specific cure and, although individually they are very rare, they have a total prevalence estimated around 1% in the general population. Each person is on average a healthy carrier, usually asymptomatic, of about 2.8 genetic mutations and when two carriers of the same mutation are encountered, the children who are born may be affected by congenital diseases, early mortality, mental retardation and permanent disabilities.

Who should we contact to perform PGT-M?

For couples who wish to undertake PGT-M treatment, the first step is a preliminary interview with the specialist in Medical Genetics who, after assessing the couple’s medical history, will explain the procedures, diagnostic possibilities and limitations, success rates and risks related to the treatment. Couples who approach the specialist will have the opportunity to get an accurate picture of what their path might be if they decide to undertake an IVF cycle. A simple collection of peripheral blood from the couple and saliva from some of their relatives will be necessary and sufficient for the genetic team to build the molecular probes needed for pre-implantation genetic analysis. Subsequently, the gynaecologist specialized in Reproductive Medicine will be able to start the IVF treatment. During IVF treatment, a number of embryos will be produced on which a biopsy at the blastocyst stage (5-7 days of in vitro preimplantation development) will be performed. This biopsy consists of the collection of a fragment belonging to the extra-embryonic portion (trophoblast) which gives rise only to embryonic attachments such as placenta and amniotic sac.

This portion of the embryo has the same genetic make-up as the internal cell mass from which the fetus originates. Consequently, the genetic analysis carried out on the fragment taken is sufficient to diagnose whether the embryo is affected, a healthy carrier or not affected by a specific genetic pathology. Furthermore, there is no procedural risk to the embryos when the biopsy is performed at the blastocyst stage. In fact, their chances of implantation in the maternal uterus are not compromised. Therefore, the implantation rate following embryo transfer of unaffected embryos or healthy carriers of a monogenic pathology is equal to patients of the same age who undergo a common IVF cycle without pre-implantation diagnosis.

WHAT IS PGT-A OR PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDIES?

PGT-A is designed to identify embryos with a normal chromosomal assessment among those produced during an IVF cycle. This technique aims to achieve an increase in the efficiency of each individual treatment, while minimizing the possible risks. The onset of chromosomal abnormalities is, in fact, a de novo (i.e. not hereditary) event that may occur in the maturation process of the oocyte or spermatozoon. The risk of producing chromosomally abnormal embryos is, however, strictly proportional to the increase in the woman’s age.

What is the goal of PGT-A?

The aim of PGT-A (improperly known as preimplantation genetic screening, PGS) is to decrease the abortion rate (which is reduced to less than a quarter of what happens in patients of the same age who undergo a conventional IVF cycle), to increase the rate of full term pregnancy by embryo transfer (which increases on average by up to 50% for each individual embryo transferred), and to prevent the conception of children suffering from chromosomal diseases, such as Down syndrome (trisomy of chromosome 21). In addition, the excellent reproductive potential of euploid embryos allows only one embryo to be transferred, thus reducing the risk of twin pregnancies.

PGT-A, by reducing the number of inefficient and potentially risky embryo transfers for women both physically and psychologically, provides a strategy with very high potential that is finding an increasing clinical application in IVF.

Moreover, this analysis does not require a preliminary work-up and the method of analysis is common to all patients who require it.

When is PGT-A recommended?

This type of PGT is indicated for women over 35 (the average age of women accessing IVF treatments is 36 years and 30% are over 40), an age group in which the risk of chromosomal abnormalities in embryos increases significantly. At the age of 27 it is about 1 in 450 pregnancies to be characterized by a child with chromosomal abnormalities, at 35 it is about 1 in 300, about 1 in 60 for women in their 40s, up to an alarming 1 in 20 at the age of 45 (Source: www.sindrome-down.it).

Similarly, during IVF cycles without PGT-A, the Italian IVF registry reported a 38.6% miscarriage rate in women with an average age higher than 35 years. PGT-A reduces the risk of abortion to below 10% regardless of the age of the woman. This technique is therefore also indicated in cases in patients with a history of repeated implant failures or abortions in previous IVF cycles.

Is PGT-A also important for reducing the risk of multiple pregnancies?

The rate of multipe pregnancy after IVF treatment in Italy is around 15% (ISS data, 2017). The detection of embryos with a correct number of chromosomes (euploids) allows to prevent chromosomal causes on implantation failure, to the point that one euploid embryo in two outcomes in a term pregnancy, regardless of the age of the woman. This evidence allows the transfer of a single embryo even in older patients, at the same time reducing the risk of multiple pregnancy, which has always been an important complication of IVF treatments. The data of the GENERA group show a risk of twinning after PGT-A of less than 1%.

WHAT IS PGT-SR OR PREIMPLANTATION GENETIC TESTING FOR STRUCTURAL ABNORMALITIES OF CHROMOSOMES?

PGT-SR is indicated in couples where one (or both) of the two partners is a carrier of a structural chromosome abnormality. The most frequent are inversions, deletions and duplications, but mostly translocations. Where the presence of such anomalies in the parental karyotype is certified, the risk of generating chromosomally abnormal embryos is significantly increased, regardless of the age of the woman. One of the most common alarm bells to investigate the presence of these anomalies is, in fact, poliabortivity in women under 35.

What are the objectives of PGT-SR?

The main aim of PGT-SR is to reduce the risk of abortion as well as the time invested by these couples to achieve a full-term pregnancy. Clearly, it will be necessary to certify the presence of chromosomal imbalance in the paternal or maternal karyotype, and to undergo specialist genetic counselling to define the reproductive risks underlying each specific abnormality.

Does PGT-SR allow the exclusive analysis of the chromosomes involved in the imbalance?

No. The entire chromosome kit of the couple is tested, so at the time of transfer into the uterus, a chromosomally normal embryo will be transferred. This type of PGT does not require any specific set-up, but the documentation certifying the mutation must first be sent to the reference laboratory.

PREIMPLANTATION GENETIC TEST CAN BE PERFORMED ALSO FOR FERTILE COUPLES BUT CARRIERS OF GENETIC PATHOLOGIES?

In 2014 in Italy, there were about 2000 fertile couples carrying a genetic pathology, who could not access PGT due to the prohibition imposed by Law 40/2004, which allows access to this technique only to those who perform a Medically Assisted Reproduction as infertile. In fact, this law recognizes only sterile and infertile couples, carriers of genetically transmissible diseases, the possibility to have access to IVF techniques with pre-implantation investigation, prohibiting them, instead, to those fertile carriers of such hereditary diseases.

Intervention of the Constitutional Court ruling 96/2015: lifting of this ban

Now, however, thanks to the intervention of the Constitutional Court – which on May 14, 2015 declared the illegitimacy of the rule contained in the law ’40 – even fertile couples carrying genetic abnormalities, will be able to access assisted fertilization and in particular pre-implantation diagnosis, to know the state of health of the embryo.

Such prohibition, cancelled by the Council, in fact, would violate certain constitutionally guaranteed fundamental rights. More precisely:

1) the principle of equality (Article 3 of the Constitution) between those who are infertile with genetic diseases and can undergo IVF with pre-implantation investigation and those who are fertile and bearer of genetic diseases who, due to law 40, cannot carry out such investigations and thus avoid an abortion.

2) the inviolable human rights which would include the couple’s right to a healthy child and the right of self-determination in procreative choices (Article 2 of the Constitution).

3) the right to health from the point of view of the protection of women’s health (Article 32 of the Constitution)

4) Article 117(1) Constitution in relation to Articles 8 (right to respect for private and family life) and 14 (prohibition of discrimination) of the Cedu.

Since June 10, 2015, date of publication in the Official Gazette (Special Series no. 23/2015) of judgment 96/2015, therefore, also in Italy is the PGT-M for fertile couples carrying hereditary diseases. The latter, moreover, to access the pre-implantation genetic diagnosis as provided for by the ruling of the Consulta, will only need to present the certificate of a doctor attesting the risk of an interruption of pregnancy, according to the provisions of Article 6 of Law 194/78.

Preimplantation Genetic Test (PGT): couple work up

FIRST CONSULTATION

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The work up of the pre-implantation genetic test begins with the first consultation during which the physician explains to the couple all phases of the procedure, the timing, costs, risks and benefits of the treatment.  

If an identified monogenic hereditary disease is present in the parents it refers to PGT-M, if the pre-implantation test is performed for the evaluation of abnormalities in the number or structure of embryonic chromosomes it refers to PGT-A/PGT-SR.

SET-UP  (Only in case of PGT-M)

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PGT-M foresees a preliminary set-up ad hoc on the mutation(s) carried by the two partners. In particular, a blood sample of each partner of the couple will be required, as well as the buccal swabs of the parents and/or children if available, in order to define the molecular probes aimed at identifying the mutation. This procedure requires 1-2 months of preparatory work for the IVF cycle with pre-implantation genetic testing.

IVF TREATMENT AND PGT

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The IVF treatment is equivalent for both PGT-M and PGT-A/PGT-SR and differs from a standard treatment only because the blastocyst obtained will undergo embryo biopsy. Between the fifth and seventh day after fertilization, small external fragments of the embryo (trophoectoderm) are retrieved. The blastocyst is then cryopreserved by vitrification until the diagnostic result, while the trophoectoderm fragment is sent to the reference genetics centre.  

ANALYSIS AND REPORTING

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Shipping, processing, analysis and reporting takes about 15 working days. The accuracy of this test is over 98% so the rate of misdiagnosis is less than 2%. On average, in 65-70% of cases in which the biopsy is performed, viable embryos are identified in which the genetic and/or chromosomal anomaly under examination is not present.

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POST-TREATMENT COUNSELLING 

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The diagnostic result is communicated to the couple by the medical team. The transfer of cryopreserved embryos after biopsy is generally carried out in the cycle following that in which the oocyte collection took place (or in the shortest possible time as soon as the woman's psychophysical condition permits). The postponement of the transfer is required both for technical reasons related to the timing of the molecular analysis and for medical reasons related to the greater possibility of conception and better obstetric and gynecological course of pregnancies obtained from non-stimulated cycles in which endometrial maturation is more physiological.

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EMBRYO TRANSFER

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On the scheduled day of embryo transfer, a single blastocyst is thawed. The survival of the blastocyst to cryopreservation is over 95%. Single embryo transfer policies make it possible to drastically reduce the risk of multiple pregnancy and therefore of neonatal complications. Approximately 10 days after the transfer, the couple performs the pregnancy test by measuring plasma beta hCG.

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PRENATAL COUNSELLING

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In the case of pregnancy, genetic counselling is recommended with a specialist from the Centre to assess the performance of further non-invasive prenatal investigations (circulating fetal DNA analysis) or invasive (villocentesis or amniocentesis).

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