Prenatal genetic testing

It is a set of tests performed before or during pregnancy to try to monitor the correct development of the foetus and rule out the presence of possible congenital defects and also to determine the presence of maternal risk factors. These tests, both screening and diagnostic, can be invasive or non-invasive. These include: carrier analysis, first trimester screening, morphological ultrasound, non-invasive prenatal testing, karyotyping, panels and exome.

Prenatal genetic diagnosis comprises a series of genetic and molecular techniques that allow us to examine the genetic material of the future parents and/or foetus.

Our genetic material is contained in chromosomes, thread-like structures inside the cell nucleus. Our approximately 20,000 genes, most of which we have in duplicate, are distributed over 23 pairs of chromosomes. Consequently, each of our cell nuclei contains 46 chromosomes.

Changes in genetic material can lead to mental and physical developmental disorders, malformations or complex syndromes. These can be changes in the number and structure of chromosomes or changes (mutations) in individual genes.

With prenatal genetic diagnosis, the genetic material of the foetus can be examined for possible changes. There are several methods that can be used depending on the question, the patient’s own or family history and the need for certainty.

Although most pregnancies go without problems or complications, there are situations in which prenatal genetic diagnosis is necessary to identify risks in time or to clear up justified doubts and concerns. It is especially important in the case of:

• Inherited diseases in the family
• Abnormal screening in the first trimester or abnormal ultrasound findings
• In case of a history of miscarriages in the patient or the family

The type of diagnostic test and the timing will depend on each individual case. As a general rule:

• Before pregnancy: Either because of a history or because of a desire for greater certainty, one or both partners can undergo testing before pregnancy. Depending on the circumstances, it is advisable to carry out: a single gene analysis or a carrier genetic study to detect predisposition to severe recessive diseases.
• Early pregnancy: A non-invasive prenatal test from maternal blood is possible as early as the tenth week of pregnancy.
• Late pregnancy: If more certainty is required or if there are abnormalities in the ultrasound scan, an extended full genetic diagnosis can be performed. It is used to detect chromosomal alterations and mutations in individual genes.

• Non-invasive prenatal test: Allows highly accurate determination of numerical chromosomal abnormalities (mainly of chromosomes 13, 18, 21, X and Y).
• Chromosome analysis (karyotyping): Allows the identification of chromosomes in the dividing cell after staining, determining chromosome number and structure. This technique can be used to detect numerical chromosomal abnormalities (as in Down’s syndrome) and large structural chromosomal abnormalities.
• Array CGH: Allows the detection of small structural chromosomal abnormalities such as those found in several microdeletion and microduplication syndromes (DiGeorge syndrome, ngelman syndrome, Prader-Willi syndrome, Williams syndrome).
• Single gene analysis: Allows the identification of specific mutations in individual genes. This test is advised if there is a family history of an inherited disease (cystic fibrosis, spinal muscular atrophy…) or if ultrasound examination indicates a specific genetic defect.
• Exome analysis: The whole exome can be examined in a single test. It is a useful test if severe malformations (heart defects, skeletal dysplasias or brain malformations) are detected on ultrasound or if there is evidence of a complex syndrome.

These tests are sometimes also classified as follows:

• Cytogenetic: Those aimed at identifying alterations in the structure of chromosomes. These studies include: karyotyping and array CGH.
• Molecular: These allow the identification of point mutations in a gene or specific genes. They can be used to detect specific mutations (usually by Sanger sequencing) or to detect alterations in multiple genes simultaneously by next-generation sequencing (NGS).

Prenatal genetic testing allows the detection or exclusion of risks and genetic diseases in the foetus at an early or later stage. Even complex prenatal clinical pictures, sometimes associated with multiple malformations, can be diagnosed prenatally.

Genetic diseases are caused by changes in a person’s genes or chromosomes. We speak of aneuploidy when there are extra or missing chromosomes. In a trisomy, there is an extra chromosome. In a monosomy, one chromosome is missing.

Monogenic diseases are caused by changes in genes, these changes are called mutations. Monogenic diseases include sickle cell anaemia, cystic fibrosis, Tay-Sachs disease and many others. In most cases these are recessive diseases, so both parents must carry a mutation in the same gene to have an affected child.

There are also genetic diseases caused by chemical modifications of the DNA sequence (epimutations).

Array CGH is an accurate genetic technique for prenatal diagnosis of very small changes in genetic material that are not detected by karyotyping. These changes can be: microdeletions (absence of a very small piece of chromosome) and microduplications (addition of a piece of chromosome). Both defects can cause diseases that affect the intellectual and physical development of carriers. It does not identify point mutations or chromosomal alterations in equilibrium (balanced translocations).

An array CGH requires an amniocentesis or chorionic villus sampling to obtain the necessary sample (amniotic fluid or chorionic villi, respectively). An array CGH is especially recommended if:

• Abnormal findings are observed on ultrasound: organ malformation in combination with growth retardation or multiple malformations.
• If there are abnormal chromosomal findings that need to be further clarified.
• If the prospective parents have a great need for reassurance and want very detailed information about the chromosomal picture of the foetus.

Exome sequencing is a technique that allows a large number of genes to be analysed by massive next-generation sequencing.

Imaging methods sometimes provide inconclusive information. In the following doubtful cases, fetal exome testing is recommended:

• Cardiac defects
• Skeletal dysplasia
• Brain malformations
• Indications of a complex syndrome

As for an array CGH, amniocentesis or chorionic villus sampling is required to obtain the necessary sample.

There is no one better than the other, the decision depends largely on:

• The question to be answered
• The time of the pregnancy
• Family history
• Possible anomalies in the ultrasound scan
• The individual need for security of the parents-to-be

Prenatal diagnostic techniques are usually divided into two broad categories: non-invasive prenatal diagnosis and invasive prenatal diagnosis.

Non-invasive prenatal testing (NIPT)

No invasion of the foetal environment is required.

• Sample: Mother’s blood. Modern, highly sensitive methods detect small amounts of fragments of the child’s genetic material in the pregnant woman’s blood (cell-free foetal DNA).
• At what point in pregnancy should a non-invasive prenatal test be performed? This type of test can be performed from the 10th week of pregnancy and generally before the 22nd week, which is the limit for legal termination of pregnancy in Spain, subject to a medical diagnosis that justifies it.
• What is analysed? They compare maternal and foetal DNA to detect whether the foetus has a high risk of suffering from a chromosomal disorder. It is usually limited to the detection of trisomies 21, 13, 18, X and Y.

Invasive prenatal diagnostic methods

Invasion of the foetal environment is necessary. Amniocentesis consists of the extraction of amniotic fluid (where fetal cells are found) through puncture of the maternal abdomen, and chorionic biopsy, consists of the collection of placental tissue via the transcervical route.

Sample: Amniotic fluid (amniocentesis) and chorionic villi (chorionic villus sampling).

At what point in pregnancy should an invasive prenatal test be performed? As these tests are usually usually linked to suspicious NIPT or abnormal ultrasound findings, they are usually performed between the 12th and 22nd week of pregnancy.

What do they analyse? There are different techniques to analyse the sample obtained. The purpose is to detect genetic or chromosomal abnormalities before the foetus is born.

As a general rule, genetic counselling is not covered by any type of health insurance.

As far as prenatal genetic testing is concerned, it is covered by some private insurance companies and sometimes depends on certain criteria (patient’s medical history, family history, etc.). You can come to us with a certificate from your gynaecologist or with your insurance card.