Prenatal and Fetal Genetic Testing

Preconception Carrier Screening:

Screening for genetic disorders during the preconception stage before pregnancy can be a useful tool to support family planning. Carrier screening is the process of screening an individual for autosomal recessive or X-linked genetic conditions associated with changes to a single gene. The test is most commonly performed with a saliva sample, but a buccal swab of the cheek or a blood draw may also be used (8). The American College of Medical Genetics and Genomics (ACMG) and American College of Obstetricians and Gynecologists (ACOG) are two national organizations that define clinical guidelines for preconception genetic screening and testing. The ACMG performs genetic research and uses the research to develop evidence-based guidelines which help clinicians make decisions regarding genetic testing. 

When carrier screening first became available about 50 years ago, screening was mainly performed for conditions that are more prevalent in people belonging to certain ethnic groups. For example, screening for Tay-Sachs Disease is highly recommended in individuals of Ashkenazi Jewish descent. In 2008, screening for Cystic Fibrosis and Spinal Muscular Atrophy began to be recommended by the ACMG for anyone regardless of ethnicity (9). Both of these conditions can have a neonatal or early childhood onset as well as typically severe presentation of symptoms that require specified care or treatments as early as possible, which are reasons why these disorders were added to ACMG screening recommendations (14). 

As of 2023, the cost and amount of time it takes to sequence a gene has decreased significantly, making genetic testing more accessible. Now that this screening can reasonably be offered to those considering pregnancy across the United States, the ACMG recommends expanded carrier screening to most people. These panels scan for a greater number of disorders simultaneously. The ACMG does not define exactly which genes and disorders should be screened for in these expanded panels, so laboratories vary slightly in their available screening options, with panels ranging from a small handful to a few hundred different conditions (10).

It may seem more efficient to test for every genetic condition at once rather than screen for different genes in the various screening panels. However, genetic testing is complex and there are multiple types of sequencing methods that each have strengths and weaknesses for identifying different conditions. Genetic conditions are each caused by a different type of pathogenic change or changes, meaning that not every condition can be tested for in the exact same way. This makes testing for a large number of diseases with a single test more difficult and potentially less accurate than targeted testing (9).

Prenatal (Antenatal: During Pregnancy) Screening and Testing:

Prenatal screening and testing for genetic disorders during pregnancy was first introduced in the 1970s. It can be performed in the first, second or third trimester, with slight differences in method and accuracy between the trimesters (11). Historically, the process starts with a noninvasive screening test, usually a combination of an ultrasound measurement of the developing fetus and a blood test on the pregnant person to analyze biochemical markers. The screening can only determine if the fetus is at a higher risk for changes in the number of chromosomes, it cannot diagnose whether or not a genetic condition is present.

One such screening is called Non-Invasive Prenatal Screening (NIPS), became commercially available in 2011. This screening was formally called Non-Invasive Prenatal Testing (NIPT), but because it is not actually a test, they renamed it to reflect the actual type of analysis being performed. NIPS analyzes fragments of placental DNA that are found naturally in the blood of the pregnant person (12). NIPS has a much lower false positive rate than traditional serum screening, meaning that fewer individuals who are screened using this technique will need invasive diagnostic testing.

As of 2023, the ACMG strongly recommends NIPS over traditional screening methods to screen for fetal aneuploidies such as trisomies 13,18, and 21, which often go undetected when using alternative screening methods (15). Overall, modern NIPS is a promising technique for more accurate screening of genetic conditions. If an increased risk of a chromosomal abnormality was detected on a screening, the next step would be an invasive diagnostic test to confirm the presence of chromosomal differences (12).

The two most common prenatal diagnostic procedures are amniocentesis and chorionic villus sampling (CVS). In both techniques, DNA is extracted from these samples and tested to diagnose any unexpected variation in the fetus. Though amniocentesis and CVS are the current clinical standard for diagnosing fetal disorders, these diagnostic tests are associated with a slightly increased risk of miscarriage, between 1 in 100 to 1 in 500 (13). However, if NIPS was to come back positive, it may be recommended that the pregnant individual undergo amniocentesis or CVS to confirm the diagnosis, which is why the initial screening is almost always the first step (12).

During CVS, a needle or catheter is used to take a sample of placental cells from the same fertilized egg as the fetus (13).

**NOTE: Like amnio, CVS is an invasive test and comes with a risk for miscarriage (0.25 - 0.50%).**

Products of Conception

Product of Conception (POC) refers to tissue that has developed from the formation of an embryo, such as the placenta, chorionic villi, umbilical cord, or fetal tissue recovered after miscarriage, stillbirth, or abortion (5). For testing, fetal tissue or placental tissue is more informative than maternal tissue (decidua)(5).

• What types of testing can be completed?

• Example 1: After a miscarriage, genetic testing can be performed on fetal or placental tissue to investigate whether the pregnancy loss was a result of chromosomal aneuploidy (6).

• Example 2: SNP microarray analysis can detect parental origin of chromosomal variation like triploidy, uniparental disomy, monosomy X, structural anomalies, or polyploidy (6). Learn more about aneuploidies here.

• How is it generally performed? In a medical setting, POC tissue is removed from the lining of the uterus during a procedure called a D&C (dilation and curettage). The physician uses instruments or medication to dilate the cervix before utilizing sterile tools to remove uterine tissue. Samples must be stored in sterile tubes with tissue culture medium and antibiotics, then refrigerated or frozen if not used immediately (7).

• What conditions CANNOT be identified through these samples? The usage of testing POC is typically limited to karyotyping, or the detection of structural aberrations or abnormal chromosome number. It usually is not used to test for smaller changes like substitutions or SNPs (6). Learn more about Karyotyping here.