Prenatal Genetic Testing and Screening

Cell-free DNA screening (also called non-invasive prenatal screening and abbreviated as NIPT or NIPS) is a screen used to determine if a pregnancy is at increased risk for specific common chromosomal conditions. This test does not screen for all possible problems.

What can cell-free DNA screening show? / What does a cell-free DNA screen look for?

This test screens for:

• Down syndrome (trisomy 21)
• Edwards syndrome (trisomy 18)
• Patau syndrome (trisomy 13)
• X&Y chromosome variations (sex chromosome abnormalities)

Newer versions of the cell-free DNA (cfDNA) screen may include screening across all 23 pairs of chromosomes, the molecules that carry our bodies’ instructions for growth and development. These screens look for extra or missing chromosomes as well as large deletions or duplications of genetic material.

Additionally, select microdeletions and some single gene disorders, as outlined below, may also be included on a cfDNA screen. You should discuss this option with a genetic counselor before ordering advanced screening.

Microdeletions

• 22q11.2 deletion syndrome
• Prader-Willi syndrome
• Angelman syndrome
• Cri-du-Chat syndrome
• Wolf-Hirschhorn

Single gene disorders

• Achondroplasia (a kind of dwarfism)
• Noonan syndrome
• Osteogenesis imperfecta
• CHARGE syndrome

Cell-free DNA screening cannot predict whether a birth defect (such as a heart defect) will be present at a future ultrasound.

How is cell-free DNA screening performed?

Genetic specialists perform cell-free DNA screening by collecting a blood sample from the mother. This non-invasive screen analyzes fragments of DNA from the placenta, which is circulating in the mother’s blood. Geneticists use these DNA fragments to determine if there is any extra or missing genetic material to help estimate risk for certain genetic syndromes.

When can I have a cell-free DNA screen?

We can perform a cell-free DNA screen as early as 10 weeks into pregnancy.

How long will results from a cell-free DNA screen take?

Results from a cell-free DNA screen are usually available 7 to 10 days after your visit and blood draw.

What are the risks of a cell-free DNA screen?

Because this screen is non-invasive, there are no risks to mother or baby outside of a normal blood draw (very low risk).

How are cell-free DNA screening results interpreted?

Screening tests determine if a pregnancy is at an increased risk for a given condition.

• A negative (normal) screening result shows reduced risk for a pregnancy to be affected by a genetic condition. However, it does not eliminate the chance and there is a small risk for a false negative result.
• A positive (abnormal) screening result indicates that there is increased chance for the pregnancy to be affected by a genetic condition. A positive screen will require additional follow up to determine if the result is a true positive or a false positive.

What if my cell-free DNA screen results are abnormal?

In the case of a positive (abnormal) screening result, a genetic counselor will discuss with you what these results mean and next steps. We typically recommend further evaluation, including a detailed (level two) ultrasound. Your genetic counselor will also review diagnostic testing options such as chorionic villus sampling (CVS) and amniocentesis (continued below).

Maternal serum screening helps doctors determine if a pregnancy is at increased risk for certain chromosome conditions and birth defects. Maternal serum screening is becoming less common due to the availability and increased detection rates of cell-free DNA screening. This test does not screen for all possible issues that can occur in a pregnancy.

A maternal serum screen can be called different names, depending on the timing of the screening:

• First trimester screen: information from the first trimester only
• Integrated screening: combines information from the first and second trimesters
• Quad screening: information from a blood draw during the second trimester

What can maternal serum screening show? / What does a maternal serum screen look for?

Maternal serum screening looks for the following conditions:

• Down syndrome (trisomy 21)
• Edwards syndrome (trisomy 18)
• Neural tube defects (birth defects of the brain, spine or spinal cord, including spina bifida)

Other than neural tube defects, maternal serum screening cannot predict whether a birth defect, such as a heart defect, will be present at a future ultrasound.

How is maternal serum screening performed?

Genetic specialists perform maternal serum screening through non-invasive ultrasound and maternal blood tests. The blood tests analyze certain hormones produced by the placenta and the fetus that are present in the mother’s blood. You doctor will also perform an ultrasound to collect a nuchal translucency (NT) measurement, which measures the amount of fluid present at the back of a baby’s neck. A large NT (greater than 3 millimeters) increases the risk for genetic syndromes, heart defects or other birth defects.

When can I have a maternal serum screen?

We perform maternal serum screening in the first or second trimester, and sometimes in both.

How long will results from a maternal serum screen take?

Results from a maternal serum screen are typically available within 7 days.

What are the risks of a maternal serum screen?

Because this screen is non-invasive, there are no risks to mother or baby outside of the risks of a normal blood draw and ultrasound. This means that the risk is very low.

How are maternal serum screening results interpreted?

Maternal serum screening tests determine if a pregnancy is at an increased risk for a given condition.

• A negative (normal) screening result shows reduced risk for a pregnancy to be affected by a genetic condition. However, it does not eliminate the chance, meaning that there is a small risk for a false negative result.
• A positive (abnormal) screening result indicates that there is increased chance for the pregnancy to be affected by a genetic condition or neural tube defect.

What if results from my maternal serum screen are abnormal?

In the case of a positive (abnormal) screening result, we will guide you through the results and discuss next steps. Typically, we recommend further evaluation, including a detailed, level two ultrasound. Your genetic counselor will also review diagnostic testing options including chorionic villus sampling (CVS) and amniocentesis (continued below).

All people are carriers for different genetic conditions. A carrier is someone who has a genetic mutation (abnormal variation) in one of their two copies of a particular gene, which are located on our chromosomes. A carrier of a genetic condition typically does not have any signs or symptoms of a disease because they have one working copy of their two genes.

When both parents are carriers for the same genetic syndrome, each parent can pass on their mutated (non-working) gene to the child. This means that the child has no working copies of that specific gene, which causes symptoms of a genetic syndrome. There is concern for the pregnancy when both the mother and her partner are carriers of a particular genetic syndrome, because the chances of the child inheriting the syndrome are much higher.

Carrier screening can help an individual or couple determine if they are carriers of a recessive genetic disease such as cystic fibrosis. (About 1 in 25 people are a carrier for cystic fibrosis.) The results provide information about your reproductive risk and whether you might have a higher chance of having a child with a genetic condition. If your reproductive risk is higher, you may require additional care during pregnancy.

What are the chances of a carrier couple having a child with a genetic syndrome?

If both a woman and her partner are carriers for the same recessive condition, each child has a 1 in 4 (25%) chance of having the condition.

Some less common genetic syndromes, which have more complex patterns of inheritance, may have a higher or lower risk than 1 in 4. Your genetic counselor will review this information in detail if you are a carrier for one of these syndromes.

Some couples have a higher chance of being carriers for the same condition, including those of certain ethnic backgrounds, those who share a common ancestor or those who have a family history of a genetic condition.

What does a carrier screen look for?

Carrier screening can help genetic counselors determine if there is a higher chance that a child will be born with certain recessive genetic syndromes like the following (and many others):

• Cystic fibrosis
• Spinal muscular atrophy (SMA)
• Fragile X syndrome
• Tay-Sachs disease
• Sickle cell disease

How is carrier screening performed?

We can perform carrier screening before or during pregnancy. Some parents may decide to have carrier screening as part of their family planning. (For example, if they have a personal or family history of genetic defect or condition, such as a heart defect.) Others may opt to receive carrier screening during pregnancy.

To perform a carrier screening, our genetic counselors will collect a blood sample from either mom or dad, or both.

When can I receive carrier screening?

Carrier screening is available before or during pregnancy to help determine if a couple has a higher risk of having a child with certain genetic conditions.

How long will results from a carrier screen take?

Results from a carrier screen are usually available 14 to 21 days after your visit and blood draw.

What are the risks of a carrier screen?

Because carrier screening is non-invasive and performed after a normal blood draw, the risk is very low.

How are carrier screening results interpreted?

Carrier screening can determine if a mother (or a couple) has an increased risk of their children inheriting some genetic conditions.

• A negative (normal) carrier screening result means that a mother’s (or couple’s) risk of having a child born with certain genetic conditions is greatly reduced. However, it does not eliminate the risk.
• A positive (abnormal) carrier screening result indicates that there is increased chance for the child to inherit a genetic condition. If your result is positive, we often recommend additional testing for your partner to determine if they are also a carrier of the same genetic syndrome. This provides the most accurate estimate of your risk of having a child with a genetic syndrome.

Carrier screening does not provide information about risk for chromosome conditions, such as Down syndrome, or adult-onset conditions, such as Alzheimer’s disease. If you are concerned about your risk for a chromosome condition in your pregnancy, you may consider cell-free DNA screening or maternal serum screening in addition to carrier screening.

What if my carrier screening results are abnormal?

If results show your children are at an increased risk, a genetic counselor can help you understand your results and discuss your reproductive options. These options may include assisted reproductive technologies, prenatal diagnosis through chorionic villus sampling (CVS) or amniocentesis, or guidance in preparing for the birth of a child with a genetic condition.

Doctors use CVS to determine if a baby has a chromosome problem or specific genetic condition. A CVS procedure cannot test for all genetic conditions or birth defects. This test is available to all pregnant women. However, it is often performed when an increased risk for a health problem in the baby is identified based on family history or ultrasound findings.

How is CVS performed?

During CVS, your doctor will collect a small sample of the placenta, called the chorionic villi, using a small needle and ultrasound guidance. The CVS sample is typically genetically identical to the baby.

After collecting the chorionic villi, we will perform karyotype and microarray genetic testing on the tissue. These tests are described in greater detail below.

When can I have a CVS test?

A CVS is usually performed between 11- and 14-weeks’ gestation. Some doctors may prefer to wait until 12 weeks’ gestation. (This is earlier than an amniocentesis.)

What are the benefits of a CVS test?

Results from CVS testing may provide additional information about the health of your baby. This can help families and doctors with:

• Understanding why a birth defect is present
• Guiding medical management both during pregnancy and after birth
• Making decisions about carrying a pregnancy to full term
• Preparing for the birth of their child

What are the risks of CVS?

There is a risk of complications from this CVS, including bleeding, infection, rupture of membranes and miscarriage. The risk of a miscarriage is estimated to be less than 1 in every 400 procedures (less than 1%).

There is also a small risk of an inconclusive test result, which may require follow-up with an amniocentesis. For example, in a small number of cases, the genetic information in the placenta may not match the genetic information of the baby. A genetic counselor will discuss risks, benefits and limitations of CVS with you in more detail.

What should I expect during the CVS procedure?

While the appointment will last about an hour, the procedure takes less than 10 minutes to perform.

Using ultrasound guidance, your doctor will perform CVS through either the abdomen (called transabdominal) or the cervix (called transcervical).

• In a transabdominal CVS procedure, your doctor will insert a needle through the abdomen and uterus into the placenta. They use the needle to collect some of the placental cells for genetic testing.
• In a transcervical CVS procedure, your doctor will insert a thin plastic tube called a catheter through the vagina and cervix to reach the placenta. They then use a needle to collect some of the placental cells for genetic testing.

You may feel some pain or cramping when the doctor inserts the needle or catheter.

Your care team will provide detailed instructions about how to care for yourself following this procedure. You should avoid lifting more than 25 pounds for 24 hours after the procedure.

How long will it be before I receive results from a CVS?

Preliminary results for trisomy 13, trisomy 18, trisomy 21 (Down syndrome) and the sex chromosomes are usually available within 48 to 72 hours of the procedure.

Final testing results from the karyotype and microarray (see below) are usually completed within 2 to 3 weeks.

If your genetic counselor recommends specialized testing, such as sequencing, results may take as long as 4 to 6 weeks.

Most commonly, amniocentesis is used to determine if a baby has a chromosome problem, specific genetic condition or viral infection while in utero. An amniocentesis cannot test for all genetic conditions or birth defects.

Amniocentesis is available to all pregnant women. However, it is most often performed when there’s an increased risk for the baby to have a health problem based on family history or ultrasound findings.

How is amnio performed?

During an amnio, your doctor will use a small needle with ultrasound guidance to collect a small sample of the amniotic fluid that surrounds the baby. This fluid contains skin cells from the developing baby, which are used for the genetic testing.

After collecting the amniotic fluid, we will perform karyotype and microarray genetic testing on the tissue. These tests are described in greater detail below.

When can I have an amniocentesis?

We can perform an amnio after 16 weeks’ gestation.

What are the benefits of amnio?

Like a CVS procedure, amnio testing may provide additional information about the health of your baby. This can help families and doctors with:

• Understanding why a birth defect is present
• Guiding medical management both during pregnancy and after birth
• Making decisions about carrying a pregnancy to full term
• Preparing for birth

What are the risks of amniocentesis?

There is a risk of complications from this procedure, including bleeding, infection, rupture of membranes and miscarriage. The risk of a miscarriage is estimated to be less than 1 in every 900 procedures (less than 1%).

There is also a small risk of an inconclusive test result, which may require follow-up with a second amniocentesis. A genetic counselor will discuss the risks, benefits and limitations of this test in more detail.

What to expect during an amnio

Though the appointment will last about an hour, the procedure takes less than 5 minutes to perform.

Using ultrasound guidance, your doctor will determine the safest place to insert a thin needle through the abdomen and uterus into the amniotic sac to collect the amniotic fluid. Some women may feel pain or cramping and pressure in the lower abdomen when the doctor inserts the needle. Others report no pain or discomfort.

Your care team will provide detailed instructions about how to care for yourself following this procedure. In general, you should avoid lifting more than 25 pounds for 24 hours after the procedure.

How long will it be before I receive results from an amniocentesis?

Preliminary results for trisomy 13, trisomy 18, trisomy 21 (Down syndrome) and the sex chromosomes are usually available within 48 to 72 hours of the procedure.

Final testing results from the karyotype and microarray (see below) are usually completed within 2 to 3 weeks.

If your genetic counselor recommends specialized testing, such as sequencing, results may take as long as 4 to 6 weeks.

After performing a CVS or amnio, our genetic specialists will perform one or more of the following genetic tests to help determine a diagnosis. Different tests allow us to detect different genetic changes.

While karyotype and microarray testing are performed after every CVS or amnio, sequencing may not be appropriate for every pregnancy.

Karyotype testing

We perform a karyotype for all CVS or amniocentesis procedures. This test allows us to count the number of chromosomes present under a microscope and determine whether there are structural changes. These changes can include large deletions or duplications, or pieces of chromosomes that have swapped positions.

What can karyotype testing detect?

Examples of genetic conditions that a karyotype can detect include:

• Extra or missing chromosomes, such as Down syndrome
• Balanced translocations in which pieces of chromosomes have switched positions but have not lost or gained genetic information
• Unbalanced translocations in which pieces of chromosomes have switched positions and have also lost or gained genetic information
• Ring chromosomes in which a chromosome in shaped like a ring instead of it’s usual string-like appearance

Microarray testing

A microarray gives us a more detailed look at the composition of the chromosomes than a karyotype.

A microarray looks for small deletions and duplications that cannot be seen under a microscope. Essentially, this test can detect missing or extra instructions for our body.

What can microarray testing detect?

Some examples of genetic conditions a microarray can detect include:

• DiGeorge syndrome (22q11.2 deletion)
• Prader-Willi/Angelman syndrome (15q11.2-q13 deletion)
• Wolf-Hirschhorn syndrome (4p deletion)
• Williams syndrome (7q11.2 deletion)

Genetic sequencing

Sequencing is a specialized test that closely examines our genes rather than chromosomes, which carry our genes.

Genes are composed of a series of letters that need to be in a specific order for our bodies to understand their instructions. Sequencing scans along a gene to determine if there are any changes to these letters, called variants or mutations, which may cause a specific syndrome. Because there are more than 20,000 genes in our body, sequencing may involve analyzing all or just some of these genes.

This test quickly becomes complex. Your genetic counselor will help determine if sequencing is the right choice for your pregnancy. They will also determine what gene(s) may be appropriate for sequencing.

What can genetic sequencing detect?

We use sequencing to determine whether a baby has genetic syndromes such as:

• Noonan syndrome
• Achondroplasia
• Cystic fibrosis

Genetics, the study of genes, is a complex and every-changing field of medicine. At Children’s Colorado, our genetic counselors are available to guide you through prenatal genetic testing and answer any questions you may have.

We also recommend the following resources to help you learn more about genetics and genetic conditions:

• Talking glossary of genetic terms from the National Institutes of Health
• Rare disease guide for patients and families from the Genetic and Rare Disease Information Center
• My Family Health Portrait, a tool for collecting family health history, from the U.S Surgeon General