Prenatal Testing:

GENETIC TESTS PERFORMED BEFORE OR VERY EARLY

IN PREGNANCY

 
 

Genetic carrier screening is now recommended to all couples before or very early in pregnancy to see if they are carriers of particular genetic conditions that can affect their future children. Whilst some ethnic groups are more likely to carry some genetic changes, carrier screening is now recommended regardless of ancestry. This testing usually only needs to be done once in a couple’s reproductive years as results will be applicable to all future pregnancies. Most babies born with these genetic conditions have no known family history of the condition. That is, the parents did not know that they were carriers of the same condition (recessive carriers).

Genetic Carrier screening can be done for just a few conditions, or part of an expanded panel of over 100 conditions. If you are not a carrier of these conditions, you are at very low risk of having a child with any of these conditions. It is important to know that the current carrier tests detect the majority of carriers, but they cannot detect every single gene change that can cause these conditions.

The three most common conditions which are tested are Cystic Fibrosis (CF), Fragile X Syndrome (FRAX) and Spinal Muscular Atrophy (SMA).  The combined test, called “Prepair” costs approximately $385.00 and you will be billed directly by the laboratory, Victorian Clinical Genetic Service (VCGS). These types of genetic tests are unfortunately not rebatable under the current Medicare scheme. If your test is positive for any one of these conditions then your partner can be tested for the single relevant condition at a cost of $220.00 (which is also not rebatable). If you or your partner are found to be carriers of CF, SMA or FRAX, I will organise immediate genetic counselling so you can be advised about your risks and options for further testing. Results take approximately 10 working days and I will contact you directly with the results.

HERE IS A BRIEF DESCRIPTION OF THESE THREE MAIN CONDITIONS TESTED:

 
 

Cystic fibrosis (CF) is an inherited condition affecting breathing and digestion and affects approximately 1 in 2500 babies. One in 25 Caucasians are carriers of CF. CF causes thick mucus which traps bacteria, resulting in recurrent infections that damage the lungs. Thick mucus in the gut also makes digestion of food difficult. Infants and children with CF require daily chest physiotherapy to clear mucus from their lungs, frequent courses of antibiotics, and the need to take medicine to aid digestion. Until recently many children with CF died in early childhood but now many live to be 30, 40 or more. There is no cure for cystic fibrosis but better treatments are under research and development. The gene that causes CF is called CFTR.

The test from VCGS will detect about 90% of people who are carriers of cystic fibrosis. If the tests show that you have one copy of a CFTR gene change (mutation) for cystic fibrosis, then you are a carrier of this condition – but a couple is only at risk of having a child with CF if both parents are carriers of the condition. Carriers do not show any symptoms of CF but if you are a carrier of this condition your partner will be offered testing to clarify the risks for your future children.

Fragile X syndrome (FRAX) is the most common cause of inherited intellectual disability affecting around 1 in 4000 babies. Approximately 1 in 150 people are carriers of FRAX. People with FRAX can have developmental delay, learning difficulties, anxiety, autism and epilepsy. The features of FRAX vary from mild to severe with males more likely to be severely affected than females. Some, but not all females can also be severely affected. There is no cure for FRAX although some educational, behavioural and medical interventions can improve outcomes. Some females who are carriers of FRAX may have early menopause.

Fragile X syndrome is caused by an increase in the length of a particular gene known as the FMR1 gene, located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. The Fragile X carrier test will tell whether you carry a change on your X chromosome, called a premutation. Women who carry a premutation may have a child with FRAX, but it is not certain. The VCGS test will detect about 97% of people who are carriers of FRAX. It is recommended that the female member of the couple is screened first with this combined test as FRAX testing is not necessary for the male partner. Female premutation carriers have a 1 in 2 chance of passing that X chromosome down, so if the female is a carrier, further investigation of the pregnancy is available to determine if the pregnancy will have Fragile X syndrome. Males can be FRAX carriers, but they cannot have a child with Fragile X syndrome. A male carrier’s daughters will all be FRAX carriers too, and they could be at risk of having children affected with FRAX in the future.

Spinal muscular atrophy (SMA) affects approximately 1 in 6000 babies. One in 40 individuals are carriers for SMA. There are two genes which cause SMA, called the SMN1 and SMN2 genes. SMA is a condition that effects nerves in the spinal cord and causes muscles to get weaker. There are four types of SMA. SMA Type I is the most severe. Babies with SMA Type I have weak muscles from birth and usually do not live past two years of age. SMA Types II and III progress more slowly than Type I. Most children with SMA Types II or III are unable to stand or walk without help. Children with Types II and III SMA can live into early adulthood, depending on the severity of the condition. People with SMA Type IV do not develop symptoms until adulthood.  There is no cure for SMA, however there are treatments and interventions available aimed at managing symptoms and improving quality of life.

The VCGS test will detect about 97% of people who are carriers of SMA. If the tests show that you have one copy of the gene change for spinal muscular atrophy, then you are a carrier of this condition – but a couple is only at risk of having a child with SMA if both parents are carriers of the condition. Carriers of SMA do not show any symptoms of the condition but if you are a carrier of this condition your partner will be offered testing to clarify the risks for your future children.

If you’d like to discuss these options further, I recommend you contact a genetic counsellor at Genetic Clinics Australia on 9528-1910 or www.geneticclinic.com.au. This is particularly important if you and your partner are related. If you have any Jewish ancestry, I recommend you contact Genetic Clinics Australia to find out which tests are most appropriate for you, such as Tay Sachs disease testing.

 

 
 

Prenatal tests performed

at various stages throughout pregnancy

It is not possible to test pregnancies for every possible problem or medical condition but there are some conditions which can be detected during pregnancy. These include:

 
 

Down syndrome (trisomy 21) is a condition in which an extra chromosome 21 is carried in each of the cells of the body. Instead of the normal 46 chromosomes there are a total of 47 chromosomes. The extra chromosome 21 results in intellectual disability of varying degrees and may cause problems with the heart, kidneys, bowel, eyesight or hearing.

Although the chance of having a baby with Down syndrome increases with the mother’s age, babies with Down syndrome can also be born to younger mothers.

The following table indicates the risk of having a baby born with Down syndrome. The risk estimation is based on the age of the mother at the expected time of delivery.

Maternal Age Risk of baby being born with Down Syndrome
25 1 in 1302
30 1 in 895
35 1 in 356
37 1 in 220
40 1 in 97
41 1 in 73
42 1 in 41
45 1 in 10

Fragile X syndrome (FRAX) is the most common cause of inherited intellectual disability affecting around 1 in 4000 babies. Approximately 1 in 150 people are carriers of FRAX. People with FRAX can have developmental delay, learning difficulties, anxiety, autism and epilepsy. The features of FRAX vary from mild to severe with males more likely to be severely affected than females. Some, but not all females can also be severely affected. There is no cure for FRAX although some educational, behavioural and medical interventions can improve outcomes. Some females who are carriers of FRAX may have early menopause.

Fragile X syndrome is caused by an increase in the length of a particular gene known as the FMR1 gene, located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. The Fragile X carrier test will tell whether you carry a change on your X chromosome, called a premutation. Women who carry a premutation may have a child with FRAX, but it is not certain. The VCGS test will detect about 97% of people who are carriers of FRAX. It is recommended that the female member of the couple is screened first with this combined test as FRAX testing is not necessary for the male partner. Female premutation carriers have a 1 in 2 chance of passing that X chromosome down, so if the female is a carrier, further investigation of the pregnancy is available to determine if the pregnancy will have Fragile X syndrome. Males can be FRAX carriers, but they cannot have a child with Fragile X syndrome. A male carrier’s daughters will all be FRAX carriers too, and they could be at risk of having children affected with FRAX in the future.

Spinal muscular atrophy (SMA) affects approximately 1 in 6000 babies. One in 40 individuals are carriers for SMA. There are two genes which cause SMA, called the SMN1 and SMN2 genes. SMA is a condition that effects nerves in the spinal cord and causes muscles to get weaker. There are four types of SMA. SMA Type I is the most severe. Babies with SMA Type I have weak muscles from birth and usually do not live past two years of age. SMA Types II and III progress more slowly than Type I. Most children with SMA Types II or III are unable to stand or walk without help. Children with Types II and III SMA can live into early adulthood, depending on the severity of the condition. People with SMA Type IV do not develop symptoms until adulthood.  There is no cure for SMA, however there are treatments and interventions available aimed at managing symptoms and improving quality of life.

The VCGS test will detect about 97% of people who are carriers of SMA. If the tests show that you have one copy of the gene change for spinal muscular atrophy, then you are a carrier of this condition – but a couple is only at risk of having a child with SMA if both parents are carriers of the condition. Carriers of SMA do not show any symptoms of the condition but if you are a carrier of this condition your partner will be offered testing to clarify the risks for your future children.

If you’d like to discuss these options further, I recommend you contact a genetic counsellor at Genetic Clinics Australia on 9528-1910 or www.geneticclinic.com.au. This is particularly important if you and your partner are related. If you have any Jewish ancestry, I recommend you contact Genetic Clinics Australia to find out which tests are most appropriate for you, such as Tay Sachs disease testing.

Fragile X syndrome (FRAX) is the most common cause of inherited intellectual disability affecting around 1 in 4000 babies. Approximately 1 in 150 people are carriers of FRAX. People with FRAX can have developmental delay, learning difficulties, anxiety, autism and epilepsy. The features of FRAX vary from mild to severe with males more likely to be severely affected than females. Some, but not all females can also be severely affected. There is no cure for FRAX although some educational, behavioural and medical interventions can improve outcomes. Some females who are carriers of FRAX may have early menopause.

Fragile X syndrome is caused by an increase in the length of a particular gene known as the FMR1 gene, located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. The Fragile X carrier test will tell whether you carry a change on your X chromosome, called a premutation. Women who carry a premutation may have a child with FRAX, but it is not certain. The VCGS test will detect about 97% of people who are carriers of FRAX. It is recommended that the female member of the couple is screened first with this combined test as FRAX testing is not necessary for the male partner. Female premutation carriers have a 1 in 2 chance of passing that X chromosome down, so if the female is a carrier, further investigation of the pregnancy is available to determine if the pregnancy will have Fragile X syndrome. Males can be FRAX carriers, but they cannot have a child with Fragile X syndrome. A male carrier’s daughters will all be FRAX carriers too, and they could be at risk of having children affected with FRAX in the future.

 
 

HOW RELIABLE ARE THESE TESTS?

 

Sensitivity: the reliability of a test depends on its ability to detect a problem if it is there: this is known as the sensitivity of the test. This means that a test with 100% sensitivity will detect a problem every single time it is there, but if the sensitivity is 70% only 7 out of 10 babies who have this problem will be detected by this test.

False positives: the other important factor to consider in assessing the reliability of the test is the false positive rate. A test is considered to give a false positive result if it suggests there is a problem with the baby that is subsequently shown not to be there at all. Ideally a test would have a 0% false positive rate but in practice some positive results are incorrect.

 
 

 

OPTIONS FOR PRENATAL TESTING

 
 

Some people choose to do no additional prenatal testing at all. Perhaps the risk of these conditions are considered to be low, or because termination of pregnancy would not be considered under any circumstances. This is a completely appropriate decision that is entirely yours to make. I would still recommend routine pregnancy blood tests and a 20 week ultrasound, which we can discuss at your appointments.

Nuchal translucency (NT) scan (Between 11 and 14 weeks)

All babies have a small amount of fluid under the skin at the back of the neck. An excessive amount of fluid in this area is associated with a higher chance of having a baby with Down syndrome or other abnormalities such as heart or kidney problems. This amount of fluid can be measured by ultrasound and is called nuchal translucency, nuchal oedema or nuchal fold. If there is an excessive amount of fluid then further investigations will be recommended, usually in the form of invasive testing, such as a CVS. An ultrasound at this stage also has additional benefits including very accurate dating of the pregnancy, diagnosis of multiple pregnancy and the detection of many unrelated physical abnormalities. In most instances this ultrasound is done as an abdominal scan but if the area on the back of the neck cannot clearly be seen then a vaginal ultrasound will be recommended. Of course, you have the option to decline this type of examination if you prefer. In expert hands this technique has a sensitivity rate of 70% for detection of Down syndrome. The false positive rate is 5%. Most babies with an increased nuchal translucency are completely normal.

Non-invasive prenatal testing (NIPT):

Several non-invasive prenatal genetic tests are available, which all test a maternal blood sample from 10 weeks of pregnancy. These tests analyse fetal DNA found in the mother’s blood to detect Trisomy 21, Trisomy 18, Trisomy 13 and Turner syndrome and are alternatively referred to as cell free DNA tests. The test is >99% sensitive for the detection of these trisomies, and 92% sensitive for the detection of Turner syndrome. NIPT is known by several different names – the two most common are Harmony and Percept. I recommend all my patients consider NIPT as it is the best, non-invasive screening test for Down syndrome available.

Combined first trimester screening:

 

The combined first trimester test for Down syndrome involves combining the results of the nuchal translucency scan with the results of a blood test performed prior to the ultrasound. The combined first trimester test is specifically directed at detecting Down syndrome and Edward syndrome. Results of this testing are reported as low risk or increased risk. Increased risk results do not mean there is something wrong with the baby, just that additional testing can be performed to clarify the result. The sensitivity for detection of Down syndrome is over 90%. The false positive rate for this test is approximately 5%. Most babies with an increased risk on the combined first trimester test are completely normal.

 

Maternal serum screening (MSS):

Maternal serum screening is a blood test for pregnant women to determine if they may be at risk of having a baby with Down syndrome, Edward syndrome or a neural tube defect. This test does not diagnose these conditions but identifies women who could be offered further testing such as ultrasound or amniocentesis. The results are usually available within one week and will be reported as low risk or high risk for each of these conditions. Low risk means that the risk of having a baby with Down syndrome, Edward syndrome or a neural tube defect is very low. High risk means that there is an above average risk of having a baby with one of these conditions but it does not necessarily mean that there is a problem with your unborn baby. It means that further tests should be considered to see if there is a problem. It is important to remember that most women with a high risk will go on to have a normal baby. The sensitivity of maternal serum screening for detection of Down syndrome is 80%. The sensitivity of maternal serum screening for detection of neural tube defects is more than 80%. The false positive rate for this test is 5% for each condition. While this test is Medicare funded, it is not the most accurate screening test for Down syndrome available and so I do not recommend it.

Chorionic villus sampling (CVS)

Chorionic villus sampling or CVS involves passing a needle into the placenta between 10 and 13 weeks gestation. A small amount of placental tissue is taken and a chromosome analysis is then performed by the pathology laboratory. Results take approximately ten working days to become available. Some ultrasound centres will offer you the option of FISH testing. This is a very rapid test for Down syndrome with the result being available the following day at an additional cost. Further details of the actual procedure will be given to you if this is the option you choose. The sensitivity of CVS detection of Down syndrome is virtually 100%. The only exception would be a technical problem growing the placental cells in the laboratory. In these circumstances an amniocentesis may be required later in pregnancy but this is exceptionally unlikely. The risk of miscarriage from the procedure itself is 0.2%. You must remember that there is a risk of spontaneous miscarriage at this gestation of approximately 2%. The total risk is therefore 2.2% although only a small proportion of this risk of miscarriage is actually as a result of the CVS test. The false positive rate for detection of Down syndrome is 0%.

 

Amniocentesis:

Amniocentesis involves taking a small sample of amniotic fluid from around the developing baby at approximately 16 weeks gestation. Only a small amount of fluid is taken but this is enough for a full chromosome analysis to be performed. Results take approximately ten working days to become available. Some ultrasound centres will offer you the option of FISH testing. This is a very rapid test for Down syndrome with the result being available the following day at an additional cost. The risk of miscarriage from the procedure itself is approximately 0.1%. The risk of spontaneous miscarriage at this gestation is 0.5%. The total risk from the procedure and spontaneous miscarriage is 0.6%. The sensitivity of amniocentesis for detection of Down syndrome is virtually 100%. As with CVS, there may be a technical failure to grow the cells in the laboratory but this is extremely uncommon. The false positive rate for detection of Down syndrome is 0%.

 

This table summarises the sensitivity, false positive rates and risk of each test mentioned above.

Test Weeks pregnant Detection of Down Syndrome False positive rate Risk from the test
No test N/A 0% 0% 0%
NT test 12 to 13 70% 5% 0%
NIPT >10 99.9% 0% 0%
Combined first trimester test 12 to 13 90% 5% 5%
MSS 14 to 19 80% 5% 0%
CVS 10 to 13 100% 0% 0.5% to 1.0%
Aminocentesis 15 to 19 100% 0% 0.5%
 

 

SUMMARY

 
 

There is now a bewildering array of tests available during pregnancy and thinking about these types of tests can be quite confronting as they can detect some serious medical conditions in a baby.

It is important to realise that by having any of these tests there is no assumption that you will terminate a pregnancy should it be affected. Please be assured that if there is a serious condition detected, I will support informed decision making and perform a termination of pregnancy, if requested.

Please do not hesitate to clarify any of these issues with me if they are unclear. I can arrange for you to see a genetic counsellor if you would like more information. Genetic Counsellors are trained to help people understand the various genetic testing options available, coordinate testing, and to assist with decision making around the results.