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 (FXS) and Spinal Muscular Atrophy (SMA). The combined test, called “Prepair” is now fully rebatable through Medicare. If you or your partner are found to be carries of CF, SMA or FXS, 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 these results.

An alternative to the above is a more extensive panel - available through Eugene Labs: https://eugenelabs.com/carrier Eugene offers an end-to-end service including screening of up to 700+ genetic conditions (including CF, SMA and FXS). The expanded disease list makes this test relevant for people of all ethnicities and backgrounds (including, but not limited to, Jewish, Mediterranean, Asian and Caucasian populations). Genetic counselling is provided on-line both before and after the test so you can make reproductive choices based on the results. The all-inclusive cost for couples screening is $ 949.00 but results take 6-8 weeks. Alternatively the extended comprehensive test for couples is $ 1399.00 and results are available in around 4 weeks. If you are already pregnant I highly recommend the comprehensive carrier screening for couples to ensure results are complete within a timely manner. Expanded carrier screening tests are unfortunately not rebatable under the current Medicare scheme.

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.

  • Edward syndrome (trisomy 18) is a very serious condition in which an extra chromosome 18 is carried in each of the cells of the body. This condition occurs much less often than Down syndrome. Most pregnancies affected by Edward syndrome will miscarry. Those that continue may have a baby affected with serious heart, kidney or lung problems, which sadly do not survive very long. Many of the features of Edward syndrome may be apparent on ultrasound examination at 12 or 20 weeks. Like Down syndrome, the risk of Edward syndrome increases with maternal age.

  • The most common neural tube defects are spina bifida and anencephaly. Babies with spina bifida have an opening in the bones of the spine which may result in damage to the nerves controlling the lower part of the body. This can cause weakness and paralysis of the legs and sometimes inability to control the bowel and the bladder. In anencephaly, the brain does not develop properly and the baby will not survive. Around 1 in 750 pregnancies are affected by a neural tube defect if the mother has not been taking folate around the time of conception. This risk is dramatically reduced, although not completely eliminated, by taking folate.

  • Turner Syndrome is a condition where a girl inherits just one X chromosome instead of two, called monosomy X. Females with Turner syndrome therefore have only 45 chromosomes in every cell of their body, instead of the usual 46 (23 from each parent). Turner syndrome affects approximately 1 in 2000 girls born in Australia. There is great variability in the symptoms of Turner syndrome. Some girls with Turner syndrome are not diagnosed until puberty, while others might be symptomatic from birth. Many pregnancies with Turner syndrome will actually result in miscarriage. Characteristics of Turner syndrome in girls include short stature (~20cm shorter than average), infertility and oedema (swelling), which can sometimes be evident on ultrasound during pregnancy. The average intellectual performance of girls with Turner syndrome is usually within the normal range. Turner syndrome is not affected by increased maternal age, and can be a result of abnormal egg or sperm development. Girls with Turner syndrome usually have a normal life expectancy.

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.

  • 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%.

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.