Ideally, pre-pregnancy planning is recommended where there is a family history of a genetic disorder. It is better if we can establish family relationships and confirm diagnosis prior to pregnancy. This allows the team time to establish if the patient:

1. is at risk
2. if they are at risk whether there is any testing the medical team can offer in current or future pregnancies

Those who are not at risk can be reassured and discharged. We understand that the National Centre for Medical Genetics (NCMG) waiting list is long and frustrating for our patients, referrers, and NCMG staff. This sometimes leads to a pregnancy occurring prior to us being able to offer genetic counseling and pre-conceptual advice.

Before testing an at-risk individual, ideally, we first need to identify the specific genetic alteration in their affected relative.

Some genetic conditions are caused by common DNA alterations that can be easily screened for. For example, if the affected relative has cystic fibrosis, they can undergo routine genetic testing of a panel of common disease-causing alterations in the cystic fibrosis gene to identify which specific genetic alteration they have. Once clarified that the affected relative has a common DNA alteration, we can offer genetic testing to the couple considering pregnancy or confirm whether or not they carry the family genetic disorder.

Confirming diagnoses in relatives can take time - consent is often required. We understand it may not be easy to get the consent of diagnoses from close relatives. If the at-risk patient is already pregnant it may not be possible to establish risks or offer genetic testing as there may not be enough time to gather consent and the necessary information.

However, for other disorders (e.g. Duchenne muscular dystrophy), the genetic alterations which cause the condition may be unique to the particular family and may not be identified during routine genetic testing. In this instance, further work is required to identify the specific family mutation in the affected relative before establishing carrier status in the pregnant relative.
In order to establish a genetic diagnosis, we need a blood sample from the affected individual.

Genetic reports on parents are only requested where a genetic abnormality is identified in the affected child and there is a risk that it might be hereditary. Note, not all genetic disorders are hereditary. An affected child may have a genetic alteration that was not present in or inherited from either parent but arose for the first time in the affected child. The parents’ samples are analysed and then compared to their child’s. The report will include a comparison of both results.

Whilst routine pre-conceptual genetic testing can take up to 4 months, testing is expediated during an ongoing pregnancy. If there is a known genetic alteration in the family, results can be made available within two weeks during pregnancy. However, if the genetic alteration is not known, there is no guarantee that this will be possible within the time-frame of a current pregnancy. This is why the pre-conceptual referral is so important. There are 23,000 different genes (3,674 known disease genes) and testing for only ~20 is available at NCMG. Therefore many genetic tests are sourced from accredited laboratories abroad. DNA is extracted in NCMG and an aliquot is sent for testing to the foreign laboratory. Some genetic tests take longer than others to complete and for some disorders, there is no genetic testing available.

NCMG co-ordinates prenatal testing for families known to have a genetic disorder. The fetal assessment unit does not request the assistance of NCMG when prenatal testing is carried out because of advanced maternal age. The Genetic counselors co-ordinate approximately 100 prenatal tests for families annually. This number is increasing year on year. Most families are known to us and self refer to access antenatal testing.

Others are referred in pregnancy and we can establish risks in time for a pre-natal test in some cases. The majority of couples opting for testing face a high risk (25% or greater) of recurrence.
The Genetic counselor liaises with the family before testing to ensure a complete understanding of what the testing process entails and how the couple wishes to learn of the result.

The Genetic counselor requests an appointment with one of the three Dublin fetal assessment units based on the date of the patient's last menstrual period (LMP).

As many samples need to go abroad and timing is of utmost importance, all prenatal tests organised by NCMG are performed in Dublin. We aim to get a result back to the couple as soon as possible to allow an option regarding decisions on the rest of pregnancy care and management.

However, up to 25% of requests for prenatal testing to NCMG are for disorders where there is a low recurrence risk (<1% to ~<5%). These requests tend to come from families who have had a child with a severe genetic disorder and the couple cannot contemplate a recurrence.

Most of the pre-natal tests we request are done by chorionic villus sampling (CVS) as this gives a sample that produces good quality DNA that can be extracted speedily. The optimal time to perform this test is between 11-13 weeks.

Antenatal tests carried out before week 11 risk higher rates of maternal cell contamination (MCC) and failure due to sample dissection difficulties. NCMG cytogenetic and molecular laboratories process the CVS samples. A result of an at-risk fetus can be reported back to the couple within 2-3 weeks in most cases.

The cytogenetic laboratory analyses the chromosomal complement of the fetus (termed karyotyping). The main antenatal referral requests to the cytogenetics laboratory come directly from obstetricians because of concerns on antenatal scanning or the sample has been taken for maternal age/anxiety.

The molecular laboratory processes samples for single-gene genetic testing (cystic fibrosis, spinal muscular atrophy, sickle cell anaemia). Whilst the latter three disorders can be analysed locally (they are the most common requests for prenatal testing we handle), we also get requests for testing of other less common genetic disorders.

As we cannot test for all genetic conditions in-house, testing for these conditions takes place in up to 200 different foreign diagnostic laboratories. Samples are couriered with appropriate documentation to avoid delays in customs.

The molecular laboratory also performs Maternal cell contamination testing on all of our pre-natal tests to ensure that the sample that has been tested is derived from fetal DNA, and not from the mother which would give an erroneous result.

The clinical team at NCMG do not get involved with these referrals. NCMG clinical staff coordinates testing for between 30-40 families who have had a previous child with a rare chromosomal anomaly (e.g. unbalanced chromosomal translocation). These require liaison with the cytogenetics laboratory as often special Fluorescent In Situ Hybridisation (FISH) probes are required for the genetic analysis. These are high-risk cases and the analysis is targeted at the familial abnormality- it is not a routine chromosome analysis.

There are some chromosomal disorders where an amniocentesis is preferred to a CVS because of the quality of the chromosome test. We advise the fetal assessment unit accordingly.

• Sometimes the fetal assessment teams will involve us in ongoing pregnancies where abnormalities are identified on a scan or on amniocentesis.
• If the amniocentesis identifies a rare chromosomal anomaly we will see the family and advise of the likely outcomes. We source our information from the latest literature and the patient organisation “Unique” (www.rarechromo.org).
• If the scan identifies a specific genetic disorder (e.g. osteogenesis imperfecta) or an abnormality with a possible genetic explanation we are asked to help meet with the family and discuss possible diagnoses and outcomes.
• If a baby is identified on ultrasound scan to have multiple abnormalities with a normal karyotype but with a likely poor prognosis, then we may be able to “bank” DNA for future analysis. This can be useful for counseling a diagnosis in future pregnancies.
• After the birth of the child with a genetic disorder, follow-up is offered to discuss recurrence risk and options for future pregnancy and management of the wider family.

Ireland has a high birth rate and also has double the liveborn malformation rate of other European countries. The neonatal teams are well experienced in the investigation of babies with malformations. The Clinical Genetics team are asked to see neonates with multiple malformations, to see if we can make a diagnosis that might influence management. Follow up appointments involve discussion on the disorder and possible outcomes. We also discuss:

• Recurrence risk and preventative options including limiting family size, pre-natal testing, ovum or sperm donation, and pre-implantation genetic diagnosis in the future if appropriate.
• Risks to other family members.
• If the child has a disorder where the risk to more distant relatives is high (e.g. chromosomal translocation or X-Linked gene), we do try to help our families disclose this information by providing our patients with information letters or leaflets that they can pass on to the wider family. However, it is the responsibility of the person we see in the clinic to disclose this information to their relatives.
• The at-risk relative just needs to contact our department directly (with the name of the affected patient) and we can organise an assessment. Alternatively, if you are referring to such a case, let us know the name of the affected individual and we will arrange an appointment as soon as possible.
• Where birth defects occur as sporadic events and relatives are not at increased risk, we request couples to inform other family relatives to reassure them.

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