NIPD for single gene disorders
A guide for patients and healthcare professionals
What single gene disorders can NIPD be used to test for?
Currently, NIPD can be used to test for altered genes that are not carried by the mother, but are inherited from the father or have arisen afresh (de novo) at conception, for example achondroplasia, thanatophoric dysplasia and Apert syndrome (ie FGFR alterations). NIPD for these three conditions is currently being offered at the North East Thames Regional Genetics laboratory at Great Ormond Street Hospital (GOSH). For details about these available tests, see our factsheets on skeletal dysplasias and Apert syndrome. To request a test from GOSH, download this form.
This is a constantly changing field, however, and over time NIPD will become available for more single gene disorders. For example, GOSH is developing NIPD for cystic fibrosis cases where the father and the mother carry different altered genes. NIPD for cystic fibrosis to exclude paternal inheritance of the altered gene is available on a research basis – see our factsheet.
There may be some one-off cases that could be tested by NIPD, so it is advisable to discuss individual patient needs as they arise, ideally when planning a pregnancy. The North East Thames Regional Genetics laboratory at GOSH has some experience of developing bespoke tests and may be able to help with these cases or refer you to another laboratory able to help.
It is not currently possible to offer NIPD for conditions where the mother is a carrier of the genetic condition in question. This is because there will be a high background of the mother’s altered gene in her blood. If the fetus has inherited this altered gene from the mother, it is impossible to tell the difference between the maternal and fetal gene.
‘NIPD can be used to test for altered genes inherited from the father or where they have arisen afresh’
How does NIPD for single gene disorders work?
We know that there is a small amount of the baby’s DNA in the mother’s blood. This fetal DNA can be tested for the presence of specific gene alterations that are either inherited from the father, or new alterations that have occurred de novo and are not inherited from either parent. In either of these situations, the mother does not carry the altered gene. This approach can also be applied to recessive inheritance, provided that the parents who are carriers of recessive conditions carry different altered genes. NIPD can then be used to identify whether the fetus carries the paternal alteration or not.
Modes of inheritance
Autosomal dominant disorders: Individuals only need to have one altered copy of a gene in order to develop the condition. Autosomal dominant conditions can be inherited from a parent with the condition, such as neurofibromatosis (NF1). However, at present NIPD can only be done if the alteration is inherited from the father, but not the mother, as it is not possible to distinguish maternal altered DNA from the fetal DNA in the maternal blood sample.
Autosomal recessive disorders: An individual needs to inherit two altered copies of the gene to develop the condition, for example cystic fibrosis. If the parents carry two different alterations for the condition, NIPD can be used to determine if the paternal alteration has been inherited by the fetus. If the fetus does inherit the paternal alteration, an invasive test would be done to determine if the fetus also inherited the maternal alteration, and therefore affected by the condition. If the paternal alteration is not inherited by the fetus, it would not be at risk of developing the condition, although it may be a carrier if it inherits the maternal alteration.
Xlinked disorders: These are conditions where the gene involved is located on the X chromosome, for example Duchenne muscular dystrophy. Males only have one copy of the X chromosome, so a male who inherits the X chromosome with the gene alteration will develop the condition. NIPD can be done to determine fetal sex to inform couples as to the need for an invasive test. If NIPD shows the fetus is male, there is a 50% chance that it will inherit the condition, so an invasive test can be performed to determine if the fetus is affected. If NIPD shows the fetus is female, an invasive test may not be warranted as females are not generally affected with X-linked conditions as they have two copies of the X chromosome. See our guide to fetal sex determination for further information.
De novo alterations: Some conditions occur as a result of a de novo altered gene that occurs in the sperm or the egg that the fetus was derived from (ie neither parent is affected). NIPD can be used to test for de novo alterations because the mother does not carry that alteration. Thus, if ultrasound findings suggest the presence of a condition such as achondroplasia, or if a previous child has a condition caused by an identified de novo alteration, NIPD can be offered.
Who is currently eligible for NIPD for a single gene disorder?
Read through the following scenarios where the eligibility of NIPD would be considered.
“I have seen a patient with abnormalities shown on ultrasound that are suggestive of achondroplasia or thanatophoric dysplasia”
This patient would be eligible for NIPD if the health professional suspected that the abnormalities seen on ultrasound were due to an alteration in the FGFR2 or FGFR3 genes.
“Our first child was born with Apert syndrome due to a de novo altered gene, and we are pregnant again”
As the altered gene has been identified in the affected child, NIPD could be used to test the current pregnancy for the same alteration. Although the risk is low if the alteration in the first child occurred in the egg or sperm from which the fetus developed, alterations can occur in egg- or sperm-making cells, which increases the risk that other eggs or sperm may have the same alteration.
Usually women at high risk of these conditions will already be known to their local genetics department. However, if you suspect that a pregnancy is at increased risk and the family has not been reviewed by a geneticist, it is best to seek advice from your local genetics centre as soon as possible.
‘If the family has not been seen by a geneticist, you can seek advice from your local genetics centre’
What needs to be done?
For pregnancies at risk of recurrence of achondroplasia, thanatophoric dysplasia or Apert syndrome, pregnancy dates must be confirmed by ultrasound scan. For pregnancies with ultrasound findings suspicious of achondroplasia, thanatophoric dysplasia or Apert syndrome, see our factsheets on skeletal dysplasias and Apert syndrome for further information and contact the North East Thames Regional Genetics laboratory at Great Ormond Street Hospital (GOSH). To request a test from GOSH, download this form. Further information on specific genetic conditions is available from the National Genetics and Genomics Education Centre.
What results can be given?
Positive: If NIPD detects a FGFR alteration, the fetus will be affected by the condition specific to the particular alteration that is found. Positive results are highly accurate and can inform clinical management.
Negative: If no FGFR alterations are found, a second sample is usually requested to confirm and run other markers to confirm presence of cffDNA. However, for those women undergoing NIPD for abnormal ultrasound findings, it is possible that there is other underlying pathology.
For ongoing audit and confirmation of test performance, we need to know the outcome of pregnancy and whether or not the NIPD result is confirmed either by a molecular test, radiology or clinical diagnosis.
What about other single gene disorders?
“We are both carriers for cystic fibrosis”
If the parents carry two different altered genes for cystic fibrosis (for example, the mother carries p.Phe508del and the father carries p.R117H), NIPD can be used to determine if the paternal p.R117H alteration has been inherited by the fetus.
If the fetus tests positive for the paternal p.R117H alteration, an invasive test would be done to determine if the fetus also inherited the maternal p.Phe508del alteration, resulting in cystic fibrosis. If the paternal alteration is not inherited by the fetus, it would not be at risk of developing the condition and so an invasive test would be unnecessary, although the fetus may be a carrier if it inherits the maternal alteration.
If both parents carry the same altered gene (eg p.Phe508del), they would not be eligible for NIPD as it is currently not possible to distinguish the maternal DNA from the fetal DNA, but there is much effort being made to resolve this problem.
“My partner has autosomal dominant polycystic kidney disease”
As the altered gene is carried by the father, it may be possible to determine whether the fetus carries the alteration too. If the fetus tests positive for the paternal alteration, it will be affected by the condition. If the fetus tests negative for the paternal alteration, it will not be affected by the condition.
“My patient is pregnant and is a carrier of neurofibromatosis”
This patient would not be eligible for NIPD, as the test can only be used to detect paternally inherited altered genes. NIPD cannot determine whether a fetus has inherited a maternal alteration, as the test cannot distinguish between the fetal DNA and the maternal DNA in the blood sample.
“Can NIPD be used to test for genetic conditions in twin pregnancies?”
NIPD can be used in twin pregnancies to exclude paternally inherited altered genes for either autosomal dominant or recessive conditions. However, if a paternally inherited alteration is detected, an invasive test would be necessary to determine which twin (or both) has inherited the alteration in dichorionic/diamniotic twin pregnancies, unless the condition is associated with distinctive ultrasound findings (such as thanatophoric dysplasia) when ultrasound will be able to determine whether one or both fetuses is/are affected.
NIPD can also be done to exclude male fetuses at risk of serious X-linked conditions. If Y chromosome DNA is detected, and either or both of the twins are shown to be male by ultrasound, an invasive test would be needed to determine whether either or both of the twins are affected by the condition in question.
‘It is currently not possible to distinguish maternal DNA from fetal DNA, but much effort is being made to resolve this’
How are the results given?
The way in which results are given is usually discussed before the test is carried out.
Results are typically returned within one week and will be given to the woman by a genetic counsellor, midwife or other healthcare professional so that the appropriate ongoing care can be planned.