About Single Gene Disorders
What is a single gene disorder?
A single gene disorder is a genetic disease caused by a change, or mutation, in a particular gene which causes that gene to function improperly or not at all. Because the gene doesn’t work correctly, it prevents the body from developing normally. Genetic disorders are inherited and passed through families. In many cases, parents are ‘carriers’ of a gene mutation that does not affect their health, but it could put their children at risk of inheriting the disorder.
There are thousands of different single gene disorders, many of them quite rare. Examples of some of the more common single gene disorders include cystic fibrosis, hemophilia, and Tay-Sachs disease.
How do I know if I am a carrier for a single gene disorder?
If you have a family history of a specific single gene disorder, you should discuss carrier testing for that disorder with your physician or genetic counselor. However, even without a known family history, it is possible to be a carrier for a single gene disorder. In fact, most people carry a few recessive gene mutations that do not harm their health but could result in a genetic disease in their offspring. This happens when both parents carry a mutation in the same gene.
There are many laboratories across the U.S. and the world that provide carrier testing for individuals interested in learning more about their risk of having a child with a genetic disease. There are also new carrier screening panels that test for mutations responsible for many genetic diseases at the same time. Seek advice from your physician or genetics professional to learn more about this type of testing.
I am a carrier for a single gene disorder. What is my risk of having a child with the disease?
The risk of having a child with the genetic disease depends on the inheritance pattern of the single gene disorder. Single gene disorders typically follow one of the following inheritance patterns:
- Autosomal recessive
- Autosomal dominant
Below is a brief description of each inheritance pattern. We recommend that you discuss your family history and specific test results with a local genetic counselor or your physician.
- Autosomal recessive disorders are caused by two non-working copies of a gene. Since humans only have two copies of each gene, when a person has an autosomal recessive disorder it means they have no working copies of that gene. For example, cystic fibrosis (CF) occurs when an individual has two non-working copies of a gene called ‘CFTR’; they inherited one non-working copy of the CFTR gene from their mother and one non-working copy of the CFTR gene from their father. In order to be at risk of having a child with an autosomal recessive disorder, a person and their partner must both be carriers of a mutation in the gene that causes that disorder. In almost all cases, carriers of autosomal recessive disorders have no symptoms. A couple in which both partners are carriers for the same autosomal recessive disorder have a 25% chance in each pregnancy of having an affected child.
- Autosomal dominant disorders are caused by one non-working copy of a pair of genes which, by itself, causes the symptoms of the condition. The other copy of the gene works normally. An example of an autosomal dominant disorder is neurofibromatosis (NF). Individuals who are affected by NF have a 50% chance with each pregnancy of passing on their non-working copy of the gene to their offspring who would then develop NF.
- X-linked disorders are more complicated. X-linked disorders involve genes that are located on the X-chromosome. Women have two X-chromosomes, whereas men have one X-chromosome and one Y-chromosome that contains different genes than the X. When there is a non-working copy of a gene on the X-chromosome, women typically show fewer, milder, or no symptoms because they have a working copy of the gene on their other X-chromosome. Men who have a non-working copy of a gene on the X-chromosome are affected, meaning they show symptoms which are often severe because that is the only copy of the gene they have. Examples of X-linked disorders are Duchenne muscular dystrophy and hemophilia.
Women who are carriers for an X-linked disorder have a 50% chance with each pregnancy of passing on their non-working copy, but typically only male offspring will be severely affected. Men who have an X-linked disorder always pass the non-working copy of the gene to their daughters (who will all be carriers for the disorder); their sons will never inherit the condition from them as they always inherit the Y-chromosome from their father.
About PGD For Single Gene Disorders
What is preimplantation genetic diagnosis (PGD)?
Preimplantation Genetic Diagnosis, or PGD, is a specialized laboratory test used during in vitro fertilization (IVF) to test one cell or several cells from an embryo for a specified genetic disease or diseases. Embryos with results showing absence of the particular genetic disease in question are the ones chosen to transfer to the woman’s uterus. This greatly reduces the possibility the baby will have the specific genetic disease.
How do I know if PGD testing can be done for my specific genetic disorder?
With rare exceptions, Natera can test for any inherited disorder in which the parental mutation(s) are known. Testing requires that you undergo IVF to become pregnant. Once Natera receives a referral form from your IVF doctor and a copy of your mutation report, our genetic counselors and lab team will perform an initial assessment of your mutation and family history to determine whether we can develop a test for you.
How is PGD for single gene disorders performed during an IVF cycle?
Natera’s Parental Support technology uses a testing platform called a microarray to test for the presence or absence of the specific single gene mutation(s) in question with the option of also evaluating all 24 chromosomes. PGD is usually performed on Day 3 after fertilization, when a single cell from each embryo is removed, sent to Natera, and tested. The embryos themselves do not travel –they stay at your IVF center. Using a newer biopsy technique, PGS can also be performed on Day 5 by removing and testing a few cells from each embryo.
In either case, embryos are frozen until test results are returned. They are then thawed and transferred in a future frozen embryo transfer (FET) IVF cycle.
Does Natera's Parental Support check to see if the embryos are actually mine?
Yes, because our testing process references genetic data from the parents, we automatically confirm that the embryo cells match the parent samples. In fact, we are unable to issue a report if the biological parents do not match the embryo cells that were sent.
Does the biopsy harm the embryo?
When embryo biopsy is performed on Day 3, all of the cells of the embryo are similar and have not yet separated into different cell types. A single cell called a blastomere is removed for testing. In a Day 5 biopsy, a cluster of two to ten cells is removed from the mass of cells called the trophectoderm, which is the tissue that will become the placenta Removing one cell on Day 3 or several cells on Day 5 for testing does not appear to disrupt or interfere with subsequent fetal development and has not been associated with an increased risk of birth defects. Babies born after PGD that include embryo biopsy have had a similar rate of birth defects as compared to all other babies in the general population.
Embryo biopsy in the absence of PGD has been shown in some studies to be associated with a reduced rate of implantation. However most doctors feel that if the biopsy procedure is correctly performed, aneuploidy screening more than compensates for this reduced rate of implantation resulting in equivalent or better implantation rates.
No other known adverse effects associated with embryo biopsy or PGD have been reported to date. However, as embryo biopsy is still a relatively new procedure the potential for unknown consequences to a live born baby cannot be entirely excluded.
Do I need to have ICSI as part of my IVF cycle to do single gene PGD?
Natera requires that you use intracytoplasmic sperm injection (ICSI) for fertilization during your cycle to eliminate the risk of sperm contamination that can lead to inaccurate single gene PGD results.
Do I need to have prenatal diagnosis (CVS or amniocentesis) if I have PGD?
Prenatal diagnosis in the form of chorionic villus sampling (CVS) or amniocentesis is strongly recommended to people who have PGD. Although highly accurate, PGD is not 100% precise. Although PGD has been performed for years, the technology is still considered investigational.
PGD also cannot detect chromosome mosaicism because testing is typically done on only one cell from the embryo, and mosaicism can only be detected by testing the chromosomes of multiple individual cells. Prenatal diagnosis can confirm that the baby is free of the genetic condition in question, and that the baby’s chromosomes are normal.
Will PGD guarantee a healthy baby?
No. There is a 3-5% chance in any pregnancy of having a child with a birth defect or mental retardation, regardless of any testing performed before or during pregnancy. Many of these conditions are not detectable prior to implantation or even during pregnancy.
About Genetic Testing
What is allele drop out?
Allele drop out (ADO) is the failure to amplify, or copy correctly, part of a gene (allele) during the process of single gene PGD. With PGD testing, DNA from the single cell (or multiple cells) biopsied from the embryo must be amplified many times so that a sufficient DNA sample is available for testing.
With this process, some regions may amplify more or less than others. If the specific single gene mutation or markers surrounding the mutation fail to amplify in a given embryo sample, this could lead to a misdiagnosis. An embryo that appears to have normal results may actually carry a mutation that failed to amplify and “dropped out” or was not seen with testing. ADO is a normal byproduct of the DNA amplification process and affects all types of PGD testing.
What is aneuploidy?
Aneuploidy is a term used to describe an abnormal number of chromosomes. Chromosomes are structures in each cell of the body that carry genetic information, or genes, in the form of DNA. Healthy humans normally have 46 chromosomes arranged in pairs: 22 pairs of ‘autosomes’ and one pair of ‘sex chromosomes’ (XX in females or XY in males) for a total of 24 unique chromosomes (1-22, X, Y).
Aneuploidy occurs by chance and is not inherited. Fetuses born with aneuploidy usually miscarry. In the rare case that a baby is born with aneuploidy, it will have a condition such as Down syndrome.
Why does Natera check for chromosome abnormalities at the same time PGD for a single gene disorder is performed?
Checking for chromosome abnormalities at the same time as testing for a single gene disorder may increase the chance for embryo implantation, decrease the chance for miscarriage, and reduce the chance of having a child with a chromosome abnormality. Natera’s aneuploidy screening can be done as part of single gene PGD or by itself for indications other than single gene risk.
Who should consider PGD for Aneuploidy?
Aneuploidy can occur in any embryo from anyone, just by chance, although some people are at a higher risk. This testing technology is new, so clinical data is still pending, but studies have demonstrated that PGD may be particularly beneficial for:
- Women aged 35 and older
- Couples who have had a previous pregnancy with a confirmed chromosome abnormality
- Couples who have had multiple early miscarriages
Studies of couples who have had more than one miscarriage have shown a higher number of embryos with chromosome abnormalities than expected. Some studies have shown an increased rate of pregnancy, a decreased rate of miscarriage, and an increased rate of live birth following the use of PGD.
Before considering PGD, couples with a history of 3 or more miscarriages are encouraged to have their own chromosomes evaluated for the presence of inherited chromosome rearrangements, which can be done with a blood test. In approximately 5% of couples with recurrent pregnancy loss, one member of the couple is found to have a balanced chromosome rearrangement. A balanced chromosome rearrangement does not affect a person’s health, but it does greatly increase the risk for having chromosomally abnormal embryos, which will likely be lost in early miscarriage. If a chromosome rearrangement is found, there are specialized Preimplantation Genetic Diagnosis (PGD) methods that can be used to analyze embryos for the unbalanced rearrangement.
- Couples who have had previously unsuccessful IVF cycles
Data suggests that aneuploidy rates are higher in the embryos of couples who have experienced repeated IVF cycle failure. Some studies show an increased rate of pregnancy in these couples when PGD is used, although other studies show no clear indication that these couples benefit from PGD. In some couples, there may be reasons other than aneuploid embryos for unsuccessful IVF cycles.
Why can't Natera test for all possible single gene disorders at the same time?
In order to perform PGD for a single gene disorder, Natera must know the exact DNA changes, or mutations, that are responsible for the single gene disorder in the parents. Currently, it is not possible to test for single gene disorders in an embryo if the mutations in the parent(s) are not known ahead of time.
Can Natera test for a single gene disorder and HLA type at the same time?
Yes. In cases where a couple would like to decrease the chances of a specific single gene disorder and also match HLA type with an affected sibling, PGD for both can be performed simultaneously.