Genetic Disorders

Genetic disorders at a glance

• A genetic disorder is a disease caused by a change in the DNA sequence.
• Fertility doctors are primarily concerned with two types of genetic disease in embryos created through in vitro fertilization (IVF): single-gene disorder and an abnormal number of chromosomes.
• Single-gene disorders are caused by a mutation in the DNA code and include cystic fibrosis, sickle cell disease, muscular dystrophy, Huntington’s disease and Fragile X syndrome.
• A genetic disorder caused by an abnormal number of chromosomes occurs when an embryo has an extra chromosome or is missing a chromosome in one of the chromosome pairs.
• Children born with an abnormal number of chromosomes, or chromosomal aneuploidy, are typically born with significant abnormalities such as Down syndrome and Turner syndrome.
• Genetic disorders can be tested for in IVF embryos using preimplantation genetic testing (PGT).

Topic guide

What are the causes of genetic disorders?
Single gene disorders
Chromosomal abnormalities
Preimplantation genetic testing

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What are the causes of genetic disorders?

The two general types of genetic disorders, single gene mutations and those that involve malformation of chromosomes, have different causes.

Single-gene disorders are when there is a certain gene known to cause a disease. According to the National Human Genome Research Institute, these disorders are rare. They are caused when there is a gene mutation in one or both of the parents.

If an embryo has an extra chromosome in one of the 23 chromosome pairs or is missing a chromosome, it is said to have different chromosome copy number or has abnormal chromosomes. Typically, those embryos will not develop into a pregnancy or may grow for a short time but miscarry. However, sometimes this can result in a child born with an intellectual or developmental disability, heart defects, infertility and other health issues.

Another type of genetic disorder caused by abnormal chromosomes is structural rearrangements. These rearrangements are rare in the general population and occur when there is a break in the DNA at two different locations.

Single gene disorders

Single gene disorders, or monogenetic disorders, affect about 2 percent of the population. Humans have two copies of every gene, one from each parent. If an individual has one gene with a mutation and one normal gene, that person is healthy because the normal gene compensates for the abnormal gene. These individuals are called carriers of that specific genetic trait. But when an individual inherits two copies of a mutated gene, one from each parent, they are born with a disease.

This type of genetic disorder, known as a recessive genetic disease, is the most common type of hereditary genetic disease. Examples of recessive diseases are cystic fibrosis, sickle cell anemia, and Thalassemias, a blood disorder. While family history is not helpful, genetic testing can identify if an individual is a carrier and if they are at risk of having a child born with a genetic disease.  Due to advances in DNA technology, more than 200 recessive genetic diseases can be tested in a single blood sample.

When an individual carries just one mutated gene that could cause a disease in his or her offspring, this is known as a dominant genetic disease. In this situation, the disease is passed on from parent to child. In these cases, family history is used to determine who is at risk rather than a screening blood test. There are some instances in which an individual with a dominant genetic disease may not exhibit symptoms of the disorder but can still pass it along to their child. Dominant genetic diseases include dwarfism, Huntington’s disease and Marfan syndrome.

X-linked disease occurs when the gene mutation is on the X chromosome. Humans have two sex chromosomes: males have one X & one Y chromosome, females have two X chromosomes.  For most X-linked diseases, only the males have the disease. Hemophilia is an X-linked disease.

Chromosomal abnormalities

Chromosomal aneuploidy

While all human cells have 46 chromosomes, sperm and eggs undergo a process called meiosis in which the original 23 pairs (46) of chromosomes are split to a new set of 23 single chromosomes. When the egg and sperm fertilize, the embryo receives 23 chromosomes from each, bringing the embryo chromosome number back up to 46.

However, sometimes the egg or sperm cell does not split the chromosomes equally. An embryo containing an abnormal number of chromosomes will also be abnormal. For example, Down’s syndrome is when there are three copies of chromosome 21, bringing the total number of chromosomes to 47.

Because eggs and sperm develop differently, there are also different risks of chromosomal copy number errors in eggs and sperm. New sperm cells are formed throughout a man’s adult life. However, eggs are initially created during fetal life but do not complete the process of meiosis until the egg ovulates and is fertilized by a sperm cell.

As eggs age, errors in splitting the chromosomes occur more frequently. A higher proportion of eggs have an abnormal copy number of chromosomes as a woman gets older. This leads to more abnormal pregnancies, which often end in miscarriage. This is why as women get older it may take a longer time to conceive, there is a higher risk of miscarriage and a higher risk of chromosomal abnormalities.

During pregnancy, prenatal genetic screening is recommended to diagnose chromosomal abnormalities in the fetus. The incidence of chromosomal abnormalities in pregnancy increases with the woman’s age. Prenatal genetic screening includes amniocentesis, chorionic villus sampling, the first trimester screen, including fetal ultrasound and blood tests, and non-invasive prenatal testing (NIPT).

Structural rearrangements

Chromosomal rearrangements encompass duplications, deletions, inversions and translocations. These rearrangements occur when the DNA’s double helices break in two different locations, then the broken ends join together in a new, faulty genetic arrangement.

Preimplantation genetic testing

A major advancement in reproductive health treatment is the ability to test embryos for genetic disease. Preimplantation genetic testing (PGT) can be performed to screen embryos for problems that statistically might be at risk. This tool can help select the highest quality and healthiest embryo.

PGT-A, or PGT for aneuploidies, is used to test embryos for the total number of chromosomes. This type of testing can determine if there is a risk of chromosomal aneuploidy. PGT-A can identify the chance for a child with Down syndrome.

Preimplantation genetic testing for chromosomal structure rearrangements (PGT-SR) identifies chromosomal errors occurring when there is a break in the DNA strands.

In cases when the risk is known to exist based on genetic testing of the parents, PGT for monogenic/single gene defects (PGT-M) is used. In this setting, the genetic testing of the parents prior to an in vitro fertilization (IVF) cycle has identified a problem and the resulting IVF embryos are tested for that specific abnormality as well as the total number of chromosomes via PGT-A.

Recessive genetic carrier screening in patients prior to an IVF cycle will identify the 1-3 percent of couples whom are at risk for having a child born with a genetic disease. Only with this advance testing prior to an IVF cycle, can recessive genetic diseases be identified.

PGT is part of an IVF treatment. It involves the removal of 5-6 cells from a blastocyst-stage embryo, sending the cells to a genetics lab for testing and freezing the embryo. The genetic report takes about one week. Once the report is received, the best normal embryo is identified and a new treatment cycle, called a frozen embryo transfer, is performed. By using PGT, the risk of having a child born with a genetic disease or chromosomal abnormality can be decreased, and the chance of successful pregnancy and birth are increased.

The risk of losing an embryo with the biopsy, freeze and thaw is less than 5 percent. The risk of birth defects when PGT is performed appears to be no higher than that risk when IVF is used to create the embryos. But it is 1-2 percent higher than the birth defect risk with natural conception.

With PGT, the risk of miscarriage is decreased (less than 10 percent) but miscarriages can still occur. The pregnancy rate is 70-75 percent in women under the age of 40. For women over 40 years old, the pregnancy rates decrease to 55 percent. It is thought that genetic factors other than chromosome number also affect the embryo as the egg cell ages.

When PGT is done to screen for chromosome numbers, there is a chance that there will be no normal embryos. Using PGT gives more confidence with the frozen embryo transfer that there will be a live birth of a healthy baby, but there is no guarantee that there will be a normal embryo available for transfer. With the combination of lower ovarian reserve and higher chromosomal abnormalities, women who are over 40 years old still have a lower overall live birth rate with each IVF egg retrieval.