Infertility is a condition where it becomes impossible for two people to conceive even after a year of unprotected intercourse. It affects one in every six couples worldwide. For many, having a baby is a fairly straight forward process.
However, some couples face difficulty in conception. Fertility struggle is one of the major problems in our society these days. The path to infertility is complex, painful, and stressful. There are a variety of factors that affects fertility such as ovulation defects, spermatogenic failure, parental age, obesity, and infections.
Apart from these reasons the major factor that affects your fertility are genes and chromosomes. We will explain how genes hit your fertility, and how you can treat infertility issues at the genetic level.
An individual’s genetic information is packed into strings of DNA known as chromosomes. The arrangement of genes and chromosomes in DNA depicts the genetic makeup of an individual. Any alteration in this genetic makeup results in the disturbed functioning of the genes or disturbed chromosomal pattern.
Normal human cells contain 46 chromosomes or 22 chromosomes pairs. These chromosomes are labelled 1 to 22 (the autosomes) while the X and Y are sex chromosomes. Any error/s in the early development of egg, sperm, or embryo can lead to an abnormal number of chromosomes in the developing embryo (i.e., a missing or an extra chromosome). Chromosomal alterations or abnormalities can happen in various forms. When part of a chromosome is missing; it is called chromosomal deletions; and chromosomal mutations involve changes in DNA.
There are also translocations, happen when chromosomal pieces attach to the wrong chromosome. Also, there can be inversions, where the chromosome is upside-down, and then something called aneuploidy, where there are too few or too many chromosomes. An abnormal chromosome can cause infertility, implantation failure in IVF, miscarriage, or the birth of a child with chromosomal aneuploidy. Any alteration in the gene sequence can lead to single gene mutations and can cause diseases such as Cystic Fibrosis or Huntington’s Chorea etc.
Infertility at the levels of genes can occur due to various factors.
Following are some of the common ones:
Family History with Genetic Problems
Oftentimes, it is proven that, a person’s DNA can include all the genetic information with nothing missing or duplicated. Regardless, even they face infertility or miscarriage. In this case it is significant to understand the family history of the person to check if any of the family member has a history of delayed pregnancy, miscarriage, or early menopause. This information is very important because it may place you at risk.
If anyone in the family has experienced early menopause (before age of 40 years) the risk of having an early menopause for the subject is doubled. If someone is a carrier of an irregular chromosome, his or her embryo could receive either missing or extra genetic information, which could result in a miscarriage or other reproductive concerns. It is worth noting that these abnormalities can also occur randomly in a foetus from chromosomally normal parents, but several are passed down from generations as well. For example, consider that your mother has one X chromosome that is abnormal.
This means there is 50% chance that you can inherit that irregular X chromosome which may cause conditions such as fragile X syndrome, cystic fibrosis (CF) and Tay-Sachs disease etc. All of these can cause fertility issues. Reproduction is a process that is controlled by multiple genes involved in the development of gonads, production of gametes, embryonic development, and delivery of the new-born. Any genetic mutation will hamper the process and results in reduced fertility, infertility or foetal defects.
Among the infertile couples, 40% of infertility issues are due to male factors. The main cause of male infertility that is now gaining importance is genetic infertility. Any change in gene or chromosomes can cause infertility as they affect the sperm production.
The following are some of the most common causes:
- Fragmented DNA
- Y Chromosome Deletion
Y chromosome is important for sperm production. Y Chromosome Deletion is a condition where you have genetic material missing from your Y chromosome.
Klinefelter Syndrome (Rare).
It’s a condition in which males are born with an extra X chromosome or Y chromosome. DNA test (Y-DNA test) is used to test Mutations or Deletions in the AZF genes. They are associated with inability or lessened ability to create sperm. It may cause azoospermia (not having any sperm in semen). In such males, during ICSI procedure, TESA (Testicular Sperm Aspiration) sperms are used. TESA is a surgical procedure done under anaesthesia in which sperms are directly aspirated from testes. Thus, along with ICSI there is the possibility of passing on these genetic issues to the progeny.
DFI (DNA Fragmentation Index): DFI test is done to check abnormal genetic material within the sperm, which in turn may lead to male subfertility failure and miscarriages.
MACS and Microfluidics are the two methods which they can use for sorting out sperms with decreased DNA damage and can use them further in IUI and ICSI.
The main causes of female infertility at the genetic level includes ovulatory disorders such as fragile X syndrome, turner syndrome, deletion of one X chromosome, and chromosomal abnormalities. Premature decrease in ovarian reserve is also one of the major factors affecting infertility in females before the age of 40 years. Decreased ovarian reserve can also run in the family history. If anyone in your family has this condition you are at double risk of having decreased ovarian reserve.
Moreover, any mutations in the follicle-stimulating hormone (FSH), luteinizing-hormone (LH), gonadotropin-releasing hormone (GnRH) receptors, or in the genes supporting pregnancy can also lead to infertility or miscarriages. One of the major benefits of opting IVF (In Vitro Fertilization) is that couples may be tested for potential genetic problems before the start of the cycle.
IVF is a medical procedure for conception in couples who fails to conceive naturally. In this procedure we fertilize woman’s egg with the partner’s sperm outside body in the lab and the embryos formed are then transferred to the woman’s uterus. Genetic testing of an embryo prior to transfer helps in minimizing the miscarriage rate or implantation failure and it enhances the rate of take-home babies.
Karyotype is a simple blood test by which we can get a snapshot of an individual’s chromosomes. Parental karyotype is advised before IVF to have a look at the parent’s chromosomal health. Any missing or extra pair of chromosomes either in male or female partner can lead to miscarriage. If any of the parent karyotype shows abnormal karyotype, PGT A (Preimplantation Genetic Testing for Aneuploidies) is advised to have a look at embryos chromosomal health.
IVF is helping infertile couples to get pregnant but still the success rate of IVF is stuck at 40-50%. Sometimes, miscarriages happens even though everything seems well. Pregenetic testing of embryo(s) has increased the success rate by evaluating the health of embryos chromosomes. PGS, or Preimplantation Genetic Screening, is performed on IVF embryos with the goal of improving the IVF success rate. This is done by checking the embryo’s chromosomal health.
Embryo Biopsy & Genetic Testing
After IVF, embryos are grown in lab up to 5 to 6 days. PGS is usually performed on 3 days or 5 days old embryos. Biopsy of 3-6 cells is taken from the embryo’s trophectoderm layer on day 5 Blastocysts and is sent to genetic lab for testing. Next Generation Sequencing (NGS) is a novel technique used for chromosomal testing of embryos created during IVF. After biopsy all embryos are frozen in liquid nitrogen at -198 degrees while PGS report is awaited.
After the result of PGS those embryos with the correct number of chromosomes are transferred; whereas embryos with an extra or missing chromosome are rejected. This transfer is known as Frozen Embryo Transfer (FET). By transferring an embryo with the correct number of chromosomes, you have higher likelihood of achieving an ongoing, healthy pregnancy.
PGT A (Preimplantation Genetic Testing for Aneuploidies) test is done in couples who have normal karyotype and still fail two cycles of IVF. It also reduces the chances of having a child with extra or missing chromosomes which result in disorders such as Down Syndrome.
PGT M (Preimplantation Genetic Testing for Monogenic) test is done if any of the parent/s’ karyotype is abnormal or are a carrier for any specific gene mutation. In case of any abnormalities the chances of having miscarriage are high during IVF. This genetic test help in reducing the risk of having a child with an inherited condition.
You may consider a PGT M test if:
- You and your partner are carriers of the same autosomal recessive condition (e.g., Cystic Fibrosis/Sickle Cell Anaemia etc).
- Either one of you are a carrier of an X-linked condition (e.g., Duchenne Muscular Dystrophy).
- An autosomal dominant condition carried by either you or your partner (e.g., Huntington Disease).
- You or your partner have a mutation associated with a hereditary cancer syndrome (e.g., BRCA1 & 2).
- You had a pregnancy with a single gene disorder, or a child with the same condition.
- You want to perform HLA matching (e.g., HLA typing is done for the treatment of affected sibling with Sickle Cell).
PGT SR/PGD: Couples with chromosomal rearrangements are at an increased risk of producing embryos with the incorrect amount of genetic material and these embryos do not lead to a successful IVF. This test minimises the risks of having child with structural abnormality, and this technique involves testing of embryos created through in vitro fertilization (IVF) and then transferring only normal embryos.
Therefore, with advanced technology and judicial use of genetics in this modern era, they can ensure better evaluation of the infertility in couples and use a personalised plan for each patient. This will play a major role in not only eliminating the chances of a new-born with genetic diseases but also ensure a successful parenthood you can cherish with the help of modern science.