In this webinar, Elisa Moya Gutiérrez — Embryologist & Dr Francisco Anaya Blanes — Gynaecologist at PreGen (UR Vistahermosa), Alicante, Spain provided some of their past patients diagnosed with genetic problems. They explained their diagnosis, previous failed attempts, protocols used and treatment offered that helped them to achieve their final goal.
A genetic disorder is a disease caused by a change in a DNA sequence. It can be caused by a mutation in one gene, which we call a monogenic disorder, or by a mutation in multiple genes, called multifactorial inheritance disorder. There might also be a combination of gene mutations and environmental factors or damage to the chromosomes, and it would result in changes in the number or the structure of entire chromosomes.
Almost all diseases have a genetic component, some diseases are caused by mutations that are inherited from the parents and are present in the individual at the birth, but other diseases can be caused during the person’s life, such mutations are not inherited from the parent, they occur either randomly or due to some environmental factors.
Monogenic genetic disorders – real-life cases
The first case Elisa presented described an issue with the monogenic disease called Cystic Fibrosis, which is an autosomal recessive disease. It is most common in the Caucasian population, and it is a disease that causes thick, sticky mucous to build up in the lungs, digestive tract and other areas of the body, it is one of the most common types of chronic lung diseases in children and young adults. It’s also a life-threatening disease.
PGT-M – is one of the genetic studies in embryos
- a 31-year-old female with low ovarian reserve, Cystic Fibrosis carrier
that allow detecting genetic alteration or mutations in a specific gene in embryos that would cause a monogenic disease in the offspring. When there is a known reproductive risk, it’s necessary to know the genetic cause of the disease.
The couple came for the first consultation when the female was 31, her mother had early menopause at 39 years old, and the partner was 38 years old with a normal sperm analysis. Before they started the treatment, they decided to do a basic panel of monogenic diseases, and both obtained a result that they were carriers of Cystic Fibrosis, therefore, with this result, the approach of the type of treatment had to be changed. They were recommended to undergo PGT-M.
The female was prescribed 9 days of treatment with antagonists, Bemfola and Meriofert, 7 follicles suitable for puncture were obtained and of which 7 oocytes were obtained, 3 fertilized, and these 3 fertilized oocytes continued to develop up to day 3 of culture with good quality. All 3 embryos were biopsied on day-3, and they have grown until day-5. Two embryos were affected, and 1 was a carrier. The 2 affected embryos were discarded, and the carrier was transferred
. The carrier embryo was transferred in a fresh embryo transfer on day-5, and the patient became pregnant.
- a 33-year-old female was a carrier of Fragile X Syndrome
The next case presented concerned Fragile X Syndrome. This is the most common form of inherited intellectual disability
. This disease is caused by a specific gene. Normally, this gene produces an unnecessary protein that is needed for brain development, but a defect in the scene causes a person to make little or no such protein. People who only have a small change in the gene do not have symptoms of Fragile X syndrome, but people with major changes can have severe symptoms, such as intelligence problems, ranging from some learning disabilities to severe intellectual disability, emotional and social problems, speech, and language problems. It is more severe in male patients because fragile X syndrome is caused by annotation in a gene that is located in the X chromosome, and as we know, women have 2X chromosomes, while men have 1X chromosome and 1Y chromosome, so women with the abnormal gene in 1X have another X chromosome with the normal genes. It is less common and less serious when it comes to women. However, when men have this X chromosome with the abnormal gene, they will have more severe symptoms.
In this case, a female patient knew she was a carrier of the Fragile X Syndrome since she had 2 male cousins affected by the syndrome, and she had a normal ovarian reserve. Her 36-year-old husband was a non-carrier of the mutation and had a normal seminogram.
Antagonists protocol was also used, and we obtained 13 oocytes, 11 fertilized, and we obtained 8 embryos which we biopsied on day-5. Two of the biopsied embryos were non-carriers of the disease, so they were suitable for the transfer. We froze them, and when the patient’s and when the endometrium was ready, one of the embryos was transferred, and the patient became pregnant.
- a 36-year-old affected by Steinert disease with low ovarian reserve
The 3rd case described Steinert Myotonic Dystrophy, which is an autosomal dominant chronic multisystemic hereditary disease with slow progression and high variable heritability, and it can manifest at any time, from birth to older age, in both men and women. This is a muscle disease characterized by myotonia and multi-organ damage that combines varying degrees of muscle weakness, arrhythmias, cardiac conduction disorders, cataracts, endocrine damage or sleep disorders.
The woman was affected with Steinert disease, and she also had a low ovarian reserve, her husband was 42 years old and had a normal sperm analysis. She took antagonists for 8 days, and we obtained 5 oocytes, only 3 of them were in the specific moderation stadium, 2 of them were fertilized, and 2 embryos were biopsied on day-3 of culture, and we also vitrified them on day-5. We obtained 1 suitable embryo, and the other was a carrier of the mutation, so we transferred the healthy embryo, and the patient got pregnant.
Genetic abnormalities – real-life cases
- a 38-year-old female with normal ovarian reserve and hypothyroidism had 3 miscarriages; a 39-year-old male partner had oligozoospermia & DNA fragmentation
In the case presented, a patient had a normal reserve, but she dealt with 3 miscarriages in the past, she also was under hyperthyroidism treatment. Her 39-year-old husband’s sperms analysis showed oligozoospermia and high DNA fragmentation. She took antagonists for the ovarian stimulation for 11 days, 18 oocytes were obtained, of which 16 were in the specific stage to fertilize, 15 were fertilized with the sperm of the patient, and it was preceded with MACS technique to reduce the DNA sperm fragmentation in the sample. We got 8 embryos that were biopsied on day-5, but none of them was suitable for an embryo transfer because all of them were aneuploid.
The couple decided to try again some months later with the same stimulation, and we obtained 13 oocytes, 11 were fertilized, we biopsied 5 embryos, we obtained 3 suitable embryos, and the rest were aneuploid. We performed a cryotransfer where we transferred 1 embryo, and the patient became pregnant.
The other type of genetic test that is performed is the Pre-Implantation Genetic Test for Aneuploidies (PGT-A), it detects chromosomal alterations in embryos before they’re transferred to the uterus and thus prevents the transmission of serious diseases to offspring and the transfer of embryos that could lead to miscarriage. PGT-A allows discarding those embryos that present a genetic alteration and transferring the ones that have the best quality.
Repeated miscarriages are a pathology that is recognized after the accumulation of 3 or more pregnancies interrupted by spontaneous miscarriages. This type of miscarriage is suffered by 6% of the population, and the percentage of the risk increases when it has already happened on some occasion. The most frequent causes of repeated miscarriages (60%) are because of aneuploid embryos. Although the parents have a normal number of chromosomes, the embryo has the wrong number. This occurs more often in couples where the mother is more than 35 years old.
- a 41-year-old female with a very low ovarian reserve had 1 cancelled IVF cycle; a 41-year-old male partner with asthenozoospermia & altered FISH result
The FISH analysis
is Fluorescence in situ hybridization, and it is done on the sperm samples because when you have an altered FISH result, it means that a percentage of sperm presents chromosomal alteration compared to the percentage of abnormalities that a control population presents. This fact indicated that the individual in question has a higher risk of producing sperm with chromosomal abnormalities and, therefore, embryos carrying aneuploidies. When you have this kind of result, it’s recommended to do an IVF cycle with PGT-A analysis.
The last case presented a couple of 41-year-olds, who had 1 cancelled IVF cycle in another clinic as there was no ovarian response. Therefore, they’ve decided to go ahead with egg donation this time. The male partner had asthenozoospermia and an altered FISH result. We obtained total disomy of sexual chromosomes of 0.9 and an autosomic chromosomes disomy of 0.5. This referred data is out of range with respect to the control population, and the XY disomy rate is increased 3 times over the control value. The diploidy rate is increased to 2.7 times the control value.
From the egg donation, we obtained 21 follicles and 17 oocytes in the specific stadium, 13 fertilized and 7 embryos were biopsied and vitrified. We obtained 3 suitable embryos, and the patient got pregnant in the first cryotransfer.
We have exposed 5 successful cases with complications, they are successful mainly because of seeing the complication of each patient, they all became pregnant on the first or second try, but it’s not always the case. If you look at some data from our clinic (Vistahermosa UR) about the success rates in every treatment. The 90% success rate
corresponds to 3 IVF tries that include fresh transfers and cryopreserved transfers. The chances of pregnancy are related to the number of attempts and the personalization of the treatment. They will depend on the age and the number and the quality of the eggs and the sperm sample.
Egg donation is one of the treatments that have the best results, its high percentage of success in 2 cycles is 95%, and this makes it a safe technique that reduces the rate of miscarriages and malformations. This technique is also not influenced by the age of the patient, it’s important that the patient has a normal uterus.
IVF combined with PGT-A allows us to select the embryo with the best implantation possibilities increasing the success rate in the chances of having a healthy baby at home and also reducing the rate of miscarriage and malformations. One IVF cycle with PGT-A would give a 75% of success. Each patient has their own medical history and a number of factors that can lead to infertility. Above all, genetic factors are more complex and highly varied, this is why it’s important to study each case and select the best treatment for each couple, and that’s why we always try to do everything we can to get the best solution.