Karyotype Analysis

Disorder: Translocation Carrier/Robertsonian Translocation (21;21)

1. Diagnostic testing for Translocation Carrier/Robertsonian Translocation is available in pregnancy where one partner carries a ‘balanced’ chromosomal rearrangement (condition where there is no loss or gain of chromosome material) through either CVS (Chorionic Villus Sampling) or amniocentesis (A procedure where a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for genetic abnormalities). These tests are associated with a small risk to the pregnancy and thus should not be undertaken without appropriate genetic counseling and indication for having the testing. On the other hand, those couples who are at risk for having a child with a chromosomal change and who do not wish to undergo prenatal testing may be able to utilize the relatively new technology of Preimplantation Genetic Diagnosis (PGD) in conjunction with assisted conception using IVF (In Vitro Fertilization) or ICSI (Intracytoplasmic Sperm Injection). Preimplantation Genetic Diagnosis (PGD) involves the testing of certain genetic conditions in an embryo prior to implantation (process of transferring the embryo to the uterus and allowing it to develop normally). PGD is an alternative to prenatal diagnosis and is performed using ART (Assisted Reproductive Technologies) such as IVF and ICSI (Intracytoplasmic Sperm Injection). The main advantage of PGD is that it avoids selective pregnancy termination as the eggs are fertilized under assistance and counseling.

In accordance with PGD, another procedure called the FISH (Fluorescence in-situ hybridization) is also used. This procedure is used for sex determination for X-linked conditions and to investigate the status of embryos from couples where one partner carries a chromosome rearrangement.

2. A chromosomal condition occurs when an individual is affected by a change in the number, size or structure of his or her chromosomes. This change in the amount or arrangement of the genetic information in the cells may result in problems in growth. A translocation is a chromosomal condition involving rearrangement of chromosome material with two or more chromosomes. If the transfer of genetic information between two chromosomes appears to be complete and is not associated with a loss of material, the translocation is reciprocal and balanced. On the other hand, an unbalanced translocation means that an individual has more or less chromosomal material than usual.

There are particularly two types of translocations – Robertsonian translocation and Reciprocal translocation. However, since this disorder is an example of Robertsonian translocation (21, 21), we will keep our discussion limited to this disorder only.

Robertsonian translocations only involve exchanges between chromosome numbers 13, 14, 15, 21 and 22, which are different from the other chromosomes as their centromeres lie very near the tip of the chromosome, giving a chromosome with a long arm and a very tiny short arm. In Robertsonian translocations, the long arms of these two acrocentric chromosomes fuse at the centromere and the two short arms are lost. As a result, one long chromosome with two arms of either the same numbered chromosome, or two different chromosomes is formed. The resulting karyotype in humans leaves only 45 chromosomes since two chromosomes have fused together.

Robertsonian translocations between the two chromosomes of the same pair are very rare and almost always occur as a spontaneous event, during the formation of the egg or sperm or during or shortly after conception. No other individual in the family would have a similar chromosomal arrangement.

In this case, the long arms of two chromosomes of the same pair – chromosomes 21 – have fused, but no genetic material has lost (balanced chromosomal arrangement). As a result, this person (male) is completely normal despite the translocation.

An abnormal karyotype in either partner, especially featuring a translocation and/or inversion is considered to be a cause of recurrent miscarriages. It is generally assumed that recurrent miscarriage might be due to recurrent chromosomal abnormalities in the fetus due to a balanced aberration in one of the parents being inherited by the offspring in an unbalanced form. If the transfer of genetic information between two chromosomes appears to be complete and is not associated with a loss of material, the translocation is reciprocal and balanced.

3. As mentioned earlier, translocation carrier is also known as Robertsonian translocation carrier. This disorder affects about one in every one thousand individuals. In a study, 1,284 couples were tested and 58 or 4.5% of them had translocations. 11 individuals were ROBs carrier and 11 of the 18 were males or 61.1% as compared to 72.4% females that were the carriers. As you see, male and females are affected ‘almost’ equally with the disorder and the outcome concerning the baby is almost always positive (offspring are affected). It is also known that if a parent, no matter the gender, has an offspring it is 100 % chance of the baby to have Down syndrome. However, there are slight differences according to different data. This is because, in another study done with males as the carriers, 4 out of 10 (40%) couples had normal babies. This means that 60% of those babies born were born with birth defects like Down syndrome. So the results will differ from couple to couple because in one data it states that there is a 100 % chance for offspring’s to be born with defects; while on the other hand, there is data that support the claim of healthy offspring. This difference in offspring is because of the different chromosome matches and the carrier’s genes interaction with the female genes. In addition to this, it is known that ROBs can occur between chromosomes 13 and 14 (75%), while in 21 and 21 there is a 10% chance. Although this is said to be one of the rare forms of ROBs there are still high chances for defects in the carrier and offspring of the carrier.

Also, Robertsonian translocations between the chromosomes of the same pair are very rare compared to Robertsonian translocation between the chromosomes of different pairs, which is much more common. (The most common of these is between chromosome 13 and chromosome 14, which is about 33% of all Robertsonian translocations).

4. People with Robertsonian translocations have only 45 chromosomes in each of their cells, yet all essential genetic material is present. Carriers of Robertsonian translocations are phenotypically normal, but there is a risk of unbalanced gametes which leads to miscarriages or abnormal offspring. Robertsonian translocations are associated with a loss of genetic material, but generally not associated with phenotypic abnormalities and originate through translocations of the acrocentric chromosomes. Men carrying Robertsonian translocation have a normal phenotype. However, they may have spermatogenesis alterations expressed by oligozoospermia or azoospermia, and they may be affected by reproductive failure owing to imbalances in chromosome meiotic segregation.

In more clear terms, a parent who is a carrier of a translocation may not have any problem with their growth, development and health but, depending on the chromosomes involved, they may experience reproductive problems such as infertility, miscarriage and having a child with an unbalanced chromosomal complement. In fact, when a mother is a carrier of a balanced Robertsonian translocation between chromosomes 14 and 21, there is a substantial risk of the child having Down syndrome of the translocation type. However, if a child has the same balanced chromosomal translocation in their cells as their parent, the child is unlikely to be affected by the chromosomal rearrangement.

Talking precisely about Robertsonian translocation (21;21), this disorder has a 100% chance of having a child with Down Syndrome. This is because, no matter which parent has this disorder, he/she will either pass on the (21;21) translocation chromosome and have a child with Down syndrome, or he/she will fail to pass on the (21;21) translocation chromosome and the fetus, with monosomy 21, will be miscarried.

Lastly, ROBs carriers also have the chance of uniparental disomy, which is the inheritance of both chromosome copies to be from a single parent. Uniparental disomy is detrimental to health because it effects the gene expressions.

5. During the last four years, 13 couples with reciprocal translocation in 25 PGD cycles were examined, of whom translocation carriers were women in 6 cases and men in 7 cases. In addition, four other couples with Robertsonian translocation were examined in 4 PGD cycles. The proportion of abnormal embryos varied depending on the type of translocation and their origin, with the mean percentage of chromosomally abnormal embryos as 78.7% (55-97.3%).

Furthermore, a higher frequency of chromosomally abnormal embryos was found in couples where the woman was a translocation carrier: 81.7% versus 76.4%. Pregnancy rate was 20%.

Moreover, the prognosis of couples with Robertsonian translocation was even more favourable. The mean percentage of chromosomally abnormal embryos was 64.7 (46-66.7) and the achieved pregnancy rate was 50%.

On the other hand, even FISH method was used to assess the frequency of chromosomally unbalanced spermatozoa in male carriers. According to the data, it was found that Frequencies of spermatozoa with abnormal segregation of translocated chromosomes ranged between 40.1 – 70.3% and 5.8 – 23.5% in the carriers of reciprocal translocations and the carriers of Robertsonian translocations, respectively.

A carrier of Robertsonian translocation is phenotypically normal and thus can lead full and active lives and can expect a normal lifespan. The problem in the carriers’ lives does not occur, however, until conception or mating. As mentioned earlier, a parent who is a carrier of a translocation may not have any problem with their growth, development and health but, depending on the chromosomes involved, they may experience reproductive problems such as infertility, miscarriage and having a child with an unbalanced chromosomal complement. Thus, carriers of this disorder are often recommended to go through assisted fertilizing of the egg. Moreover,

it is also advisable, that any couple whether male or female carrier, should have a combined first trimester screening for aneuploidy. (also known as combined first trimester risk assessment) In this screening, the female has fetal measurements, maternal blood pregnancy markers, maternal characteristics like age, weight, medical conditions are taken into account.

Thus, although there is no cure for this genetic disorder, proper advice and counseling can not only help the carrier live a normal life but may also enable them to have a normal offspring.