Balanced translocations: what to do?

Usually, subjects with a balanced reciprocal translocation are clinically normal, because the translocation consists of a simple reciprocal displacement of genetic material between a chromosome and another, without loss or acquisition of genetic information (or disruption of a gene sequence). However, carriers of a reciprocal balanced translocation often experience problems of recurrent pregnancy loss (RPL), reduced fertility or even sterility. This happens because during gamete formation (eggs and spermatozoa), an event during which chromosomes recombine and divide, cells with an imbalanced set of chromosomes are very likely to be produced.

Theoretically, an individual with a balanced translocation should have the following probabilities at each conception: progeny with imbalanced karyotype in 50% of cases, progeny with balanced karyotype in 25% of cases, and progeny with a normal karyotype in the remaining 25% of cases. In reality, the percentage of newborns with an imbalanced karyotype and consequent pathological phenotype is much lower, due to the fact that gametes and embryos with imbalanced karyotype are often negatively selected (i.e. they are depleted even before conception of before the pregnancy can go on, explaining infertility and recurrent pregnancy loss of translocation carriers).

So, the probability of arriving at term of the pregnancy with a newborn having an imbalanced karyotype and hence a pathological phenotype (i.e. congenital malformations and/or mental retardation), depends on some factors:

1. the sex of the parent who carries the balanced translocation
2. the type of chromosome involved and the size of the chromosomal portion exchanged.
3. the method of ascertainment of the imbalanced translocation in the parent (e.g. if the balanced translocation has been diagnosed following the birth of a malformed child with an imbalanced karyotype or during the exams for recurrent pregnancy loss or infertility).

As a general rule, if there are no persons in the family affected by an imbalanced translocation, the reproductive risk to have a newborn with an imbalanced karyotype and so being affected by congenital malformations and/or mental retardation is the following: 7% if the carrier of the balanced translocation is the mother, 3% if the carrier of the balanced translocation is the father. This risk may be further reduced if the parent carrier has been diagnosed during the ascertainments for recurrent pregnancy loss: in this case the risk of having an affected baby with an imbalanced karyotype at term of pregnancy is as low as 2%. By contrast, if the parent has been found to be a carrier of a balanced translocation because a baby with an imbalanced karyotype was born, the risk of having another baby with an imbalanced karyotype is higher and is empirically estimated to be 20% at each pregnancy (the reason is clear: in this case, the imbalanced translocation generate a pathological phenotype which is however compatible with life, being genetically less challenging than a translocation that causes recurrent pregnancy loss, i.e. the formation of an embryo that is chromosomally so imbalanced that it cannot reach the term of pregnancy).

As said above, subjects who inherit a balanced translocation from a carrier parent are generally healthy. However, also in this case, a risk remains that the child will be born with a neonatal pathology (i.e. a malformation syndrome and/or mental retardation). This could happen because, during the formation of the gametes (eggs and spermatozoa), there might have been a small (but important) loss or gain of chromosomal material, which would not be even detectable by standard karyotype at villocentesis or amniocentesis. Such risk is estimated to be 1%.

By contrast, in the case the balanced translocation has not been inherited by a carrier parent, but has been identified de novo in that fetus, the probability to arrive at term of pregnancy with a newborn affected by congenital malformation and/or mental retardation is higher and is of 3-5%. The reason is clear as well: the presence of the same balanced translocation in healthy individuals of the family (e.g. in one of the parents) represents a positive prognostic factor, indicating that the balanced translocation has a high chance of being transmitted to the progeny without problems, whereas a new, de novo translocation, although apparently balanced, represents a new entity, still clinically unknown and less predictable in its probability of being microscopically imbalanced, hence pathologic.