This post is for the Wiki, so if you have any perspective on Structural Rearrangements, please contribute. We ask that you stick to answers based on facts and your own experiences, and keep in mind that your contribution will likely help people who know nothing else about you (so it might be read with a lack of context).
When you’re dealing with structural rearrangements (SR or rearrangements for simplification), it is important to understand the type of mutation you have, and what it means for your odds of conceiving without assistance or via IVF. Different rearrangements have different outcomes and limitations. The intent of this post is to:
· Inform the basic reader on the different types of mutations
· Understand how rearrangements are found
· Additional support offerings
—— Additional perspective from our members with Structural Rearrangements will be helpful for the following questions:
· How was your SR found?
· How has this affected your perspective around infertility?
· What ART (assisted reproductive technologies) have you pursued and how has your SR influenced the outcome?
· If you found success, what did this mean for monitoring during your pregnancy? note for our SR commenters: stay neutral and to the point. This is highly relevant for SRs, as pregnancy without assistance is possible, but carries significant risks. We appreciate anything you can share neutrally that is a knowledge add. note for our community – I expect us all to act like adults. Be compassionate and understand that their infertility has radically affected their life and their pregnancy. It is not against the rules to neutrally discuss, and it is highly relevant here
· Did I miss something important? Add it in the comments please!
—— Disclaimer: I am not a medical professional; this is just information I have learned due to our diagnosis. If there are errors or you have a recommendation to clarify something confusing, please reach out to me so I can correct this post. I have the most knowledge around balanced reciprocal translocations since this is our diagnosis, FYI.
PART TWO delayed until late Nov - on meiosis and the impact of structural rearrangements on fertility
Rearrangements change the chromosomal structure and can alter the function of one or more genes and can change the pattern of gene transmission. Of the 23 pairs of chromosomes (46 in total for humans), there are 4 types of rearrangements
that can affect our 46 chromosomes, with each type having distinct cytological
and genetic consequences. Sidenote: These mutations can be spontaneously created (de novo) or inherited. Most of the rearrangement mutations we discuss in this post are most likely inherited from family members. We are not discussing any possible implications of one's health with a rearrangement (mostly minimal), instead we are discussing the outcomes of infertility with respect to the particular rearrangement. 1) Deletion
A rearrangement that removes a segment of DNA, and sometimes known as partial monosomies. Deletions
can be located within a chromosome (interstitial
) or can remove the end of a chromosome (terminal). Deletions can be small (intragenic
), affecting only one gene, or can span multiple genes (multigenic
). Deletions that are too small to be detected under a microscope are called microdeletions
. A person with a deletion has only one copy of a particular chromosome segment instead of the usual two copies. A deletion does not always lead to infertility or repeat pregnancy loss (RPL), but it can sometimes be the cause of non-obstructive azoospermia
. The effects of the deletions depend on their size, with most multigenic deletions having severe consequences up to and including lethality. Deletions are further complicated by recessive traits, gene expression, deletion loops, pseudodominance, and heterozygous v homozygous
genes. 2) Duplications
A rearrangement that results in an increase in copy number of a particular chromosomal region, sometimes known as partial trisomies. A person with a duplication
has three copies of a particular chromosome segment instead of the usual two. Like deletions, these can happen anywhere along the chromosome. There are two types of duplications – tandem
where the duplicated regions lie right next to one another, or non-tandem
where the repeated regions lie far apart on the same or different chromosomes. Again, this doesn’t always lead to infertility, but it depends on the duplication. 3) Inversions
A rearrangement in which a chromosomal segment is rotated 180 degrees. Inversions
are defined by the involvement of the centromere
. Pericentric inversion
includes the centromere (peri means around/about), and Paracentric inversion
does not include the centromere (para means beside/beyond). In other words, an inversion is where a chromosomal region is flipped around so that it points in the opposite direction. Most inversions will result in reduced infertility, as the inversion will lead to a larger amount of unbalanced gametes (heterozygous v homozygous
is relevant here). This can also have deleterious effects on a person, with hemophilia also being caused by an x-linked inversion in the factor VIII gene (although most inversions do not have any effect on the person). 4) Translocations
A rearrangement in which part of one chromosome becomes attached to another chromosome. A reciprocal translocation
involves two chromosomes swapping segments; a non-reciprocal translocation
means that a chunk of one chromosome moves to another. Translocations can be balanced
(in an even exchange of material with no genetic information extra or missing) or unbalanced
(where the exchange of chromosome material is unequal resulting in extra or missing genes). For the most common type of translocation
, balanced reciprocal translocation, this occurs in an estimated 1 in 560 people across the world. Balanced translocations, unless interrupting large and important gene sequences, do not have any other side effects other than infertility due to a higher than average rate of aneuploidy. A special type of translocation is called a Robertsonian translocation
—— Structural rearrangements and viability:
Note that any rearrangement resulting in a significant loss of genetic material is most likely to be lethal. While many rearrangements do not result in a loss of genetic material, the position of a gene on a chromosome can affect its expression
. In humans, this can often lead to fetal demise. As with any gene mutation, mutations can be neutral, deleterious, or lethal. Because rearrangements affect much larger regions of DNA, they are much more likely to be deleterious or lethal. Of the above rearrangements, Inversions and Translocations are most likely to cause recurrent miscarriages and carry significant risks of offspring with an unbalanced amount of chromosomes. PGT-SR
is indicated for all of the above known structural rearrangements, and varies on the ability, cost, and time to create a probe for your specific mutation. How are Structural Rearrangements found?
Via a Karyotype, the basic definition being that it is an individual’s collection of chromosomes. The term also refers to a laboratory technique that produces an image of an individual’s chromosomes. The karyotype is used to look for abnormal numbers or structures of chromosomes. A further dive into karyotyping chromosomal abnormalities
may be helpful if you like to understand the process.
For some, their mutation is not found until IVF (this was us) and PGT-A screening for aneuploidy found the recurrent abnormalities. What is this weird sentence they’re using to describe my structural rearrangement?
That’s called Cytogenetic Notation
45,XX, der(13;14)(q10;q10). That sentence is like a probability or financial mathematics equation, with each symbol and number giving you essential information about your structural rearrangement. (in this instance a Robertsonian translocation) I’m having a hard time visualizing this. What does this look like? Example of a Deletion, Duplication, or Inversion Example of reciprocal and non-reciprocal Translocation I don’t know if I have a structural rearrangement. How do I know? What are the signs?
It depends. Some experience repeat pregnancy loss (RPL) and their doctor will do a RPL panel. Some, like me, just don’t ever get pregnant, or only experience chemical pregnancies. Some do conceive and find out either during the pregnancy or after birth, some experiencing Termination for Medical Reasons (TFMR). The only way to truly know and confirm is via a Karyotype for you and your partner. Where can I find more support and research on Structural Rearrangements? (I am not linking the facebook groups. I found them entirely unhelpful and full of triggering content) Rare Chromo Org (Unique)
- This is a source of information and support to families and individuals affected by any rare chromosome disorder and to the professionals who work with them. UK based charity but welcomes members worldwide. Free membership, heavily reliant on donations. ARC (Antenatal Results and Choices), UK
—— Common research links: https://www.ncbi.nlm.nih.gov/pubmed https://scholar.google.ca/ http://www.nature.com/ejhg/ https://www.fertstert.org/ https://academic.oup.com/humrep