A simplified explanation of unbalanced translocations

David is ready for a car ride

Originally posted 16 September 2023

Parents who have had a child with Phelan McDermid syndrome (PMS) often ask about the chances of PMS in a subsequent child. It can be a scary possibility considering the amount of resources that an individual with PMS requires from a family. The probability of a new child with PMS depends upon the amount of genetic testing that has been carried out on the child with PMS and the parents. I am willing to share some of the published statistics, but only a qualified geneticist can offer testing and properly guide parents through the process. What I can do is explain some of the science behind how a repeat can occur and how that affects probabilities.

The major mechanism that leads to a repeat occurrence of PMS is a chromosomal balanced translocation in one of the biological parents. Indeed, I harbor a balanced translocation and have had two children with PMS. See my introductory blog page. Thanks to this circumstance, I have thought a lot about how my balanced translocation became an unbalanced translocation ( = PMS) in my children.

This blog is written as a made-up story. It is an analogy, almost a parable. It tells the story of a fictitious cousin from a fictitious county in an unnamed state who works as an emergency medical technician. Mostly, it is the story of the two emergency packs he carries to incident scenes. Let us see if this story helps the reader to understand balanced and unbalanced translocations in genetics. I hope so.

The importance of standardization

My cousin, Dan is an emergency medical technician (EMT) for the Jefferson County Fire Department. It is a big county and the EMTs are very well funded and organized. When his ambulance is dispatched, he carries two large red medical packs marked #1 and #2. Pack #1 has mostly equipment, like a stethoscope, a defibrillator, forceps and magnifiers. Pack #2 has drugs and other expendable supplies, like splints, intravenous (IV) kits, and bandages. The two packs are highly standardized. When Dan returns to the station from a call, he can either restock Pack #2 or just grab a fresh Pack #2 if he does not have time. The same is true for Pack #1. If a piece of equipment was lost or left at the scene, Dan only needs to trade his old Pack #1 for a new one. Jefferson County is very good at keeping spare packs carefully standardized and ready for deployment.

Occasionally, two ambulances are dispatched to a scene, especially if there may be multiple victims. If Dan is working an incident and runs short in supplies, he can dip into the other crew’s packs and grab exactly what he needs. With standardized medical packs there is no guesswork.

Perry County is adjacent to Jefferson County. It is a small county with a limited budget. The one fire station has one ambulance. The Perry County EMTs use the same size and color medical packs as Jefferson County, mainly because Jefferson County was willing to supply some from a bulk purchase. However, Perry County EMTs do not organize the contents of the two medical bags. They pack the two bags with all the necessary materials and equipment, but not at all in the same way as Jefferson County. That is where the trouble began. Dan responded to a car accident near the border of Perry and Jefferson Counties. He was met there by a Perry County EMT. They worked the scene together. On his way to another emergency call, Dan accidently picked up one of the Perry County medical bags thinking it was his Pack #2.

When Dan got to the scene of the second call he did not have the IV supplies he needed.  The Perry County bag gave him an extra defibrillator, some of the essential drugs, but no infusion sets or IV bags. A second ambulance had to be dispatched.

This story is about chromosomes. Chromosomes are highly standardized. Each chromosome has a specific set of genes. Human cells have two of every chromosome, one from each parent. All parent chromosomes are supposed to be organized the same.  Dad’s chromosome 22 should be organized just like mom’s chromosome 22, and everyone else’s.

This world-wide organization of human chromosomes can go astray. I know. I am a dad with two chromosomes where the genes are haphazardly distributed across them. Just like the Perry County EMT, my arrangement does not cause me any immediate problems. I have everything I need.

In my case these somewhat scrambled chromosomes are chromosome 22 and chromosome 19. They came from my father who had the same unusual arrangement. Note that I also have a normal 22 and a normal 19, both from my mother. When my wife and I decided to have children, something bad happened very similar to Dan’s experience picking up a nonstandard medical pack.

Nature’s rule about having children is that each parent contributes one copy of each chromosome. This guarantees that the child has two of every chromosome, just as his parents and everyone else. This works well if everyone has standard chromosomes. Chromosomes 22 and 19 from my father are nonstandard. Like the medical packs, some components will be missing if a Perry County pack is brought along with one of the standard Jefferson County packs. PMS occurs if the nonstandard chromosome 22 from my father is delivered with a standard chromosome 19 from my mother. The standard chromosome 19 does not have any chromosome 22 genes, like SHANK3, PLXNB2, and BRD1.

People who have chromosomal translocations of 22q13 always have a chance of delivering a standard chromosome along with the nonstandard one. If both nonstandard chromosomes are delivered to the offspring, that offspring will not have PMS. But he or she now becomes a “carrier” of PMS like me. A future child may get PMS. If my child gets the chromosomes I received from my mother, my child would be as normal as the general population. Interestingly, if my child gets the nonstandard chromosome 19 and a normal chromosome 22, there is no telling what might happen. It would be a chromosome 19q13 deletion. However, there seems to be no such syndrome. Most likely, an embryo with a 19q13 deletion does not survive. At least, that is the best guess at the moment.

The moral of this parable is that standardization is important.

arm22q13

Understanding translocations in 22q13 deletion syndrome: genetics and evolution

Originally posted 11 June 2015
Updated 16 September 2023

My dad

That’s my dad.  No, not the dapper gentleman standing in the back.  He is the diapered baby sitting in front.  One interesting thing about this circa 1924 photograph, I can tell  you unequivocally, is that both males in the photograph are carriers of 22q13 deletion syndrome.  I can say this even though neither man was ever genetically tested and neither ever had children with a known diagnosis of 22q13 deletion syndrome.  How can I be so sure? I spent several years contacting relative and having them tested.  It was an interesting and often challenging undertaking.  My motivation was to warn family members and at least prepare them for the possibility of having to raise a son or daughter with 22q13 deletion syndrome.  Along the way I received “thank you” from some family members and angry words from others.  Some family members simply did not want to know.  It is a story for some future blog, I suppose.

From this family research I was able to deduce that Joe, my dapper grandfather, was a carrier of 22q13 deletion syndrome with a “balanced translocation” of genetic material between chromosome 22 and chromosome 19.  Some of my grandfather’s siblings were carriers and at least two of Joe’s sons were carriers.  My dad was one of the carriers.  He had four sons, including me, and I am a carrier.  My dad did not have children with 22q13 deletion syndrome, but I had two.

The power of genetic principles

I know my dad was the carrier (not my mom) because a few of dad’s relatives are carriers. (See the line chart on my page “Who is arm 22q13?“.)   I was able show that my grandfather was a carrier using similar family evidence.  Genetics and inheritance follow certain rules and those rules can be used to peer into the past.  Genetics and evolution are two different aspects of the same rules, and understanding them can be very powerful tools for understanding where we come from and where we might be going.

Somewhere between 15% and 24% of all children with terminal deletions inherit that deletion from a carrier parent.  If your family has carriers, nature has provided a curious way to remove carriers from future generations: have small families.  This graph shows why.

(right click on graph to enlarge in a new window)

The main graph has three colored lines. (Ignore the small “inset” graph with bars; it provides details some researchers might want to see.)  The green line on the main graph represents what happens when people in the extended family have relatively large families (4.4 children, on average).  The black line shows the same process when the average family size is less (3.6 children per family).  The red line shows the impact of small families (1.5 children per family, on average).  What impact are we talking about?  The beginning of the graph starts today.  The end of the graph shows what happens after 10 to 50 generations from today.  Since most people assume 25 years for each generation to pass, the first 10 generations will take 250 years.  Here is the point.  If people have only small families, we can expect carriers to disappear (reach 0.0 on the scale) from the population in fewer than 10 generations.  However, if people choose to have large families (green line), carriers are unlikely to ever disappear (green line never reaches zero).

Let me be clear.  I am not advocating for any specific choice.  This is not about ethics.  In a sense, these are God’s rules.  They are inferred from the statistics of inheritance in the same way quantum tunneling is inferred from the statistics of nuclear emission.  I worked with a member of my family to generate this graph using a mathematical simulation.  I wanted to know how long 22q13 deletion syndrome has been in our family.  The answer comes from the green line.  Historically, my European ancestors had large families.  My great-grandfather had six children.  His children had an average of 4.8 children each.  These numbers suggest that the translocation could have existed in our family for tens of generations.

arm