Friday, January 25, 2013

Genetics Lottery


This is Brad.  I'll be guest posting from time to time and this is my first.  Sorry I'm getting started with such a long post.
The last 3 months has been an amazing roller coaster of emotions.  Thursday was a good day.  I’ll explain in a minute, but first some background…
One of the many questions (and trust me there were many questions) we asked the neonatologist after he explained that he was “suspicious” of Down syndrome in Caleb was “What does this mean for our future of having additional children?”  He explained to us that most likely Caleb received an extra 21st chromosome spontaneously upon his conception, but there was also a chance that the extra material was inherited (implying a higher probability of a future child being born with Down syndrome as well).  Caleb had a FISH test done while in the NICU and that test confirmed the doctor’s suspicions that Caleb had 3 copies of the 21st chromosome.  However, the detailed karyotype test would take weeks to produce results.
In the weeks after his birth we learned a lot about Down syndrome.  One thing that we learned is that Down syndrome occurs in one out of every 700-1000 live births (statistics starting… more on this later).  We also learned that the only known factor that significantly increases a couples odds of having a child with Down syndrome is advanced maternal age.  Another thing that we learned is that the karyotype test would tell us which of the three types of Down syndrome Caleb had (we knew he didn’t have Mosaic based on the FISH test as all not a portion of his tested cells reported 3 copies of the 21st chromosome).  For Caleb it really doesn’t matter, but it could for future kids.  The three types are:
o   Trisomy 21 (or nondisjunction) – Nondisjunction results in an embryo with three copies of chromosome 21 instead of the usual two. Prior to or at conception, a pair of 21st chromosomes in either the sperm or the egg fails to separate resulting in the baby receiving three copies of the 21st chromosome.  The three 21st chromosomes each stand independently.   As the embryo develops, the extra chromosome is replicated in every cell of the body. This type of Down syndrome, which accounts for 95% of cases, is called trisomy 21.  It is never inherited.  It just happens.
o   Mosaic (or mosaicism) – Mosaicism occurs when nondisjunction of chromosome 21 takes place in only a portion of the cells in the body.  When this occurs, some cells contain the usual 46 chromosomes and others contain 47.  Those cells with 47 chromosomes contain an extra chromosome 21.   Mosaicism accounts for about 1% of all cases of Down syndrome.  It is believed that people with this form of Down syndrome can achieve a higher level of function and/or have less visible features, but that is largely unproven.  This again is never inherited.
o   Translocation - Translocation accounts for about 4% of all cases of Down syndrome.  In translocation Down Syndrome there are three copies of chromosome 21, just like in trisomy 21, but one of the chromosome 21’s is attached to another chromosome, instead of being separate.  The extra chromosome 21 is frequently attached to a copy of the chromosome 13 or 14, but sometimes it can be attached to 15, 22 or in some rarer cases, two #21 chromosomes can be attached to each other.  The main point of a translocation is that the total number of chromosomes in the cells remains 46.  It just happens that one of the 46 is a combo of sorts and has a little extra chromosome 21 tagging along.  The presence of an extra part of chromosome 21 causes the characteristics of Down syndrome.  Because of its nature, this form of Down syndrome can be inherited if either parent is a balanced carrier of the translocation.  However, the translocation can also be “de novo” (or “occurring first in the child”).  I can’t find any reliable stats on how frequently translocation is inherited and how frequently it is “de novo”.
After Caleb came home, we began reading online that there is a 1/100 chance of additional children being born with Down syndrome, unless it was an inherited translocation.  This made no sense to me, as a numbers guy.  If any event is spontaneous and unique, how could it be more likely to occur again next time?  I mean…flip a coin.  50/50 shot for heads right?  So you get heads… still a 50/50 chance for heads on the second flip, right?  When we later met with a genetics counselor, I asked this question and I found that there is no real scientific reason for the increased risk nor a solid reason for how much the risk is increased by.  The increased risk simply accounts for the fact that something didn’t go right the first time and we don’t know why.  An implied inherent risk if you will.  Added simply because there could be something that we don’t understand working behind all of this.  Any auditor friends out there probably understand this idea of implied risk or inherent risk.  For example:  Maybe that coin has something wrong with it that we can’t see that predisposes it to land on heads… probably not, but maybe…  All of this to say that the risk is “probably no higher next time, but maybe it is… so it’s accepted to just say 1%…”
We also read that if the child has a translocation then either parent could be a balanced translocation carrier and in that circumstance, the chromosome abnormality was inherited.  In that case, the odds increased to 10-15% if the mother is the carrier and 3-5% if the father is the carrier.  Nice statistics, but as we would later learn, not universally true for all translocations.  There are more variables in play that make it a little more complex.
So back to our story…  Steph and I asked a lot of doctors what the odds of a family with two children with Down syndrome were and the general consensus was that the odds are very small.  This was reassuring.  It seemed that most people assumed that Caleb had the most common form: Trisomy 21.  And so did we.  Until two weeks ago when we Caleb’s karyotype came back and we learned that Caleb has a translocation.  Beating the statistical odds again…  The genetics counselor told us the findings were “rather significant” and we should come back in to discuss and also have a karyotype test done on each of us.
When we visited with the genetics counselor, he told us that Caleb did not even have the typical translocation, but rather he had the more rare version in which that extra 21st chromosome is attached to another chromosome 21.  It’s called translocation 21:21.  Beating the stats again… Feel like I should have bought a lottery ticket…  So why is that “rather significant” you ask?  Didn’t you just explain that if you were a carrier that the odds are 3-15% if either mom or dad was a balanced carrier?  Well yes… except in this rare case.  In this case, the “worst” case if you want additional kids, if either of us was a carrier the odds are 50% miscarriage and 50% Down syndrome.  Ugh.  100% of live births will have Down syndrome.  No if, ands, or buts.  Why is this you ask?  It’s not that complicated, but it is hard to explain without pictures.  It reminds me a lot of high school biology.   If you really want to know, ask me and I will draw you a picture.  Anyway, 100% is a big number.  It’s pretty overwhelming to contemplate the possibility that you were born with no genetic shot of having a typical child.  It was more overwhelming for me than the actual diagnosis of Caleb.  I felt like I was stuck in the middle of a bad science fair project and a bad science fiction novel.
So we did the lab work and then we waited.  We were told that it was more likely than not that we were not carriers.  At this point, I was tired of stats.  I wanted facts.  It took a long two weeks to get the results, but Thursday we got the call that neither of us is a carrier.  Good news.  Good day.  Finally back on the right side of the stats.  Never thought that I would be so happy to see 1/100 odds (implied inherent risk and all).  Now, all of this is no promise we will have another child or that this next child will be “typical”.  That’s my assumption, but I’m learning not to depend on stats and assumptions… you could always be that one.
So to summarize:
·         1/700 have down syndrome                                                    check
·         4% of those have translocation                                               check
·         A fraction of those have translocation 21:21                        check
Or look at it this way… there are about 400,000 people in the United States living with Down syndrome.  About 4% of those, or 16,000, have a translocation.  A fraction of those 16,000, have translocation 21:21.  Our little Caleb is pretty unique!
We won the genetics lottery if you will.  But we are happy today that we know that Caleb was the start of the small odds and not either of us.

This lady in Europe does a good job of explaining it too if you want more info. 

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