CARRIER STATUS & TRANSMISSION OF MECP2 DUPLICATION SYNDROME
This describes how the X-linked MECP2 Duplication Syndrome is inherited across generations
First, this is not intended to be medical advice and individual factors may vary. So if you need expert help to make important reproductive decisions, consult your physician or genetic counselor. Second, I need to say I am not a geneticist and certainly not an expert, so this is just my understanding. If anyone has important additional information or corrections, let me know. I will take them under consideration. Third, even for my level of knowledge, this is a simplified explanation.
How it works
Most cases are transmitted as X-linked genetic traits from mothers to sons.
Let’s look at how this works, but first let’s just look at how chromosomes determine whether an individual is a male or female.
All females have two X chromosomes. Each female inherits one of those Xs from her mother and one X from her father.
All males have one X chromosome and one Y chromosome. Each male inherits one X from his mother and one Y from his father.
Mom has 2 Xs and either one can be passed on. Dad has one X and one Y and can pass either one to his child. If the baby gets an X from dad, it will be a girl because mom always gives the baby an X. If the baby gets a Y from dad, it will be a boy. So there are 4 possible combinations. So there are four possible combinations, but two make girls and two make boys. So there is roughly a 50% chance that a baby will be a boy and roughly a 50% that it will be a girl.
Now lets assume that Mom is a carrier of MECP2 Duplication Syndrome. That means that one of her X chromosomes will have an extra copy of MECP2 on it. This will almost always be the X that she got from her mom. In theory, it could also be transmitted from the father, but this is very unlikely because if the father had it on his X, he would have MECP2 Duplication Syndrome, which causes a very severe disability and makes it unlikely that he will become a father. In the future, with better treatment, that might change.
So let’s look at a slightly different version of the previous table
This time, instead of X2, we will call it Xdup to indicate that there is and extra MECP2 gene. If we look at the 4 possible combinations, two get X1 from mom and the duplication is not passed on. Two others get the X with the duplication from mom.
If Mom’s X1 chromosome is combined with either X or Y from Dad, the baby will not have the duplication and not be affected. If Mom’s Xdup is combined withe either X or Y from Dad, the baby will have the duplication. If it combines with Dad’s X, the baby will be a girl and a carrier. If it combines with Dad’s Y, it will be a boy with MECP2 Duplication Syndrome.
Each conception is independent, so no mater how many children are born previously, the odds don’t change. Because human families are small, there can easily be lots of variability, for example it is very possible to have 2 or 3 or even 4 0r 5 kids and none of them will be affected, but it is equally possible to have them all be affected. If we looked at 100s of pregnancies of carriers, the outcome would be closer to 25% carrier girls, 25% affected boys, and 50% unaffected boys and girls. It is like flipping a coin, it is very possible to flip two heads or two tails or even get three or four in a row of either one. It is almost impossible, however, to get 20 heads or 20 tails in a row.
Inactivation and Skewing
Everyone (both males and females) needs one active X chromosome in each of their cells, but two active ones would be too many. For males, this is simple because they only have one X, but for females who have two Xs, one is inactivated or shut down in each cell. This is usually a fairly random process, about 50% of cells shut down X1 and about 50% shut down X2. So for a girl or woman with MECP2 duplication on one of her Xs and random inactivation, about half her cells would produce excess MeCP2 protein. This might not be as bad as for an affected boy since all of his cells will produce too much, but the excess would still be enough to produce very significant symptoms.
Fortunately, cells ordinarily can selectively shut down the X with the duplication. So skewing refers to the selective inactivation of one or the other. Women, who are carriers and do not have symptoms or may only have very mild symptoms, selectively inactivate the X with the duplication. Instead of 50-50 inactivation, they inactivate the X with the duplication in most cells, frequently 95% or more. This allows them to lead normal lives and not have the syndrome. As part of their normal lives, they can have children and this allows the inheritance of the MECP2 Duplication to future generations.
Some duplications on the X occur in children of mothers who are not carriers. These are de novo or new mutations. This means that in some cases a boy with the syndrome or a girl who is a carrier could be born to a mother who is not a carrier. Another kind of de novo duplication is not on the X. In this case, a fragment of an X chromosome breaks off and attaches to another chromosome. This affects both boys and girls since the other chromosomes cannot be inactivated. In theory, these could be inherited, but since the boys and girls with these translocations are have severe disabilities, they are unlikely to have children of their own. Therefore translocations are not normally passed through generations.