Since cystic fibrosis is the most common genetic disease in white Americans, it's important to understand how it is inherited. As we understand more and more about CF every day, we are recognizing that it is a more complicated disease than previously thought. But for simplicity's sake, we will discuss inheritance of the most common mutation, ∆F508 (pronounced delta-F-508), which Lyss and I have.
∆F508 means that there is a deletion (indicated by the ∆) of a phenylalanine (the amino acid) at the 508th spot in the gene that encodes for the CFTR protein. As I mentioned in a previous post, CF is almost more like a collection of diseases that are caused by different mutations that end up disrupting function of the CFTR protein, and these mutations can disrupt the protein in different ways. These different ways are usually grouped into five classes, but for now (again), I will not be going too deeply in the biology and biochemistry of it all.
We inherit a copy of each chromosome from each of our parents. Cystic fibrosis is inherited through what is called an autosomal recessive pattern. This means that, to inherit CF, you must received a mutation from both of your parents. This essentially means that parents of children with CF – carriers, as they're called – have worse CFTR function than wild types, or people that have both copies of a normal CFTR gene. It isn't known exactly, but the common belief is that at most 50% CFTR function is required to have zero clinical presentation of CF. That could mean that, for some people, you only need 20-30% function. It's impossible to tell right now due to so many other genetic factors. I'd surmise, by my lab experience and own background, people with ∆F508 typically have less than 5% CFTR, and probably closer to 1-3%.
In biology, a way to demonstrate inheritance patterns, especially one that obeys such simple Mendelian genetics like CF, is what are called Punnett squares.
(credit: http://www2.kumc.edu/genetics/risk/punnett.html
(For the record, I am trying to get better at photoshop and stuff and spent about 20 minutes trying to make a graphic to better describe this and it didn't go well. I'll get better soon, I promise.)
In that chart about, the top row indicates the two copies of the gene in parent #1. The large C's represent wild type copies of the chromosome, while the small c's represent mutant copies, or "CF" copies of the CFTR gene. The first column represents parent #2. As you can see, both parents are carriers of CF, while not actually having CF. The term to describe them are "heterozygotes."
Punnett squares are used to map out the possible outcomes of two people having children, but they are simply a formalism to demonstrate likelihoods. In reality, it possible for two adult carriers to have 4 straight children with CF or 4 straight children that don't carry a copy of the mutation or any iteration in between.
This means, when two carriers have a child, there is a 1 in 4 chance that child will have CF, as indicated by the "cc" box. This also means that there is a 3 in 4 chance that child will not have CF, as indicated by the "CC" and "Cc" boxes. However, there is a 1 in 2 chance that their child will be a carrier, indicated by the "Cc" boxes, or heterozygotes, otherwise called "carriers" like their parents. While that child will be healthy, it is possible that CF will still pop up in future generations. The other 1 in 4 chance, the "CC" box, is what called a homozygote recessive, which means that child has both normal copies of the CFTR gene.
One of the most common questions I get asked is "Man, so what is the likelihood that both you and Alyssa would have CF?" Even though each child has exactly the same chance of having CF, it is still possible to calculate the likelihood that both children will have CF.
To do this, you multiply the likelihoods. Since Alyssa and I both had a 1 in 4 chance independently, or (1/4), to determine the combined chance, you multiply those together. The likelihood we would both have CF was a lowly (1/4)*(1/4) or (1/16) chance. In a percentage, that's 6.25%...so not very likely.
A common discussion in the CF community is whether or not parents should have a second biological child once they have already had one with CF or once they are aware that they are both carriers. That's a discussion for another day, and to be honest, that discussion becomes a bioethical, moral, philosophical, and even religious discussion for some so I'm not sure I'll touch on that (I definitely would like to so I probably will. We'll see.). I'll explicitly state: neither Alyssa nor I hold absolutely any ill will towards our parents for choosing to have multiple children, especially in my case, knowing that it could happen again.
Lyss and I were close for a lot of reasons but I think having CF drew us closer. The life we had as siblings was undeniably defined by our concern for each others' health and well-being. In that way, I'm glad we were able to battle together, so maybe that 6.25% chance was a victory in some way. I'm not too sure but I hope I explained all of this clearly.
TL