The Genetic Dice
While dating, my husband and I always joked that our kids would have spaghetti limbs. Simon’s got long fingers that bend in crazy ways and is really prone to rolling his ankles. My arms or legs will occasionally pop out of their joint and then just slip back in, and my shoulder blades can stick out a good 3–4 inches to make really creepy “wings.” I’ve never really thought about medical consequence — it’s just an easy way to make kids say “ewwww...do it again!!”
Simon also has a heart condition, aortic stenosis, which he has had since birth. His heart valves didn’t form properly prior to birth which then puts stress on his aorta. It doesn’t affect his life in major ways; exercise is OK, but weight-lifting is too strenuous on the heart so he’s not allowed to get ripped, darn. The doctor told him that if he gets his heart checked on every year we can watch its progression and should be able to have surgery before anything dramatic happens. Probably he’ll have heart surgery in his thirties and then be good as new.
I had a really hard time with this — not as a girlfriend, but as a geneticist. Throughout graduate school I have been surrounded by rare diseases. Not only was I researching a genetic disease and reading about others, I had several friends who had rare diseases themselves. When I thought about his long fingers, his terrible eyesight, his heart condition, I undoubtedly concluded that he had Marfan syndrome. He disagreed. If I was right, having an official diagnosis from someone who has a medical degree and who isn’t his girlfriend wouldn’t change much for Simon. He’d still get the same check-ups with the cardiologist and he still couldn’t get ripped. However, Marfan syndrome is inherited in an “autosomal dominant” fashion; it doesn’t skip generations, and symptoms arise with just one copy of the disease-causing gene. This means if he has Marfan, he must have gotten it from somewhere — is one of his parents at risk of heart failure? This is why I couldn’t let the subject drop.
He let me tag along to his next cardiologist appointment, so I snuck my question in at the end of the visit. “No, he doesn’t have Marfan…” said the doctor, and I have never been so pleased to be wrong, “…but he might have Ehlers-Danlos Syndrome.” The doctor pulled on his skin and looked at his teeth and measured his scars and bent his fingers backwards. As I watched, I kept thinking about my own goofy joints and would then dismiss the thought, paying attention to the diagnosis. The doctor explained that Ehlers-Danlos is related to Marfan — they are both mutations in genes that encode connective tissue proteins. Patients of both Marfan and Ehlers-Danlos Syndrome (EDS) tend to be tall and lanky (check and check), have loose joints (check) and sometimes there are other effects including heart valves that don’t form correctly (check). EDS is sometimes less severe than Marfan and tends to be underdiagnosed because most people who have it just think they are double-jointed; it causes them no problems so they never get it checked out. The whole question-to-diagnosis took about 5 minutes. As we were walking to the car I was mentally going through punnett squares; this would mean that our kids would have a 50/50 chance of also having EDS. I hardly consider that a deal breaker ’cause, I mean, I think he turned out pretty well. He threw my whole genetic world into a whirl when he said: “Funny how your dad has the same heart thing, huh?”
Marfan syndrome is inherited in an “autosomal dominant” fashion; it doesn’t skip generations, and symptoms arise with just one copy of the disease-causing gene. This means if he has Marfan, he must have gotten it from somewhere — is one of his parents at risk of heart failure?
I forgot! My dad never talks about it because he thinks it’s no big deal, but he was also diagnosed with aortic stenosis about 10 years ago. We are both tall and my shoulder blades really are exceptionally weird…what if I have Ehlers-Danlos too?
Simon and I both have goofy joints, but don’t have quite the same symptoms. Still, that wouldn’t be so strange if we had different mutations in the same gene. One reason connective tissue disorders are more common than others is that the connective proteins are long, so there’s lots of different places to mutate that may have slightly different effects on the protein’s function. And if it’s under-diagnosed, maybe EDS isn’t as “rare” as the numbers currently indicate. What are the odds that we could both have slightly different versions of it?
Forget the odds, what are the consequences?! The punnett squares come back. This time, the inheritance pattern looks kind of like autosomal recessive, only everyone carrying at least one copy of the gene will display symptoms. There’s a 50% chance our kid could get one mutated gene from either Simon or I but would still have a normal copy from the other parent. They would have symptoms, just like we have symptoms, but that would presumably be no big deal, ’cause, I mean, I think I turned out pretty okay too. There’s a 25% chance the kid would inherit normal genes from both of us and be more “normal” than either of us…score! Then there’s another 25% chance that the kid would inherit one mutated gene from each of us. That poor hypothetical kid has two mutated genes, and nothing making the normal version of this very important protein. Suddenly the consequence of our “spaghetti kid” seem very scary. Would she have exacerbated connective tissue problems? Would she be born with not only loose joints, but weak blood vessels and a severely deformed heart? Problems with her digestive tract? Would her body have trouble forming the basic parts needed to hold together skin? How severe could this be?
We are both tall and my shoulder blades really are exceptionally weird…what if I have Ehlers-Danlos too?
“Calm down,” I had to tell myself, “It’s okay. You literally have training for this. You literally have been preparing for this.”
Through graduate school I studied a devastating disease called Spinal Muscular Atrophy (SMA). Many people are familiar with Lou Gehrig’s Disease, or ALS, so I often tell them that SMA is like ALS, but it’s usually in kids — most die by age 2. I am terrified of SMA. I have met many brave SMA families and heard their struggles to keep managing symptoms, day by day. Because of this, the moment I heard about family planning screening, I studied up on it and decided that my husband and I would be tested for things like SMA before we think about having kids.
The testing is simple: spit in a tube and then ship it off. Unlike other genetic testing, these results won’t tell you where your ancestors migrated from or whether you are at risk for cancer. This test simply tells you whether you are a “carrier” for a panel of genetic diseases. Unlike Marfan and EDS, we’re talking autosomal recessive diseases here, which means that you can have one “bad” copy of the gene, but as long as you’ve got one functional copy, you have no symptoms. Despite the fact that you are healthy, you are still carrying the “bad” gene (or often a deleted gene) that could cause your child to inherit the disease, hence it is said that you are a “carrier” for the disease. Diseases like SMA come about when both parents pass on their “bad” copy of the gene. For SMA, about 1 in 50 people are carriers. They are healthy and have no family history of the disease, so they have no way of knowing that they are at risk for passing SMA on to their child. This form of genetic testing will determine our carrier status for not only SMA, but about 100 other conditions as well.
If you don’t get tested, you live quite happily unless your roll of the genetic dice goes poorly:
At first, the idea of discovering you are a carrier is a terrifying concept if you want to have kids. Again, you will still be perfectly healthy, but being a carrier can affect the next generation.
However, like most things in life, I consider this to actually be a “knowledge is power” situation. If you get tested and find out you and your spouse are not carriers for the same disease, you just have kids like normal. But if you are a carrier, there is much good you can do with that information.
Not all diseases are as devastating as SMA. On the list of diseases commonly screened for, many conditions are much more mild. For example, if you find out you are a carrier for a MTHFR mutation (a relatively common condition with carrier frequency of about 1:2 or 1:3), consult a doctor, and you may have to take extra folate when you are pregnant or have a higher chance of miscarriage. Carrier for DFNB1 nonsyndromic hearing loss and deafness (carrier frequency 1:33)? You may have to navigate the waters of deafness, but the child will have no other symptoms from this disorder, so you may just want to have children like normal. Even if your child inherits the condition, they can potentially get a hearing aid or just enjoy being part of a vibrant deaf community. Other conditions have treatments that can help symptoms dramatically. For example, Wilson’s Disease causes inappropriate copper build-up which can be managed with medication. While symptom onset is usually in the teenage years, if you know your child is at risk, your doctor can monitor the child and begin treatment even before symptoms onset.
If you get tested and find out you and your spouse are not carriers for the same disease, you just have kids like normal. But if you are a carrier, there is much good you can do with that information.
Say you are a carrier for something very serious, like SMA, or potentially serious, like our hypothetical double-mutant Ehlers-Danlos Syndrome kid. You may think you fall into the “no kids for us :(” category. Actually, if you find out you are carriers, there are actually lots of options depending on how important it is to you that you are both the biological parents.
Certainly, each of these have their own benefits and drawbacks, and nobody can make this decision for you. There are physical, financial, and ethical considerations to each option. For example, if you decide to take the 25% risk, you may find yourself confronting the decision between aborting the fetus or bringing it into a world where your child must suffer before certain death. In vitro fertilization with preimplantation diagnosis is a process in which doctors use the egg and sperm from you and your partner to create several fertilized eggs. When these eggs have divided just a few times, one cell is removed for genetic testing. You and your doctor choose those eggs that do not carry the genetics for the disease to be transferred back into the uterus for implantation and normal development. In this scenario, realize that you may have extra fertilized eggs in a freezer that you need to decide whether to keep. You may also end up with twins or triplets and should be prepared for a busy household. None of these options are cheap, as even avoiding all the crazy medical procedures by adopting can cost tens of thousands of dollars. When I am considering this, the real question becomes: “is it worth making hard decisions to avoid being blindsided by a disease that we could have seen coming?” I think so. This is a panel tests that look for some of the most common mutations that are known to cause disease. Many insurance companies cover this type of screening for parents-to-be, leaving the cost around $200.
When I am considering this, the real question becomes: “is it worth making hard decisions to avoid being blindsided by a disease that we could have seen coming?” I think so.
Genetic diagnosis can be hard. First, I worried that if we are both diagnosed with Ehlers Danlos, it would be irresponsible to have kids: spaghetti-arms could be managed, but a child with two mutated copies encoding every connective tissue in the body sounds to me like a recipe for severe, quality-of-life-compromising problems. Next I worried that we would have to get started on the process of adoption ASAP because I’ve heard it can be a slow and arduous process. I was sad that I’d never experience pregnancy, or that our kids wouldn’t inherit some of Simon’s best qualities. Then I realized that if we decided we wanted to, in vitro fertilization with preimplantation genetic diagnosis could be an option for us to have kids that are genetically related, but protected from disease. Finally, I realized that I don’t have to figure this out all right now, and that there are steps I will be happy to take.
Step 1: We need to figure our own genetic diagnoses to take care of ourselves and our parents accordingly.
Step 2: We will talk to a certified genetic counselor, get tested, and determine our carrier status.
Step 3: We will choose from our list of options.
Step 4: We will love whatever baby fate and/or medicine provide.
Authors note: The medical information in this article regarding my husband and I is currently speculative. We don’t have confirmed diagnoses for ourselves, much less know yet what that means for our children. However, this experience has served as a reminder to me that though they are classified as “rare,” the reality is that 1 in 10 people have a genetic condition, and therefore we are never too many steps away from genetic disease.