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Journey towards Diagnosis - Genetics Update

Is it weird that I sit through genetics appointments and phone calls and am half heartbroken because we are talking about the rare of rare that has happened to my family, and half totally intrigued by the incredible beauty and intricacy of genetic science?? (true NERD right here!) Last week we had our first appointment with our official geneticist at Children’s…and let me say that we lucked in to probably the ONLY normal, handsome (wink wink) geneticist to exist in the world…those crazy smart brains have a stereotypical way of lacking all social skills. But I digress. Until now we have only worked with genetic counselors, mostly because until Abby was diagnosed our case was relatively boring. Most genetic epilepsy cases are “de novo”, meaning there is a random, accidental gene mutation present in the child that is not present in the parents. When Emma had normal results from all existing genetic testing, they told us she was likely “de novo” and that it was a low chance of happening in a second child. Enter Abby….now the geneticists are intrigued! We aren’t boring anymore! And the insurance companies are consequently willing to pay for more experimental testing. Enter Whole Genome Sequencing…

OK, timeout. Let me do a super quick high school science class refresh…

We are all made up of Genes, they are the building blocks of what makes you, you. We have two copies of every gene, one that we got from our mother, and one that we got from our father. And we all have tons of random mess-ups, or “variants” on copies of our genes.  If one of our copies has a mess-up that prevents the gene from functioning, the healthy copy takes over. But what happens if both of your copies of the gene have a mess-up? That means you won’t have a healthy copy to takeover for the messed up copy. And that takes us back to the story…

Through Whole Genome Sequencing, our geneticist found that Mark and I both have a broken copy of one particular gene. Well actually I have a broken copy (scientists call that “loss of function”), and Mark has a slightly confused copy where some of the letters of DNA got swapped (science nerds call that “missense”).  And apparently we both passed our broken copies of this gene to Emma AND Abby. Think about that for a minute…first off, what the heck are the chances that out of alllllll the crazy ton of genes we all contain that Mark and I would both have issues on the SAME gene. But then to actually pass them on to not one but both of our children. That can only happen in one of four scenarios… We both pass on our working copies (YAY). Mark passes on his working copy and I pass on my broken copy (his working copy takes over my broken copy and baby is fine, YAY). I pass on my working copy and Mark passes on his broken copy (My working copy overrides his broken copy and baby is fine, YAY). ORRRRR we both pass on our broken copies and baby is affected (Crap). So by that math, there is a 1 in four chance of passing this on to a kiddo. But passing this on to TWO kiddos….it’s a 1 in 16 chance. ON TOP OF the bazillion to one chance that Mark and I could both have mess-ups in the same gene. Our geneticist who by definition works day in and day out in GENES even told us that we are rare. C’mon universe!!

So if I totally ignore that this is happening to my family…I can admit to finding interest some of the crazy cool science-y stuff that our geneticist shared with us. The messed up gene that we passed on to the girls is called PRKRIR. Google that and get ready to read a very limited number of papers written in very foreign science talk that will just leave you very confused. Bottom line…there is like NO research on this gene. So how do we know this gene is the cause of the girls Epilepsy? We don’t. But there are some factors that convince us this is a likely (or at least possible) candidate, primarily the idea of “mutation intolerance”. The theory behind this concept is that if lots of healthy people have mess-ups on a particular gene, then that gene isn’t likely to be linked to disease. So that gene is tolerant of mutations. If we rarely see mess-ups of a particular gene in the population, we assume that is because mess-ups on that gene causes disease, and those diseases then prevent affected people from reproducing and passing those mess-ups on to future generations. Those genes are mutation intolerant. So in short…the more common the mess-up, the less likely it is to cause disease. The more rare a mess-up, the more likely that it is disease causing. That’s evolution at work…natural selection! Our geneticist showed us the statistics on our PRKRIR gene. Taking a group of 1,000 healthy people, on average a gene like PRKRIR should have 30 people with “loss of function” mess-ups like I have. But there were only 4. On average there should be 375 people with “missense” mess-ups like Mark has. But there were only 250. So apparently mess-ups on our gene are pretty rare. This indicates our gene is “mutation intolerant” and more likely to be disease-causing.

So that’s where we ate at…Now where do we go from here….

  • Ideally we could find another family that has passed on their messed up PRKRIR genes to their child. If the child has similar issues as Emma and Abby we can be more convinced the PRKRIR gene causes those issues. Our geneticist has entered us into a program called “Gene Matcher” that tries to do just that. It’s a global database (let me say that again…GLOBAL) that tries to match up families with the same undiagnosed genes. So far we haven’t found any matches. That plus some serious scouring of research papers from our doc and we are officially the only recorded case of this genetic condition in the WORLD! Really? REALLY??

  • If we can’t find another family to compare ourselves to, the next best way to prove this gene is the cause is to inject it in to animals to see if they seize (worms and zebrafish…not cute puppies, don’t worry). Our geneticist has pitched our case to a scientist who does this, fingers crossed he accepts us. But as back-up I have found the names of a few other scientists that use animals to study rare genes and I’m prepared to pester them until they take on our case just to get me to shut me up

  • I’ve reached out to a wonderful scientist named Heather Mefford that I met at the LGS conference this past May. She runs a lab in Washington and has agreed to look at our case. Her lab’s primary goal is to diagnose undiagnosed genetic epilepsies. They have our whole genome raw data and are doing their own independent analysis. It will be very telling if they also come to the conclusion that PRKRIR is a likely candidate, just like Children’s Hospital did.

  • We are still part of a research study called The Rare Genome Project. They are also doing their own independent analysis of our whole genome raw data.

  • And we FINALLY got word that we were accepted into the Undiagnosed Disease Network. They are a well-funded study with some of the most cutting edge resources. Being part of this study requires us to travel to Standford in California for an in-person exam with doctors, so plans for participation in this are still in the works.

Other than that….we wait. We wait for science to catch up to our family. We wait for funding. We wait for research. We wait until we can get an accurate genetic diagnosis. Then we wait until genetic editing technology progresses and we can inject our girls with working copies of their broken genes. We wait for a cure. And while we are waiting….we live. We attend therapies and camps and watch our girls trying so hard. We attend support groups and counseling and bombard our hearts with positive thought. We cry and fight and grieve and laugh and hug and celebrate inchstones. We cook good food and drink too much wine. We soak in baby snuggles and smiles when we can them. We cherish every moment even when those moments are unimaginably hard.

Overall this is HUGE progress for us. A possible gene is one step closer to THE gene. And one step closer to someday finding better treatment. Our family is on the forefront of genetic science, what a crazy thought that is. Our girls are gonna change the world, I know it!




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