Exomes as prevention

There is something hiding in your DNA. There are couple of things I’d like to take issue with in my own genetic code, but alas, we have no say in the mistakes, flaws, mutations and additions to our genes.
My boys had flaws on Chromosome 22 - a result of the unfortunate genetic mash-up between their mother and father. Their chances of being affected - just 25 percent - and their chances of survival  - zero percent - shows what road maps our exomes can be.

But exomes aren’t just for affected babies and their parents. Answers can come for the healthy and living, too.

Actress Angelina Jolie made big headlines this week with the news that she underwent a radical double mastectomy because she carries a fault on gene BRCA1, which increases her risk of breast cancer and ovarian cancer. Her mother died of ovarian cancer at age 56. In her New York Times op-ed piece, Jolie notes that her chance of developing breast cancer was 87 percent. She also has a 50 percent chance of developing ovarian cancer.

“Only a fraction of breast cancers result from an inherited gene mutation. Those with a defect in BRCA1 have a 65 percent risk of getting it, on average,” she wrote.

I can’t speak for what “most women” would do if given the same odds, but I can say that a double mastectomy before a cancer diagnosis is not something I think insurance companies would eagerly cover, leaving most at-risk women to self-test at home and worry. In fact, I wrote a story for my local newspaper in 2009 about how the United States Preventive Services Task Force tossed the standard of mammograms at age 40, instead recommending women get their first mammogram at age 50.
The doctor I interviewed said he wasn’t concerned about fellow doctors supporting early cancer detection for women at age 40.
“It is the insurance companies I am worried about,” (he) said. “I am concerned insurance companies will take this study and turn it into an opportunity to decline to cover mammograms. That is the concern.”

I wrote on this blog about how expensive exomes are, but how beneficial they could be to the people who need them most but can afford them least. This is not a test run for “no reason” or because your mother died of cancer. There is a consensus among my doctors - most of them stunned that the test was covered for us - that our insurance company simply didn’t know what the exome was, that it was coded as a genetic test like all the other genetic tests we had ordered, and that they literally ‘didn’t know to deny it.’

I’m certain that Jolie, who wrote of her concern about the genetic line of cancers in her family, didn’t think twice about having the genetic testing - at an average cost of $3,000. I’m certain that if her health insurance denied a non-medical double mastectomy, she was able to fund the procedures herself.

The question is - who should decide if you get an exome? A doctor? An insurance company? You? Who should make the decision about a double mastectomy or other “elective” surgery? Should the discovery of the faulty BRCA1 gene make the decision? Will testing for that gene become as common as mammograms for prevention?

“For any woman reading this, I hope it helps you to know you have options. I want to encourage every woman, especially if you have a family history of breast or ovarian cancer, to seek out the information and medical experts who can help you through this aspect of your life, and to make your own informed choices,” Jolie wrote.

But I am skeptical that it comes down to a woman’s own “choices.” Given my own rocky experience with making my own “choices” about my health and body and children around laws and regulations written for women who make elective choices instead of necessary ones, I don’t buy it. If the state of Ohio cared about me and my situation, I would not have had to seek health care in Pennsylvania from doctors I didn’t know or trust. My experience was a nightmare plucked straight out of a horror film and it was directed by the law makers of my state.

I don’t believe they can be trusted to let women make these sort of choices about their own health. Mark my words - radical double mastectomies will go from being viewed politically as the smart choice of brave women to become the superficial choice of women who want free breast implants.

But wait! What about the blood test? What about pinpointing BRCA1 to make the determination?
I have a diagnosis on gene ALG12. If I got to week 22 of an affected pregnancy, the proof of that blood test would mean NOTHING. There is not a health care professional in Ohio that could help me.  I would pack my suitcase and go back to the chop shop in Pennsylvania. Because that would be my only “choice,” genetic finding or no genetic finding.

More people need exomes. More insurance companies need to cover exomes and the procedures they dictate after findings. This is serious science that can not only save lives, but direct us down our individual medical paths toward longer, disease-free lives. I’m not talking about just prenatal glycosylation or breast cancer — heart disease, prostate cancer, liver disease, kidney disease, Cystic Fibrosis, Alzheimer’s! Imagine if the disease that killed your grandmother could have been prevented 20 years before her diagnosis. Imagine what that would have meant for her, for your family.

For the record, I think Jolie made the right choice, but my heart hurts for the hardworking Ohio women who will never have the benefit of preventative genetic testing or the surgeries that could save their lives.

The Still Point of the Turning World

In the middle of my exome madness, in my daily blanket coverage of the internet and all things related to DNA/exome/Baylor/genetics, I stumbled across the book “The Still Point of the Turning World” by Emily Rapp.
Rapp’s 6-month-old son, Ronan, was diagnosed with Tay-Sachs, a fatal autosomal recessive disorder with no treatment and no cure. He died just before his third birthday.
The book is astounding. It reaches deep into my chest and puts words to my grief. I always feel a bit crazy in my thoughts - like I wonder why people are so afraid of me now. No one wants to talk to me, in case I should burst into tears or want to talk about something unpleasant, like grief or dead babies. Nobody wants to be the person who makes the Dead Baby Girl cry.
Rapp explains it. She writes about the Earth-shattering moment after diagnosis and the total devastation it leans on a life, on a marriage. She writes about those days of uncertainty - the what in the world are we going to do? times. She writes about the things no one can relate to until they experience it for themselves. We mothers of the dead all have the same, different story, but no one can stretch their imaginations around the horror of it all until they live it and NO ONE wants to live this.

A quotable quote from the book:

"Grief, we understood, would now hijack a part of our day for the rest of our lives, sneaking in, making the world momentarily stop, every day, forever."

One of the most interesting things about Rapp’s story is that she was prenatally tested for Tay-Sachs. Her husband is Jewish, so he was high risk for carrying one of the common mutations. Rapp decided to be tested and she was told that she was not at risk to pass on the disease (recessive = two parent carriers).
BUT (always that genetic BUT) it turns out she carries a rare, Moroccan mutation for Tay-Sachs, a mutation so rare that it didn’t show up on the prenatal screen.
The book shows a lot of Rapp’s background in academic literature. She goes on and on (and on) about her favorite classic books and how they related to how she was feeling. But that dialogue got in the way of her story, dragging it down to the point where I found myself skipping these parts in anticipation of more information about Ronan.
Rapp does discuss Ronan — his decline, the way every moment with him was heartbreaking and precious at the same time, the way it forces parents to live their lives backwards, grieving before a death while they wait for death.
But there are some missing parts that I, as a reader, found a little maddening.
A part of me wanted this book to be a roadmap of grief — a tourist’s guide to how to live when you want to die. I wanted to read about her relationship with her husband — did they disagree on treatment? Did they grieve differently? I wanted to read about how people treated her — was she the Dead Baby Girl at parties? Did she lose friends who think Tay Sachs or dead babies are contagious? Were there any insurance issues, how did they pay for everything? I understand how this experience changed her, but how did it change the world around her to a new experience? Will they try for another baby? Will they do it naturally?
The book, finished before Ronan’s death, also stubbornly omits the details of his death. In an interview with NPR, Rapp said she left that out to maintain some privacy in her situation, which I think I can understand, but who really writes a book about a dying child and they doesn’t discuss how she felt, how she coped, when he actually died?
Rapp also mentioned in the NPR interview that she would have chosen to terminate her pregnancy if a diagnosis had been made prenatally. But she doesn’t address this revelation in the book.
But maybe that is just me, looking for validation.

The book “The Still Point of the Turning World” by Emily Rapp is available at Amazon.com.

Awww, crap.

Awww, crap.

I did it again. I read too much. I Googled one too many times. I’ve filled my brain with the worst of it again.

I have been pointedly ignoring the Google search bar lately. There is a part of me that doesn’t want to know any more about glycosylation 1g. WHhAAaattT? cry the masses! YOU don’t want to KNOW? YOU don’t want to READ and RESEARCH and KNOW!?!?

That’s right. I know what my genetic counselor and Wikipedia told me on E-Day, and that’s as far as I have taken it. My boys are dead and I know what killed them. The truth of it is that there isn’t much to read. There are 10 (now 11) recorded cases of 1g. Those cases have across-the-board anomalies. Just two (in sibs) presented heart defects. BOTH my boys had heart defects. Dandy Walker is also a mentioned presentation, but not in all cases. The problem is this: There aren’t enough of us to survey to fit into symptoms. This is a syndrome that is “syndromatic,” meaning that there is this and that problem and they all add up to something, but no one is sure what that something is until a genetic test confirms it or an exome finds it.
The only thing that is really consistent about glycosylation 1g is that all the babies died. ALL OF THEM.

So I made the decision to choose peace, to enjoy the high of diagnosis and just live in the relief. I pinned to Pinterest instead of worrying about genetics. It was a lovely vacation from being me.

Then I had to read something about it. Not so much about glycosylation, but more about recurrence. This is hard to nail down statistically for all the same reasons it is hard to stuff these poor dead babies into syndromes using birth defects. There just aren’t enough of us to know.

Of course I found something, mostly because I wouldn’t have stopped looking until I found SOMETHING.

www.ncbi.nlm.nih.gov reports:

In the autosomal recessive disorders, the theoretic risks to each sib of an affected individual are, at conception: a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. However, based on outcomes of at-risk pregnancies in families with a child with PMM2-CDG (CDG-Ia), the risk of having an affected child is closer to 1/3 than to the expected 1/4.

What?

You mean to tell me that the rarest of rare diseases diagnosed with a previously undiscovered micro-deletion presents itself in an above-average recurrence than the assumed autosomal recessive theory?

Of course it does.

Now the question is: Does the 1/3 recurrence risk carry across all 19 variables of glycosylation? This study quotes 1a, which is the most common and the mildest form of glycosylation. Does it mean the same for 1g? Or again, are we too rare to know?

Damn you, Google. You win again.

Looking back, moving forward

The last two weeks have been good to me.

I woke up this morning and realized that I have not had a panic attack since E-Day. The panic used to wake me up in the middle of the night — that crushing feeling in my chest and the certainty that I wouldn’t get through the night. This feels like a milestone to me, and I haven’t had many milestones since my second son died.

Yesterday my genetic counselor called to follow up. Good news: Baylor College of Medicine will not only test my first son’s DNA in an attempt to confirm the glycosylation killed both boys, but they will do it for FREE. All I have to do is sign the paper and write a $25 check for DNA transfer.

Of course I had to ask the question no one wants to think about: WHAT IF my first son’s DNA shows no glycosylation? What then? What if that really teeny tiny deletion on my husbands half of his genetic makeup isn’t there? Then what?

“I think that is our fear,” the GC said. “But we will cross that bridge if we get to it.”

How quickly this mama’s mind jumps to genetic disaster!

I also received my summary of care from the clinic, which sort of briefs up the total visit with genetics in case I forgot anything or have any questions. These summaries are fantastic for me. I keep them and read and re-read them because they are, in a way, like the maps through this journey. They show all the dead ends we have met in “going to the wall.” This last summary shows that we reached out and touched the wall and got answers. It is the X that marks the spot.
In the summary, there is a note that my first son’s DNA (tested via microarray) clearly showed my Chromosome 22 mutation (rare, but discovered), but not my husband’s, as it was too small and completely undiscovered and not on the map of things to look for.
Now I can take some very small comfort in the fact that it is discovered now, that someone out there who may only get to the microarray testing of Chromosome 22 will have the benefit of the discovery — a benefit we did not have. If this had been discovered sooner, we would have known what happened to our first son at the microarray and had answers nearly a year earlier.
I’m here to tell you that at my advanced maternal age of 34, a year makes all the difference in the world.

So here’s to another two panic-free weeks in the Ohio sunshine (I hope). And thanks to the ladies who commented on my last post. A writer is only as lucky as the readers who read, yes?

What would you do?

One in four. One in Four. One in FOUR. Twenty-five percent. Seventy-five percent. Risk. Gamble. IVF. Recurrence. Success. Termination. CVS. High risk. Paint the nursery. Order the headstone.

The words run through my head like a news ticker. All day. All night. What should I do?

What would you do?

In the days following our big exome reveal, the shock sustained by our hearts has settled beyond the autosomal recessive recurrence risk. I’m not sure if I would say that our thoughts have extended beyond the understanding of the genetic gamble or if I would describe it as not having gotten any farther than the sheer statistics of our situation.
If I am a carrier of a very rare mutation, a ONE IN A MILLION mutation, and my husband is another one in a million (though it is more rare than that, he is the ONLY known mutation), plus the chance that we would meet and mate, and then the one in four chance of affected pregnancy - holy crap that’s a sad statistic.
And it isn’t fair. Not that any part of this journey has been fair, but come on! I never win the lottery. Heck, I never win a prize basket at the local animal shelter spaghetti dinner. I am never the one in a million. I am never the one in a thousand. Of all the things, of all the ways to be the ONE, why do we have to each be THE ONE and then be THE ONE together?
Thinking about it makes me sad and tired. It makes me irrationally, explosively angry. It brings out a new wave of fresh grief, on a new level of grieving.

Let’s break it down: One in four for any disease is the same outcome, depending on your luck. But one in four for the ultra-rare variant that no one else in the entire world must suffer is mind-bending. I don’t know where to start in untangling this knot of reasoning in my mind.

Let’s get to the action part of this situation - what do we do? Try naturally and roll the genetic dice? It was a 75 percent chance of success the last two times and that didn't happen. The genetic counselors are careful to stress that it is a one in four chance with each pregnancy regardless of the outcome of the previous pregnancy. So, yes, one in four of affected baby, but three to one for a healthy baby.

IVF/PGD? Well, let’s take out a mortgage on the house, shall we? At $15,000 to $20,000 a pop, IVF is a not so fun way to throw money at the problem. I do want to say that it is nice to have this as an option because a lot of people don’t have a diagnosis and I do, which means I have a shot at it. Some people would pay double for this shot. This is the money that puts that addition on our house. It’s the money that sends our daughter to college. It is our retirement, which I’m guessing we will need someday. Or it is IVF, which may or may not work. A lot of ladies like me have no trouble getting pregnant naturally, but then spend $20,000 on science and it fails. Heartbreaking.

Do nothing? What if - and stay with me on this one - what if we just didn’t get pregnant again? What if after all the stress and struggle and science to get the exome with diagnostic results and we just didn’t use it? What if I get a prescription for birth control instead of a referral to an endocrinologist? I don’t think I would regret this decision in the short term. Long term is a different story. I don’t want to be 37 or 39 or 42 and figure out I desperately want a baby.

So readers - are you out there? I’m breaking the third wall and asking - if you were in my very special, one-in-a-million situation, what would you do?

The rarest of the rare - a diagnosis, definitive

"We found it. We found it," our genetic counselor blurted out. "It's recessive."

And I started to cry. And then she started to cry. So we cried.

For the last 34 years I have been carrying a rare mutation on Chromosome 22, gene ALG12. My husband has spent his 32 years on this Earth carrying the only known mutation of its kind, also on gene ALG12. This causes, specifically and definitively, Congenital Disorder of Glycosylation type 1g - a rare and fatal form of a rare disease, caused by rare mutations on rarely affected genes. There are 500 known cases of glycosylation in the world. Our type - 1g - has only 10 (now 11) known cases. In all cases recorded in medical literature, not one of the babies survived.

"Literally, there is a one in a million chance you carry a mutation on this gene and then for the two of you to find each other..." the GC said.

Factor in the 25 percent chance of affected pregnancy - multiply that by two - and you have some really big numbers and some really sad statistics.

So I hold the exome data from our second son in my hand - a scant six pages of heartache and wait and worry. The printout tells the tale of a little boy who would never be born, who would never grow or play or cry, a little boy who held mutations on five other genes for four far more common autosomal recessive disorders and was a carrier for the dominant Cornelia DeLange syndrome - and the rarest thing, the thing no one in Vegas would have worried about statistically - ended his life and our dreams for him and his brother.

We spent all of yesterday trying to wrap our heads around this new information. First, I think, is the stunning realization that the exome found the cause. We had a 25 to 30 percent chance of diagnosis. Of the 30 exomes reviewed by the doctors at our hospital, ours is one of the few to offer such helpful information.
Then, out of the doctor's office and at a ironic hipster coffee shop, we wrapped our hands around mugs of warm chai and wrapped our heads around our future. The autosomal recessive 25 percent has always been our "best case scenario," though we've lost this gamble twice so far.
IVF with PGD is a possibility for us now. Cost is a huge factor, and so is the time frame. It would take weeks to begin the process and for doctors to begin the PGD probe that would find potentially skewed genes in our embryos. But, that said, I'm not sure I would be ready for a pregnancy any sooner than that, either.

I think the one thing that is most notable to me at the end of the exome is the blanket of peace that seems to be tucked around our little family now. The diagnosis in no way brings my babies back to me. It doesn't change any outcomes. But knowing what we know now, saying that we have the information, that we took this to the wall for our boys, is like balm on my still-raw heart. I have so struggled with this unknown killer - was it me? Was it my husband? How could this happen with no prior family history? My questions are answered and there is a calm in my mind and a stillness in my soul that I welcome with all my heart. This is peace. The decisions we made as new parents of lost boys were the right decisions. We have been validated in all the ways every parent hopes to be validated. No one can tell us otherwise.

This is not the end of our genetic journey, by the way. Far from it.
Baylor will now retrieve our first son's banked DNA for comparison to our second son's exome, to confirm - once and for all, that this is the gene mutation that killed both boys. This will put a diagnosis once and for all on the syndromatic physical evidence from MRI's, ultrasounds, genetic testing and autopsies on both boys.
We have been approached by the lead geneticist at our hospital, as she would like to write a medical paper - to be published in a medical journal - about our boys and our genes and our exome. We have also consented to an interview with a major metro newspaper to tell our exome story. This only furthers what I hoped to do with this blog in the first place - to shed a beam of light on the medical and very emotional journey of the exome - what it means for people, for families like mine, who never dreamed they could be so touched - and so saved - by science. I hope that the brilliant minds at Baylor College of Medicine and all the other major and minor players in the world of Sanger sequencing keep congratulating each other on the successes of the exome process, but also take a minute to remember that the results are as emotional for their patients as they are significant for science. At the end of the day, exomes are for people, not just scientists. Exomes may save lives, but they also heal souls.

Keep an eye on this blog space - I'm not done with this journey.

The long end to a long wait (2 days)

I woke up this morning feeling like the sky was going to crush me. The anxiety of the day is overwhelming. I nearly passed out in the shower - I tremble as I type.
The weekend was fine, but mostly because I was insanely busy with a family visit out of town. But back home, in my own bed, with my own laundry waiting for me in the washing machine and my job beckoning, I became crippled by my own thoughts.
Two more days.
My genetic counselor called on Friday to tell me that the Baylor lab had finished the exome and was awaiting a sign-off by the medical director there. The report will be released today or tomorrow and we meet to go over the results on Wednesday.
After 96 days of countdown, it is here. It is here. But now I have to face what comes with the “here and now.” Either we find out what killed my boys or we don’t. It is a classic situation of THIS or THAT. CUT and DRY. BLACK and WHITE.
That said, I got the “but” from my genetic counselor.
She warned me, again, that the test could come back without answers. Of course they will have found everything they can find as of now, but what the clinical significance of those findings mean could be unknown.
She also noted that the exome could uncover “other issues,” meaning that our son could have been a carrier for Cystic Fibrosis or another recessive disorder. Lots of little things that could mean a lot or nothing could rise to the surface of our genetic pool.
So I am going to spend the next two days jotting down all my questions for the genetic counselor - what does THIS mean? What does THAT mean? Can we cross-reference or target test to see if the findings in my youngest son match anything in the genetics of my oldest son?

I need strength. I need peace. I need answers.