Genetics

I met with the genetic counselor the other day. He remembered me from the last time I was there (after my anencephaly pregnancy, before my omphalocele pregnancy was diagnosed).  He was (obviously) very sad to see me again. His expertise is genetics and, unsurprisingly, based on our history, age, and the low heart rate, was of the mind that the question was not if this pregnancy is doomed, but when we diagnose what the issue is.  Gotta love a realist.  We talked through our plan for finding the issue.

The next step is my 9 week appointment next week.  Assuming there is still a heartbeat the next step is….

A blood test.  The high-risk OB runs a free cell DNA test through Natera that can be done as early as 9 weeks.  It tests for the fetal fraction of DNA in mom’s blood—it cannot be done before 9 weeks because there’s not enough DNA there.  Even at 9 weeks, they might not be able to get a result, especially if mom is heavy (over 200lbs).  Fortunately I’m a skinny-minny (although less skinny by the day) so we are going to give it a try right at 9 weeks.  That test looks for common chromosomal issues, including Down syndrome, Trisomy 18, etc.  It also tells us gender.  (If we did it through the regular OB’s office, we couldn’t do it until 10 weeks.  Their testing lab is Harmony.)  We should get the results in about a week, although we are not expecting a bad result from that—my genetic problems have not been chromosomal, and the risk even at my age (39) for a bad result is only like 3%.

After that, the next step is the 12 week appointment at the high risk OB. They will do what’s called a level 2 ultrasound, which will look at growth, heart rate, and nuchal cord measurement, and should be able to diagnose anencephaly (which we’ve had in the past) and omphalocele (also something we had in the past).  It is not usually able to detect spina bifida or other minor structural issues. 

After that, the next step would be another scan at 15/16 weeks, again at the high risk OB.  Once again, we’d be looking for major structural defects, including those of the heart.  It should also be able to catch a severe case of spina bifuda.

If we have reason to think there’s a chromosomal issue that was not picked up by the free cell DNA test, we could do an amnio sometime around 15 weeks.  That test look for all chromosomal issues, not just the common ones.  But if we don’t have some reason to think that’s an issue, we likely will not do an amnio.

Also at 15 weeks, we could do an AFP test—which looks for anencephaly / spina bifida.  Not sure if we will do that, because anencephaly should be picked up at the 12 week scan, and spina bifida should be picked up at the 15/16 week scan.  The AFP test can miss minor cases of spina bifida that would be more likely to get picked up on a scan, so there’s no obvious reason to do it if you’re having those scans and looking for the problem.

The next step would be the 20 week appointment.  That’s the big one that would catch most structural issues.

So that’s it. We’re approaching this pregnancy like there’s something wrong, we just want to find it as soon as possible.  That’s pretty depressing.

We also talked about what the likely cause is.  The geneticist says there’s nothing obviously jumping out at him because we have a living child, so whatever the issue is, it’s not 100% fatal.  At the same time, we have had so, so many losses, and they do not appear to be the same thing each time.  It’s confounding!

Thinking out loud, here were some of his thoughts:

·        It could be a recessive genetic condition.  He thinks that’s unlikely because recessive genetic conditions should only have a 25% recurrence, and we have had 9 pregnancy losses (soon to be 10?) and only one live born child.

·        It could be a dominant genetic condition.  For the same reason, that’s unlikely because there should only be a 50% recurrence, and we are far beyond that.

·        It could relate to mitochondrial genetics, which have a unique inheritance pattern and are passed on from mother.  (I do not understand this one.)  He said this was unlikely because it is not generally related to the issues we see.

·        It could be one or more mutations on the MTHFR gene.  MTHFR is a common mutation: ½ of the population has 1 mutation, 10% have 2, etc.  He acknowledged that nothing was proven, but there is a theory that the more mutations there are the increased risk there is for pregnancy loss and particularly NTDs.  The mutations can affect the way you metabolize folic acid.

o   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385168/ (“Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects”)

·        It could be a defect in some other way I metabolize folic acid or something else.  I wasn’t surprised to hear that because I’d previously read a theory that some NTDs could be caused because mom wasn’t properly metabolizing folic acid.  For example, obese women and women with diabetes are more likely to have pregnancies with NTDs.

o   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982189/  (“Intersection of complex genetic traits affecting maternal metabolism, fetal metabolism, and neural tube defect risk: Looking for needles in multiple haystacks”)

·        It could be a germline mosaicism.  A mosaicism is when some cells differ in their genetic component from other cells, caused by a mutation early in development. When the mosaicism is germline, that means it affects the eggs or sperm. So, it might be that one or both of my/hubby have some defective/fatal genes we are passing on, but they are combined with normal cells so there is some development, and sometimes they are not fatal (see my kid).  The fatal cells do cause problems, if there are enough of them.  (To be clear, this means the baby is a mutant.)  I read a number of articles on this, it’s very complex. 

o   https://www.ncbi.nlm.nih.gov/pubmed/3033033 (“Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin.”)

o   http://www.nature.com/nrg/journal/v14/n5/full/nrg3424.html?foxtrotcallback=true (“A genomic view of mosaicism and human disease”)

His theory is that it’s likely some genetic alteration of an in important gene in fetal development, either from me or hubby.  That would explain the recurrent pregnancy loss with different problems, and would also explain why it does not mean we have 100% loss.  He also thought it could be the way I metabolize folic acid or some other metabolic issue.  Let’s be honest, it’s probably multifactorial.

We talked again about exome sequencing.  He thought it was unlikely to yield results.  It generally only provides a potential answer 30% of time, and he thinks our likelihood might be less because we are not seeing the same thing over and over again suggesting there’s a “simple” answer.  He told me that in the past year he saw a couple who had a situation eerily similar to our own.  They had a living child, but had a number of miscarriages and two pregnancies with severe issues—one with a NTD (spina bifida) and another with severe birth defects.  They chose to do exome sequencing and did not get a result.

That made me really sad for this couple I'll never know. Because they're like us.