Tuesday, April 19, 2016


Since Tessa was first identified as “developmentally delayed” when she was 12 months old, she has been tested for all sorts of things in search of a diagnosis that would explain her difficulties. They often tell us that she has “some features consistent with X”, but not enough for a diagnosis. There were several times over the years that we were sure it was this or that, and then it wasn’t (hearing loss, apraxia, dyspraxia, autism, etc).

Well, it seems that now we actually have an answer.

We did a genetic test called whole exome sequencing back in December, and the results are in. Tessa has a mutation in a gene called SCN8A, which makes a voltage gated sodium ion channel. My understanding is that this particular sodium channel is mostly located on neurons in the cerebellum, and defects in the channel affect the ability of the neurons to effectively pass signals to each other. I am not a neurobiologist, but I am learning all I can about sodium channels now!

It is considered ultra rare to have a mutation in this gene, and there are only about 100-150 people with this diagnosis worldwide so far. Most of them have epilepsy, which Tessa does not, so we will have to take her to neurology to see if she might have seizures that we are unaware of. Tessa’s mutation was de novo, which means that it was not inherited from Jeff or me, but arose spontaneously. Tessa is the only one with this particular mutation so far, so the geneticist said that they are >95% sure that her mutation created her phenotype (based on the type and location of the mutation), but they can't be 100% sure. Because this type of genetic testing is new, they expect that more people will be found to have these mutations as the testing becomes more common, and we will learn more with time.

Tuesday, April 12, 2016

SCN8A mutation

Our genetics appointment has been moved up to April 19. I asked if there would be anything to actually report to us, since we don’t really need to go in just to hear “this test didn’t come up with anything new”.  She sent me the cover sheet of the test report, which is a little hard for me to interpret (thus I need to go to the appointment!) but it looks like Tessa has a mutation in a gene called SCN8A.

The report says “causative variant in disease gene associated with reported phenotype”. It is autosomal dominant, and she is heterozygous, which means one copy shows the phenotype. The mutation she has is de novo, meaning it happened spontaneously and was not inherited from me or Jeff.  The particular mutation she has (c.2890 G>C) is classified “likely pathogenic variant”, as opposed to “pathogenic” or “variant of unknown significance”. That is how much is on the report. The rest is courtesy of Doctor Google!

This gene makes a sodium channel that is mostly present on neurons in the cerebellum. From what I can tell, if you have a mutation that makes it more active, then you end up with a condition called EIEE13, which is a type of epilepsy, and if you have a mutation that makes it less active, then you end up with a condition called CIAT, which stands for Cognitive Impairment with or without cerebellar ATaxia.  CIAT symptoms include delayed cognitive, delayed motor, ADHD, uncoordinated gait, uncoordinated hands/arms, speech problems. The only symptom she doesn't have for this is crossed eyes.

Most of the stuff I have found online regarding SCN8A mutation relates to the epilepsy type, but even for that it seems pretty rare. Severity of symptoms seems to depend on how each mutation affects the protein function and there is a wide variety of the severity and type of symptoms. I do not see her particular mutation documented previously.  By my research, this mutation is in the middle of the helix of domain 2, subunit 6 of this protein which has 4 repeated domains of 6 subunits each, but I don’t know the significance of that yet.

Since most of this is what I have found on my own with google, this may not be what the doctor actually wants to tell me at all. I will have to find out when we go see her. But this is the latest on what is going on here!

Whole Exome Sequencing Results

My 7 year old daughter was first identified as developmentally delayed when she was 12 months old. Over the years, she has had a lot of testing for various diagnoses, but the tests always come back negative. So we know lots of things that she doesn't have, but have no explanation for her delay. There have been several times that we were just *sure* it was this or that, and then it wasn't. A lot of the tests are sort of subjective, like for apraxia or autism. But some are more conclusive. She's had genetic testing in the past too, but all came back negative.

In December, we went back to genetics for a 3 year follow-up, and they offered us Whole Exome Sequencing, which was not available last time we were there. They did tell us that in our case, with autism-like symptoms, the chances were quite low (about 5%) that they would find anything of interest. And that the test is super expensive if your insurance doesn't pay for it (and a lot don't because they still consider it "experimental"). It turned out that in our case, it would be completely covered (not even a copay!), so we went ahead.

The results just came back (it takes several months), and they do show that my daughter has a mutation in a specific gene which codes for a sodium ion channel which is active on nerves in the cerebellum. My daughter's mutation was not inherited from myself or my husband, but was de novo. Apparently, if a mutation in this gene makes the channel turn on too much, then it causes seizures/epilepsy, and if it makes the channel turn off too much, then it impedes the interaction of the nerves, causing difficulties with motor, speech, attention, and cognitive skills.

After all this time, it is kind of shocking to actually have an explanation and a mechanism for her difficulties. But it is definitely comforting to have a real diagnosis. I have already found a Facebook group for families with mutations in this gene (though most of them seem to have the epilepsy symptoms, which we do not). I also think that when you know a mechanism, there is a possibility of a treatment down the road that might help.

I just wanted to share this experience, in case anyone else is considering Whole Exome Sequencing.