genetic test results

Fiona's whole exome sequencing came back today. They didn't find anything. Does that mean her deficiency is not a genetic mutation? Nope, it's most likely a genetic mutation they haven't seen before, or it isn't manifested in the exome (more below). I'm not really surprised, because she is so unique, even among rare disorders. They say that 1 in 3 kids gets a result from the test. I'm still waiting for a copy of the test. I really wanted them to find something. Not having a diagnosis is hard.

Fiona didn't get sick at all this summer. We sent her to primary last Sunday for the first time. She loved it. I think we'll keep sending her unless she gets sick. Being around other kids is a good test for her immune system.

Her arm healed really well. She was casted for about 7 weeks. When we were on the Vineyard we took her to the beach. When they took the cast off she had some sand in it. The sand got stuck in her skin, and we had to pick it out. She still thinks there is sand in her skin.

I feel like genetic testing was our last real hope for a diagnosis. Until research catches up I don't think we'll know what Fiona has. I'm curious to know what this means for her future treatment. Unknown combined immune deficiencies are treated with a watch and see approach. Which means that we wait to see if she gets sick before we transplant.

I've copied some information about why whole exome sequencing didn't find her mutation below. Feel free to stop reading, some if it is pretty technical.

The 10 Exceptions
Understanding the limitations of exome sequencing is important because it’s already here. "Be one of the first to get your personal exome sequence," proclaims 23andMe, about its pilot Exome80x project, offered direct-to-consumer, "for research and educational use only."
The first CLIA-certified test, Clinical Diagnostic ExomeTM, became available from Ambry Genetics earlier this year. A news release announcing the diagnosis of three tough cases calls the technology "essentially a human genome project for an individual patient." Said CEO Charles Dunlop, "Some of these families have been trying to figure out what was ailing their children for years, and we solved the riddle in weeks."
But exome sequencing won’t help every family, and here’s my list of reasons why. The technology won’t detect:
1. Genes in all exons. A few exons, such as those buried in stretches of repeats out towards the chromosome tips, aren’t part of exome sequencing chips.
2. Mutations in the handful of genes that reside in mitochondria, rather than in the nucleus.
3. "Structural variants," such as translocations and inversions, that move or flip DNA but don’t alter the base sequence (detectable other ways).
4. Triplet repeat disorders, such as Huntington’s disease and fragile X syndrome. Their mutations don’t change the DNA base sequence – they expand what’s already there.
5. Other copy number variants will remain beneath the radar, for they too don’t change the sequence, but can increase disease risk.
6. Genes in introns. A mutation that jettisons a base in an intron can have dire consequences: inserting intron sequences into the protein, or obliterating the careful stitching together of exons, dropping gene sections. For example, a mutation in the apoE4 gene, associated with Alzheimer’s disease risk, puts part of an intron into the protein.
7. "Uniparental disomy." Two mutations from one parent, rather than one from each, appear the same in an exome screen: the kid has two mutations. But whether mutations come from only mom, only dad, or one from each has different consequences for risk to future siblings. In fact, a case of UPD reported in 1988 led to discovery of the cystic fibrosis gene.
8. Control sequences. Much of the human genome tells the exome what to do, like a gigantic instruction manual for a tiny but vital device. For example, mutations in microRNAs cause cancer by silencing various genes, but the DNA that encodes about half of the 1,000 or so microRNAs is intronic – and therefore not on exome chips.
9. Gene-gene (epistatic) interactions. One gene affecting the expression of another can explain why siblings with the same single-gene disease suffer to a different extent. For example, a child with severe spinal muscular atrophy, in which an abnormal protein shortens axons of motor neurons, may have a brother who also inherits SMA but has a milder case thanks to a variant of a second gene that extends axons. Computational tools will need to sort out networks of interacting genes revealed in exome sequencing.
10. Epigenetic changes. Environmental factors can place shielding methyl groups directly onto DNA, blocking expression of certain genes. Starvation during the "Dutch Hunger Winter" of 1945, for example, is associated with schizophrenia in those who were fetuses at the time, due to methylation of certain genes. Exome sequencing picks up DNA sequences – not gene expression.

From http://blogs.scientificamerican.com/guest-blog/10-things-exome-sequencing-cant-do-but-why-its-still-powerful/

broken arm

Last Friday we went to the movies for date night. During the previews Katherine started calling me. I thought that was strange, so I walked out of the theater and called her back. She told me that Fiona jumped off the couch and broke her arm. I asked how she knew it was broken, and she told me that her arm wasn't straight. I could hear Fiona screaming in the background. I went back and got Christian. We went home and took her to the hospital. They tried to start an IV for pain meds, but her veins kept blowing. They only had 1 arm to work with, so they decided to stop trying. Have I mentioned that as much as a port scares me, I would love it if every vein access was easy? The doctor came in and splinted her arm so they could xray it. Her radius was completely broken, and needed to be set. They gave her some medicine for conscious sedation. and sent us to the waiting room. It bothers me that they didn't try harder to give her something for the pain. When we got back her eyes were red like she had been crying. She got a pink cast from just below her shoulder to the end of her hand. She can still use her  her fingers. She wasn't quite awake, but she kept sticking her tongue out. When she woke up she was so funny! She thought we were in space. She wanted to see a meteor. When we sat her up she told us that she felt dizzy. When we were getting her ready to leave she said something about being back on Earth. She is doing really well. We take her back next week to have her arm xrayed again. In 4 weeks she'll get a shorter waterproof cast.
This week is the Immune Deficiency Foundation conference. I'm really looking forward to it!

more test results

Fiona's gastroenterologist had to go over the slides from her biopsies with the pathologist to interpret the results of her tests. They've diagnosed her with duodenitis, which is inflammation of the duodenum, which is the first part of the intestine. No big surprises. They are going to start watching her for celiac disease. The hard part about testing her for celiac is that most tests use IGA to test. Because she is IGA deficient, the blood tests won't work.

tests results

We got some of Fiona's test results back this morning. They were from the biopsies they took during her endoscopy and colonoscopy. I'm not really sure what the clinical significance is. Everything looks normal, except, "Mild increase in villi intraepithelial lymphocytes, patchy." Intraepithelial lymphocytes are just white blood cells in the gastrointestinal tract. The increase shows inflammation. The report also mentions some, "mild villous blunting overlying prominent Brunner's gland." My first reaction was that villous blunting is from celiac disease, but after some reading it can be caused by an immune deficiency. Hopefully we will hear back from her doctor soon.

We're not sure if Fiona is sick or if she has some allergies starting. She has a really productive runny nose, and a cough without a fever. I'm keeping an eye on her just in case.

Cincinnati yesterday

Fiona had her tests done in Cincinnati yesterday. Everything went well. Her gastroenterologist said that everything looks normal and healthy. They took some biopsies, which should have results in a week. Her pancreatic function test will take a little longer. She was cranky when she woke up, but recovered quickly. We left the hospital just before noon. She's doing fine today.

symptoms

Fiona is having some urinary tract infection symptoms. We're going to the doctor this afternoon. She's also having loose stools. TMI? probably. She seems to get groups of infections. I'm looking forward to the results from her procedures on Friday.

tests

Fiona is scheduled for an endoscopy, colonoscopy, and pancreatic function test on May 15th. The prep for the procedures sounds pretty miserable. The day before her surgery she has to stop eating at 1 pm. After that just clear liquids with miralax for four hours, then just clear liquids. I can't imagine that will be pleasant for either of us. I'm trying to figure out how to keep her from finding snacks, she's a pretty determined kid when she really wants something.