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
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:
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
2. Mutations in the handful of genes that reside in mitochondria, rather than in the nucleus.
"Structural variants," such as translocations and inversions, that move
or flip DNA but don’t alter the base sequence (detectable other ways).
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.
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.
"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.
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.
(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
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.