Personal Genomes Get Very Personal
A scientist believes he is close to finding the cause of his daughter’s disease.
After five challenging years of searching, Hugh Rienhoff might
be near the end of his quest. The bio-entrepreneur, a clinical geneticist by
training, is trying to find the cause of an unusual collection of symptoms in
his daughter Beatrice, including muscle weakness, curled fingers, and long
limbs. About a year ago, Illumina, a
California-based genomics company, sequenced parts Beatric’s genome, along with
that of Rienhoff and his wife. The determined
father has spent the last twelve months searching through the data for mutations that only
Beatrice possesses.
Her symptoms resemble those of a collection of rare genetic
disorders, including Marfan’s syndrome, a condition that leads to defective connective
tissue and serious heart problems. So far, Beatrice doesn’t have any of the
mutations known to cause those diseases, and her heart looks healthy. But that
has done little to assuage her father’s worry. “My primary concern is that she is at risk for
vascular disease,” he says.
Rienhoff has focused his search on genes involved in the molecular
pathway of transforming growth factor beta (TGF-β), a molecule that provides a
common thread between different disorders with symptoms resembling Beatrice’s. The protein is involved in different aspects
of development, including that of smooth muscle. (Prior to the Illumina
sequencing, Rienhoff had been doing his own genomic analysis. He bought equipment
for amplifying DNA and began isolating genes involved in the TGF-beta molecular
pathway from his daughter’s blood, sending them out to be sequenced.)
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With the help of Vincent Butty, a scientist at MIT, Rienhoff
has compiled a list of genetic variations in Beatrice’s genome, filtering out those
found in both his and his wife’s genomes. He is working on the assumption that the
genetic culprit arose anew in Beatrice’s DNA and would therefore be absent in
her parents. Rienhoff and Butty presented the latest findings from their search
at the Personal Genomes conference in Cold Spring Harbor this week–so far, they
have identified approximately 80 genes that less active in Beatrice than her
parents.
One of the biggest challenges, Rienhoff says, is the
software available to analyze the data. “To ask the questions I want to ask
would take an army,” he says. “I’m trying to connect the dots between being a
genomicist and a clinical geneticist. I don’t think anyone here realizes how
difficult that is. I’m willing to take it on because it matters to me.”
Fortunately, Rienhoff has new help in his personal hunt. He sent
the sequence information to George Church last week, a Harvard geneticist who
heads the Personal Genomics Project. And Reinhart says he has now been
approached by sequencing companies offering to do the families entire genome.
“I think there is a message–studying rare diseases is informative
of common diseases,” says Rienhoff. “If we look at the numbers of disorders
related to TGF-beta and Marfan syndrome, we might be able to explain a good
percentage of aortic aneurisms. The same drug that helps Marfan might help
them.”
According to a blog
at Nature.com, Illumina plans to expand the sequencing project.
Because Illumina sequences from mRNA transcripts, Vincent Butty of the
Massachusetts Institute of Technology – who’s been analyzing the data – has
been able to see direct relationships between the sequence of the genes and
their expression levels. For example, he found a variant of CPNE-1 with a
single base pair change. Both Rienhoff and his wife have one normal copy of the
gene and one copy of the variant, but Beatrice inherited both copies of the
variant, and her expression of the gene is drastically reduced compared to her
parents. It’s not clear yet if the variant is responsible for her condition,
however, and there are many other leads to follow in the data.
Nevertheless, Illumina plans to perform this style of transcriptome
profiling on up to nine more family trios, five of whom have children that have
been diagnosed with Loyes Dietz syndrome, and four others with a variety of
clinical presentations including autism, developmental delays and congenital
heart failure.