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.)

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.