Scientific Collaborators in New York and Jerusalem Uncover New Mutation Underlying Rare Sensory Disease

The study described below was published in the April 2012 edition of the Annals of Neurology, the journal for the American Neurological Association and the Child Neurological Society.

At a time when many people are asking when DNA sequence information will have a real application in healthcare, a nonprofit organization based in Brooklyn, New York, is proving that linkage mapping and exome sequencing are already making a major difference in people’s lives.

Bonei Olam is charged with helping families with genetic or undiagnosed diseases, many of them dealing with infertility challenges, to conceive healthy babies using tools such as pre-implantation genetic diagnosis. In 2008, Bonei Olam opened its Center for Rare Jewish Genetic Disorders to find the underlying molecular causes of some of these conditions. They responded to hundreds of families who had been unable to find a diagnosis through traditional medical routes, and established key collaborations with universities, including Hadassah Medical Center in Israel, to help perform the studies. Over the years, the center has funded SNP arrays, Sanger sequencing, variant validation, and the sequencing of more than 100 exomes for family after family.

It was through one of those studies that collaborators from Hadassah Medical Center, New York University, and Bonei Olam discovered a novel mutation that leads to a previously uncharacterized disease linked to hereditary sensory autonomic neuropathy, a group of disorders with the common theme of loss of function in peripheral sensory nerves. This new version is far more severe than its familial dysautonomia cousin and is caused by a mutation in the DST gene, which destabilizes the Dystonin protein. The study, called “Hereditary sensory autonomic neuropathy caused by a mutation in dystonin” was published by Dr. Simon Edvardson, Prof. Orly Elpeleg, and the rest of their team in the Department of Genetic and Metabolic Diseases at Hadassah in the April 2012 issue of Annals of Neurology.

Chaim Jalas, Director of Genetic Resources and Services at the Center for Rare Jewish Genetic Disorders and a co-author on the paper, says that this particular project began when two related families approached Bonei Olam, each having lost at least one child to this uncharacterized disease. The disorder was lethal: all of the affected children, three in total, died by the age of 2.

The team started off with SNP arrays to perform linkage analysis in both families, and later performed exome sequencing on one of the affected children to find the causative mutation. Much of the clinical and functional work in the eight-month project — including identifying the mutated gene and studying its effect in cell lines — was led by Prof. Orly Elpeleg at Hadassah Medical Center in Jerusalem.

Since Bonei Olam doesn’t have an in-house bioinformatics team, Jalas relies for interpretation on various software tools as well as the cloud-based storage and analysis platform from DNAnexus. For this project, he uploaded the raw sequence reads to DNAnexus and ran the Exome analysis tool followed by the Variant analysis tool, which located the mutation — the DST variant that results in an unstable transcript in Dystonin, a protein used in the cytoskeleton. “What DNAnexus does for us is all the bioinformatics, starting from uploading raw reads to performing the alignment, the variant calling, the annotation, and graphical display of the reads on the reference genome,” Jalas says. In the past, the DNAnexus Variant analysis tool has been able to find a variant that other software packages have missed, he says — but he’s most confident when two different software packages call the same variant so it’s more likely to be real.

Once DNAnexus returned the answer, Jalas shared the data with his collaborators, who could log in with their own accounts to review the information. Finally, the research team confirmed the mutation by Sanger sequencing.

Since Bonei Olam isn’t your typical research institute, the real triumph was not the research finding or the publication of this mutation; it’s that “one of the two families is currently pregnant with a healthy baby,” Jalas says.

Ultimately, the success of these studies may prompt Bonei Olam to move toward whole genome sequencing. “I think at some point we will do whole genomes,” Jalas says. “We’re looking into a pilot study of families for whom exome sequencing did not find a causative genetic mutation where we know for sure it’s a genetic condition.”

Paper information:
Hereditary sensory autonomic neuropathy caused by a mutation in dystonin
Simon Edvardson, MD; Yuval Cinnamon, PhD; Avraham Shaag, PhD; Orly Elpeleg, MD, from Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center
Chaim Jalas, from Bonei Olam, Center for Rare Jewish Genetic Disorders
Channa Maayan, MD, from Department of Pediatrics, Hadassah, Hebrew University Medical Center
Felicia B. Axelrod, MD, from Department of Pediatrics, New York University School of Medicine
DOI: 10.1002/ana.23524
http://onlinelibrary.wiley.com/doi/10.1002/ana.23524/abstract

On the Scene at AMIA: Clinical Promise and Informatics Opportunities for Whole-Genome Sequencing

I recently got to attend the American Medical Informatics Association’s (AMIA) Joint Summits on Translational Science, held in nearby San Francisco. The event had tracks for both translational bioinformatics as well as clinical research informatics and served as a unique opportunity to hear about the informatics challenges that are being faced in the clinical realm right now.

Here are a few highlights from the talks I found particularly interesting:

Howard Jacob, director of the Human and Molecular Genetics Center at the Medical College of Wisconsin, gave a very charismatic talk on genome sequencing in the clinic. He told attendees the most compelling reason to use genome sequence with patients is that it’s family history with data. Jacob described an ongoing pilot whole-genome sequencing program at the college, noting that for a patient to be considered for the program, two physicians must nominate him or her and show that the sequencing would be actionable and “end a diagnostic odyssey.” Accepted patients must determine at the outset how much information they want to receive when returning results; some choose to know just the minimum, while others want to know about genetic variations for which we don’t yet understand the disease implications. Enrolled patients receive six to 10 hours of genetic counseling as part of the process.

Jacob said that with an 20% patient acceptance rate (16 out of 80) for the pilot program, clinicians are now eager to eliminate the approval process altogether to get their patients sequenced. To my surprise, four of the 10 cases submitted for insurance approval have gone through. Jacob added that as the cost continues to drop, it will be hard for clinicians not to use this approach for patients, especially for rare diseases and for pharmacogenomics decisions. (He noted that one lesson learned already is that clinical sequencing is not ready for common diseases, with the exception of cancer.) Jacob said the challenges in scaling up sequencing operations in the clinic will be: delivering adequate genetic counseling; selecting the most appropriate analytical tools for clinical sequencing; and determining who can order whole genome sequencing tests.

In another talk, Peter Tonalleto, a professor at the Center for Biomedical Informatics at Harvard Medical School, highlighted the medical opportunities associated with a patient’s genomic variation landscape. His research group is working on analysis pipelines for DNA sequencing, RNA-seq, microRNAs, and methylation. Those pipelines, coupled with preclinical and clinical variant annotation, yield application in areas such as risk prediction, tumor classification, and pathway analysis for alternative treatment approaches. He also noted a cost comparison his team did for a breast cancer project, in which standard practice cost about $19K and next-gen sequencing practice cost about $25K. With these costs finally being on par, Tonalleto told the audience that more clinicians at Harvard Medical School are eager to adopt whole genome sequencing for breast cancer patients.

In all, the conference offered valuable insight into how next-gen sequencing is being adopted in the clinic. It was clear from the talks I saw that clinicians are eager to embrace this new technology, despite the number of hurdles — including insurance reimbursement, approval processes, and technology learning curve — standing in the way. While there are a number of challenges to consider, I walked away from this conference feeling optimistic about the uptake of whole-genome sequencing in healthcare already.

ABRF: A Quick Meeting Recap

Here at DNAnexus, we’re lucky to have a terrific team supporting our goals. In this blog post, we wanted to share highlights from the recent ABRF meeting from the perspective of our marketing manager, Cristin Smith. Here’s her recap.

Just when we thought the Marco Island resort couldn’t be beaten for location, here comes the annual Association for Biomolecular Resource Facilities (ABRF) conference, held at the lakeside Disney Contemporary Resort right in the heart of Disney World, complete with a view of Space Mountain. I’m pretty sure the team back home in Mountain View was a little concerned that we weren’t going to come back.

The meeting’s opening keynote came from Trisha Davis, who runs the Yeast Resource Center at the University of Washington. Her work has focused on using yeast as a proving ground for various technologies, noting that as her center has evolved, so too has her team’s ability to really drill down into targeted interrogations of the organism. During her talk, entitled “Technology Development in a Multidisciplinary Center,” she noted how important it is to integrate multiple complex analyses in an attempt to relate genotype to phenotype.

On the final day of the meeting, “Omics Technologies to Transform Research, Health & Daily Life” also resonated with me. This was Harvard professor George Church’s vision of a future where genome sequence information is widely used and readily available. He spoke about some current logistical limitations, such as the fact that a $100 blood draw is cost-prohibitive, and that the field will have to move toward buccal swabs and other technologies that may cost only $1 to process in order for ’omic testing to become affordable. Citing some 37 next-gen sequencing technologies as the driver for the rapid drop in sequence costs, he said that his own estimate of the current genome price — from sample to interpretation — is $4,000. In order for genome sequencing to become medically useful, Church noted a few factors that will have to be addressed: a focus on completeness and standards to give FDA confidence in these technologies; the need for significantly more genetic counselors than we have right now; and better interpretation software that makes genome analysis truly straightforward.

Overall, we were excited to see how eager the core lab community is to receive technology improvements that generate a higher quantity and quality of sequence data for their customers in support of their research. This enthusiasm was a great setting to unveil our newly redesigned booth at the exhibit hall. It’s hard to find a more tech-loving crowd than the people who run core facilities, and we were glad to meet so many of them last week.