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Friday Science Review: March 4, 2011

The Origin of Meier-Gorlin Syndrome

Dalhousie University ♦ University of Montreal ♦ University of British Columbia

Published in Nature Genetics, Feb. 27, 2011

Researchers have mapped a locus for Meier-Gorlin syndrome (MGS), a rare genetic condition characterized by short stature, small ears, and reduced or absent kneecaps. A mutation in the ORC4 gene seems to be at the root of the disorder. ORC4 is a component of the eukaryotic origin recognition complex.

To map the locus responsible for MGS researchers performed high density genome-wide SNP genotyping using a panel of 600,000 markers provided by Illumina. The next stop involved PLINK, a whole genome analysis toolset, which was able to identify a haplotype on chromosome 2 within a number of affected individuals. Sequencing of coding exons located in the ORC4 gene led to the identification of a missense mutation that causes a tyrosine (residue 174) to cysteine switch in the ORC4 protein. The tyrosine residue affected in MGS is completely conserved across eukaryotes suggesting it has an important function; the amino acid is also believed to interact with a conserved arginine residue on a nearby helix motif in the protein structure. In the absence of this interaction the structural integrity of the protein could be compromised in part.

The origin recognition complex consists of six proteins in humans and is essential for DNA replication. It plays a critical role in recognizing origin sites on DNA and in the formation of DNA replication forks. This is the first report of an inherited mutation in any gene of the origin recognition complex in the vertebrate literature.

The Human Serum Metabolome

University of Alberta ♦ National Institute of Nanotechnology

Published in PLoS ONE, Feb. 16, 2011

Human biofluids are very important from a clinical standpoint given the insight they can provide into the disease conditions of a human being. The study of metabolomics attempts to identify, on a large scale, the composition of metabolites found in these biofluids. The advent of advanced analytical techniques along with mounting pressures for scientists in the metabolomics community to document the entire human metabolome, led to the development of the Human Metabolome Project. The project is supported by Genome Alberta and Genome Canada, the latter of which is a private, non-profit, corporation that received $600 million in funding from the Canadian government to develop and implement a national strategy in genomics and proteomics.

The most recent contribution to the project is a comprehensive multicentre study led by Dr. David Wishart at the University of Alberta. Using a diversity of metabolomics platforms researchers were able to identify, and quantify, metabolites found in human serum. The use of different methods, including nuclear magnetic resonance (NMR), and various mass-spectrometry platforms (GC-MS, LC-MS), increased the overall coverage of the serum metabolome. Data gathered via these platforms was linked to computer-aided literature mining which allowed for the development of a virtually complete set of metabolites. In total the group found 4,229 metabolites, but this number may increase in coming years as more powerful characterization techniques are developed.

Dr. Wishart and his colleagues previously characterized the human cerebrospinal fluid metabolome.


Personalized Medicine Conference Highlights a Busy Month

Last week, Harvard Medical School held a conference entitled “Personalized Medicine: The Time is Now.”  Is the time now?  Looking around, it seems like personalized medicine has had a pretty good month:

PBMs Drive Demand

CVS Caremark, the country’s largest pharmacy services provider, partnered with Generation Health to expand pharmacogenomic testing for cancer, cardiovascular diseases, and HIV.  According the GenomeWeb story, CVS Caremark joins Medco‘s 60 million people, meaning the top two PBMs in the U.S. are investing heavily in personalized medicine.

Though note that PBMs’ interest in personalized medicine isn’t wholly neutral, as this post at IVB by Michael McCaughan points out.

Corporate Deals

Three pairs of corporations found the economics sufficiently attractive to strike new partnership deals:

NCI Investment To Advance Research

Finally, helping ensure that there is sufficient research output to advance the field, the National Cancer Institute put out a program announcement entitled “Development, Application, and Evaluation of Prediction Models for Cancer Risk and Prognosis,” which NCI says will be “essential for tailoring therapy to appropriate groups of patients.”

Counterpoint

Still, as the Washington Post notes in its article on the new “Ignite Institute” in Fairfax County: “[y]ou’d be right, of course, to be a bit skeptical,” citing decades of promise and so far few commercial successes in the region.

Bottom Line

Given this month’s developments, our Magic 8-Ball says “Outlook good.”  Stay tuned to see what develops, particularly as personalized medicine and comparative effectiveness grow in prominence at the same time.

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Trends in 2009: Direct-to-Consumer Genetic Tests Come to Canada

B&W_DNA_sequenceThis week saw the introduction of what I believe is Canada’s first personal genomics service offering.  Toronto’s Medcan Clinic paired up with California-based Navigenics to scan individuals’ genomes for a variety of disease markers.

Personal genomics is a burgeoning trend this year, which according to a special report in April’s Economist, will only be further boosted by a Moore’s Law-type improvement in sequencing power and price.  Available service offerings range from whole genome sequencing (e.g., Illumina and Knome) that costs tens of thousands of dollars to targeted scans typically offered for under $500 by a much wider variety of providers (Navigenics, 23andMe, deCODE and Pathway Genomics).

Regulation of DTC Testing:

In the U.S., the regulatory environment has settled down somewhat over the last 6 months, with most U.S. states regulating DTC genetics companies as clinical labs and the providers registering as such on a regular basis, including CLIA certification.  However, the HHS Secretary’s Advisory Committee on Genetics, Health and Society is due to meet in October to further discuss whether DTC genetic tests should be regulated as medical devices.  The CDC has released a report entitled “Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions” setting out best practices both for testing and interpretation.

In Ontario, there are a number of regulatory considerations (thanks on these points for input from Will Chung, of our renowned Life Sciences team):

  1. Private labs and specimen collection centres require licenses and are governed by the Laboratory and Specimen Collection Centre Licensing Act (LSCCLA). However, blood collection at such facilities is governed by separate legislation which controls who may draw blood and for what purpose.
  2. The LSCCLA requires that only “legally qualified medical practitioners” are permitted to examine specimens, which means that patients may not directly order testing of their own blood at private licensed labs.
  3. Ontario’s Regulated Health Professions Act stipulates that communicating a “diagnosis” is a “controlled act” which may only be performed by a person authorized by a health profession Act, although it is not clear that DTC genomics results are a “diagnosis.”

Medscan seems to have navigated the regulatory waters, but time will tell how these laws are applied and/or modified.

In the EU, the European Society for Human Genetics advocates for pre-market review for “truthful labeling and promotion” as well as post-market evaluation of DTC genetic tests. In May, Germany passed a law restricting the availability of DTC genomics services by requiring testing to be carried out by a licensed doctor following the patient’s consent.”

How much protection do consumers need?

Many commentators are concerned with the public’s ability to understand these tests and distinguish between those that are clinically meaningful and those that are more … snake-oily.  Others object on the basis that there is little value added absent any available treatment — many preventive measures are things we already know we should do, like eat well, exercise, etc.  A number of groups, including advocacy group Genetic Alliance and the Genetics and Public Policy Center at Johns Hopkins University have called for a national registry of DTC genetic tests that would include performance data.

Others (and not just 23andMe’s founders) take a more libertarian view.  Ronald Bailey, the science columnist at Reason, agrees that people probably don’t need to be “protected against learning such information without the guidance of a knowledgeable physician or genetic counselor.”  In fact, a lawsuit in May brought by a girl born with Fragile X syndrome against the sperm bank that didn’t test for the predisposition may drive  higher demand for genetic testing in the fertility context which may in turn drive supply of services and diagnostic tools and may contribute to normalizing broader parental testing and pre-implantation screening.

Interestingly, a NEJM report a couple of weeks ago showed no lasting psychological damage from a genetic prognosis of increased Alzheimer’s risk.  By the time a year passed after the results, subjects who had an increased Alzheimer’s risk were no more depressed, anxious, or distressed than when they started the study.

Most importantly, 98% of patients in the Alzheimer’s study who tested positive said they would still get tested if offered the choice again.  98% is a lot. It suggests that DTC services will be increasingly popular, particularly as the price drops and the quality of the data, the analytics and the available counseling continue to improve.

Stay tuned to this page for further DTC genetics news and analysis.

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