Traditional screens miss many recessive childhood diseases. In a recent paper in Science Translational Medicine, Stephen Kingsmore and his colleagues, then of the National Center for Genome Resources, report results from a screen they developed that takes a more comprehensive look at recessive disease risk. Genome Technology's Christie Rizk recently spoke with Kingsmore — who is now at Children's Mercy Hospital in Kansas City, Mo. — about the screen and his plan for implementing it in the clinic.
Genome Technology: Are there a significant number of childhood recessive diseases being missed by traditional screening methods?
Stephen Kingsmore: Yes. [For] preconception testing today, the recommendations are cystic fibrosis for the general population, and a total of five conditions for Ashkenazi Jewish populations, like Tay-Sachs. Spinal muscular atrophy has not yet been approved by the American colleges, but is now moving into general population testing. On top of that, then, there are a number of individual gene tests on the market and a number of panels on the market, but there are still literally hundreds of disorders for which there is not a test available today — or if it is available today, it's really quite tough to figure out how to get it done.
The issue is that individually, most of these [conditions] are very rare, so they're not commercially viable using standard approaches.
GT: Can you tell me about the method you used for your screen?
SK: We used next-generation sequencing. We had to do target enrichment, and in this particular manuscript we had 437 target genes, about 2 megabases of sequence representing their exomes, and some intronic sequences, for a total of about 7,700 targets. So we enriched those, followed by next-generation sequencing, and then applied a bioinformatic pipeline to actually turn sequence information into genotypes and haplotypes, and then to interrogate the [Human Gene Mutation Database] of human pathogenic mutations.
GT: Do you think this method could be used in a clinical setting?
SK: That's our intent. The paper describes its use in a research setting, but the intent from the get-go has been to put it into the clinical setting and that's why I'm in Kansas City.
We're setting up what we're going to call the Center for Pediatric Genomic Medicine, what will be the first hospital-based CLIA genome center to offer this test for diagnosis in children and also for preconception testing.
GT: In the paper you talk about the need for a "mutation database" and "a comprehensive carrier testing strategy." How do you envision these being implemented?
SK: There are a whole bunch of human variant databases in existence, and probably the best known human mutation database is HGMD out of Cardiff. Most of the databases are voluntary submission and they pretty much accept information [from anyone]. HGMD is a little bit different — it's based on literature curation rather than submissions, so it's of a higher quality. But what we found in our paper, quite alarmingly, was that there was a relatively high rate of incorrect mutation annotations. … What that means is that I believe we really desperately need a very high-quality database for these diseases where we have well-validated clinical correlation, and we would like to be a part of setting that up.
Several of us have moved [to Kansas City] with NCGR's blessing to further develop the test and move it into a CLIA-compliant environment, and then to bring it up for general use. Obviously there are many, many, many questions to be resolved, and we're working our way steadily through that. ... How exactly this should be done and who should be tested are questions we are working diligently on. We've also revised the list of target genes ... and we're now up to 568 diseases.