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    Tests of unknown significance

    see Communicating new knowledge on previously reported genetic variants

    Clinical genetic testing and the increased use of whole-genome sequencing are rapidly widening the gap between the volume of information generated and the medical community’s ability to keep up to date. Take the case of genetic variants of unknown significance, which are identified by the thousands in broad sequencing applications. Immediate issues arise as to where the responsibility lies for informing physicians and patients of clinically actionable information. In this issue, investigators at Partners HealthCare Center for Personalized Genetic Medicine, in Cambridge, MA, argue that information technology support to provide timely updates must be developed in parallel to the tests themselves. The center’s Laboratory for Molecular Medicine currently tracks 10,155 unique variants in 219 clinically relevant genes. Tracking changes in variant classification for just one genetic disease—hypertrophic cardiomyopathy—revealed that over a six-year period, new knowledge pertaining to genetic variants altered 756 patient reports in a clinically meaningful way. To address this growing knowledge gap, Partners launched a health care–provider Web interface to provide updates as new information on genetic variants becomes available, with the intention of eventually integrating it into a unified electronic health record. Through their experience, the authors make the point that IT support for genomic testing must develop in parallel with the tests themselves. —Karyn Hede, News Editor

    Microarray analysis misses some cases of UPD

    see Uniparental disomy: can SNP array data be used for diagnosis?

    The reliability of chromosomal microarray analysis (CMA), a now-standard test for detection of copy-number variants in suspected cases of autism spectrum disorders, is relatively untested for detecting cases of uniparental disomy (UPD), the inheritance of both homologs of a chromosome pair from a single parent. To help assess the test’s diagnostic appropriateness in instances of suspected UPD, investigators at the University of British Columbia, Vancouver, retrospectively analyzed 11 confirmed cases of UPD in chromosomes 7 and 15, which contain clusters of imprinted genes associated with recognizable syndromes, most prominently Prader–Willi syndrome. CMA failed to detect UPD in 4 of the 11 cases. In all 4 cases, complete heteroUPD suggested a final failure of maternal recombination. It is unclear how many cases of UPD on other chromosomes may also be missed by CMA. More sensitive single nucleotide polymorphism–based CMA should detect most UPD cases, but it will not pick up cases of complete heteroUPD. If a strong clinical suspicion remains after CMA analysis, additional testing is warranted. —Karyn Hede, News Editor

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    In This Issue. Genet Med 14, 701 (2012). https://doi.org/10.1038/gim.2012.97

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