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Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism
Vise andre og tillknytning
2014 (engelsk)Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, s. 1090-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.

sted, utgiver, år, opplag, sider
2014. Vol. 15, s. 1090-
Emneord [en]
Bioinformatics, Clinical diagnosis, Inborn Errors of Metabolism, Mendelian disease, MPS, WGS
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-159625DOI: 10.1186/1471-2164-15-1090ISI: 000347574000001PubMedID: 25495354Scopus ID: 2-s2.0-84924290563OAI: oai:DiVA.org:kth-159625DiVA, id: diva2:787155
Forskningsfinansiär
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council, 12198The Karolinska Institutet's Research FoundationKnut and Alice Wallenberg FoundationThe Swedish Brain Foundation
Merknad

QC 20150209

Tilgjengelig fra: 2015-02-09 Laget: 2015-02-05 Sist oppdatert: 2020-03-09bibliografisk kontrollert

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