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BMC Genomics

, 15:1090

Human and rodent genomics


BackgroundMassively 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.

ResultsWe 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.

ConclusionsWe 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.

KeywordsBioinformatics Clinical diagnosis Inborn Errors of Metabolism Mendelian disease MPS WGS Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-15-1090 contains supplementary material, which is available to authorized users.

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Autor: Henrik Stranneheim - Martin Engvall - Karin Naess - Nicole Lesko - Pontus Larsson - Mats Dahlberg - Robin Andeer - Anna Wr

Fuente: https://link.springer.com/

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