Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1090) contains supplementary material, which is available to authorized users.
Highlights
Parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders
By analyzing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization, we show that clinical diagnosis of genetic disorders can be obtained within 15–36 hours
In this study we focused on Inborn errors of metabolism (IEM), a disease area where rapid diagnostics and treatment have dramatic impact on patient outcome, and where we have established an expert center containing all clinical expertise required for rapid translations of findings into individualized treatment
Summary
Parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Parallel DNA sequencing (MPS) is revolutionizing diagnostics of inherited diseases, and whole-exome sequencing (targeted capture and sequencing of all coding parts of the genome, WES) has recently entered the clinic [1]. With a targeted exome approach, the risk for unexpected and secondary findings is greatly reduced and interpretation of results is facilitated. This conforms to guidelines for genetic testing in children [2], which recommend that analysis is limited to the parts of the genome relevant to an individual patient’s presentation, as well as to international recommendations for next-generation sequencing in clinical practice [3,4]
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