Journal article

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Jenny C Taylor, Hilary C Martin, Stefano Lise, John Broxholme, Jean-Baptiste Cazier, Andy Rimmer, Alexander Kanapin, Gerton Lunter, Simon Fiddy, Chris Allan, A Radu Aricescu, Moustafa Attar, Christian Babbs, Jennifer Becq, David Beeson, Celeste Bento, Patricia Bignell, Edward Blair, Veronica J Buckle, Katherine Bull Show all



To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variant..

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University of Melbourne Researchers


Awarded by Wellcome Trust

Awarded by Medical Research Council

Awarded by Biotechnology and Biological Science Research Council (BBSRC)

Awarded by Newlife Foundation for Disabled Children

Awarded by European Research Council

Awarded by Action de Recherche Concertee

Awarded by Gebert Ruf Stiftung

Awarded by Swiss National Science Foundation

Awarded by Shriners Hospitals for Children

Awarded by UK Medical Research Council

Awarded by Academy of Medical Sciences (AMS)

Awarded by Biotechnology and Biological Sciences Research Council

Awarded by British Heart Foundation

Awarded by Cancer Research UK

Awarded by National Institute for Health Research

Awarded by Action Medical Research

Funding Acknowledgements

This work was funded by a Wellcome Trust Core Award (090532/Z/09/Z) and a Medical Research Council Hub grant (G0900747 91070) to P.D., the NIHR Biomedical Research Centre Oxford, the UK Department of Health's NIHR Biomedical Research Centres funding scheme and Illumina. Additional support is acknowledged from the Biotechnology and Biological Science Research Council (BBSRC) (BB/I02593X/1) to G.L. and G.M.; Wellcome Trust grants 093329, 091182 and 102731 to A.O.M.W. and 100308 to L.F.; the Newlife Foundation for Disabled Children (10-11/04) to A.O.M.W.; AtaxiaUK to A.H.N.; the Haemochromatosis Society to K.R.; European Research Council (FP7/2007-2013) grant agreements 281824 to J.C.K. and 305608 to O.D.; the Jeffrey Modell Foundation NYC and Baxter Healthcare to S.Y.P. and H. Chapel; Action de Recherche Concertee (ARC10/15-029, Communaute Francaise de Belgique) to O.D.; Fonds de la Recherche Scientifique (FNRS), Fonds de la Recherche Scientifique Medicale (FRSM) and Inter-University Attraction Pole (IUAP; Belgium federal government) to O.D.; the Swiss National Centre of Competence in Research Kidney Control of Homeostasis Program to O.D.; the Gebert Ruf Stiftung (project GRS-038/12) to O.D.; Swiss National Science Foundation grant 310030-146490 to O.D.; the Shriners Hospitals for Children (grant 15958) to M.P.W.; and UK Medical Research Council grants G9825289 and G1000467 to R.V.T., L009609 to A.R.A., G1000801 to D.H. and MC_UC_12010/3 to L.F. The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health.