Abstract
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 variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 717-726 |
| Number of pages | 10 |
| Journal | Nature Genetics |
| Volume | 47 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jun 26 2015 |
Funding
We thank the patients and their families who consented to these studies and the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics for the generation of the sequencing data. Additionally, we are grateful to F. Harrington, C. Mignion, V. Sharma, I. Taylor and I. Westbury for assistance with molecular genetic analysis and the staff of the Oxford University Hospitals Regional Genetics and Immunology Laboratories for the DNA preparation for some of the samples. 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\u2019s 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 Concert\u00E9e (ARC10/15-029, Communaut\u00E9 Fran\u00E7aise de Belgique) to O.D.; Fonds de la Recherche Scientifique (FNRS), Fonds de la Recherche Scientifique M\u00E9dicale (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 R\u00FCf 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.
ASJC Scopus subject areas
- Genetics