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Nature Publishing Group, 2015

DOI: 10.5167/uzh-121601

Nature Research, Nature Genetics, 7(47), p. 717-726, 2015

DOI: 10.1038/ng.3304

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

Journal article published in 2015 by P. A. Van Schouwenburg, Stefano Lise, John Broxholme, Jean-Baptiste Cazier, Andy Rimmer, Alexander Kanapin, Gerton Lunter, Simon Fiddy, Chris Allan, Moustafa Attar, Christian Babbs, Jennifer Becq, A. Radu Aricescu, David Beeson, Celeste Bento and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.