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

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Taylor, Jenny C ; Martin, Hilary C ; Lise, Stefano ; Broxholme, John ; Cazier, Jean-Baptiste ; Rimmer, Andy ; Kanapin, Alexander ; Lunter, Gerton ; Fiddy, Simon ; Allan, Chris ; Aricescu, A. Radu ; Attar, Moustafa ; Babbs, Christian ; Becq, Jennifer ; Beeson, David ; Bento, Celeste ; Bignell, Patricia ; Blair, Edward ; Buckle, Veronica J ; Bull, Katherine ; Cais, Ondrej ; Cario, Holger ; Chapel, Helen ; Copley, Richard R ; Cornall, Richard ; Craft, Jude ; Dahan, Karin ; Davenport, Emma E ; Dendrou, Calliope ; Devuyst, Olivier ... view all 110 authors (2015)
  • Journal: Nature genetics (issn: 1061-4036, vol: 47, pp: 717-726)
  • Related identifiers: pmc: PMC4601524, doi: 10.1038/ng.3304
  • Subject: HEREDITARY BREAST | 06 Biological Sciences | GERMLINE MUTATIONS | BREAST-CANCER | High-Throughput Nucleotide Sequencing | Molecular Sequence Annotation | Genetic Diseases, Inborn | OVARIAN-CANCER | Polymorphism, Single Nucleotide | Base Sequence | Genome, Human | JUVENILE MYELOMONOCYTIC LEUKEMIA | Life Sciences & Biomedicine | SEVERE INTELLECTUAL DISABILITY | Developmental Biology | Molecular Diagnostic Techniques | LONG-QT SYNDROME | Sensitivity and Specificity | Article | EXOME | Science & Technology | CANDIDATE GENES | 11 Medical And Health Sciences | Genetics & Heredity | DNA Mutational Analysis | DISEASE GENE-DISCOVERY | Humans

To assess factors influencing the success of whole genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases across a broad spectrum of disorders in whom prior screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritisation. 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, rising to 34% (23/68) for Mendelian disorders and 57% (8/14) in trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, though only four were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis, but also highlight many outstanding challenges.