Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease |
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Institution: | 1. Illumina Inc.San Diego, CA, USA;2. Combi, Matrix Diagnostics (currently Invitae)Irvine, CA, USA;3. Rady Children''s Institute for Genomic Medicine and Rady Children''s Hospital, CA, Encinitas, USA;4. Rady Children''s Institute for Genomic Medicine and Rady Children''s Hospital, CAEncinitas, USA;5. Illumina Cambridge Ltd.Little Chesterford, UK |
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Abstract: | PurposeCurrent diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test.MethodsWe performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.ResultsWe found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs.ConclusionRobust identification of CNVs by GS is possible within a clinical testing environment. |
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