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Development and validation of an expanded carrier screen that optimizes sensitivity via full-exon sequencing and panel-wide copy-number-variant identification

Gregory J. Hogan PhD, Valentina S. Vysotskaia PhD, Stefanie Seisenberger PhD, Peter V. Grauman, Kyle A. Beauchamp PhD, Kevin R. Haas PhD, Sun Hae Hong PhD, David Jennions PhD, Diana Jeon, Shera Kash PhD, Henry H. Lai, Laura M. Melroy, Mark R. Theilmann, Clement S. Chu PhD, Saurav Guha PhD, Kevin Iori, Jared R. Maguire, Kenny K. Wong MS CGC, Eric A. Evans PhD, Imran S. Haque PhD, Rebecca Mar-Heyming PhD, Hyunseok P. Kang MD, Dale Muzzey PhD
doi: https://doi.org/10.1101/178350
Gregory J. Hogan PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Valentina S. Vysotskaia PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Stefanie Seisenberger PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Peter V. Grauman
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Kyle A. Beauchamp PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Kevin R. Haas PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Sun Hae Hong PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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David Jennions PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Diana Jeon
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Shera Kash PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Henry H. Lai
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Laura M. Melroy
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Mark R. Theilmann
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Clement S. Chu PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Saurav Guha PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Kevin Iori
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Jared R. Maguire
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Kenny K. Wong MS CGC
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Eric A. Evans PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Imran S. Haque PhD
2Current affiliation: Freenome, Inc., South San Francisco, CA, United States
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Rebecca Mar-Heyming PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Hyunseok P. Kang MD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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Dale Muzzey PhD
1Counsyl, Inc., South San Francisco, CA, USA (888) 268-6795
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  • For correspondence: research@counsyl.com
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ABSTRACT

Purpose By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the diseases’ respective prevalences, and the screen’s sensitivity for identifying disease-causing variants. Here we present an analytical validation of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide copy-number-variant (CNV) calling, and customized assays for technically challenging genes.

Methods Next-generation sequencing, a customized bioinformatics pipeline, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precludes novel variant identification or interpretation. Variant calls were compared to reference and orthogonal data.

Results Validation of our ECS data demonstrated >99% analytical sensitivity and >99% specificity. A preliminary assessment of 15,177 patient samples reveals the substantial impact on fetal disease-risk detection attributable to novel CNV calling (13.9% of risk) and technically challenging conditions (15.5% of risk), such as congenital adrenal hyperplasia.

Conclusion Validated, high-fidelity identification of different variant types—especially in diseases with complicated molecular genetics—maximizes at-risk couple detection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 20, 2017.
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Development and validation of an expanded carrier screen that optimizes sensitivity via full-exon sequencing and panel-wide copy-number-variant identification
Gregory J. Hogan PhD, Valentina S. Vysotskaia PhD, Stefanie Seisenberger PhD, Peter V. Grauman, Kyle A. Beauchamp PhD, Kevin R. Haas PhD, Sun Hae Hong PhD, David Jennions PhD, Diana Jeon, Shera Kash PhD, Henry H. Lai, Laura M. Melroy, Mark R. Theilmann, Clement S. Chu PhD, Saurav Guha PhD, Kevin Iori, Jared R. Maguire, Kenny K. Wong MS CGC, Eric A. Evans PhD, Imran S. Haque PhD, Rebecca Mar-Heyming PhD, Hyunseok P. Kang MD, Dale Muzzey PhD
bioRxiv 178350; doi: https://doi.org/10.1101/178350
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Development and validation of an expanded carrier screen that optimizes sensitivity via full-exon sequencing and panel-wide copy-number-variant identification
Gregory J. Hogan PhD, Valentina S. Vysotskaia PhD, Stefanie Seisenberger PhD, Peter V. Grauman, Kyle A. Beauchamp PhD, Kevin R. Haas PhD, Sun Hae Hong PhD, David Jennions PhD, Diana Jeon, Shera Kash PhD, Henry H. Lai, Laura M. Melroy, Mark R. Theilmann, Clement S. Chu PhD, Saurav Guha PhD, Kevin Iori, Jared R. Maguire, Kenny K. Wong MS CGC, Eric A. Evans PhD, Imran S. Haque PhD, Rebecca Mar-Heyming PhD, Hyunseok P. Kang MD, Dale Muzzey PhD
bioRxiv 178350; doi: https://doi.org/10.1101/178350

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