. 2024 Mar 3;17(1):62.

doi: 10.1186/s13104-024-06723-w.

Genetic sex validation for sample tracking in next-generation sequencing clinical testing

Jianhong Hu¹, Viktoriya Korchina¹, Hana Zouk^{2

3}, Maegan V Harden⁴, David Murdock^{1

5}, Alyssa Macbeth⁴, Steven M Harrison^{2

4}, Niall Lennon⁴, Christie Kovar¹, Adithya Balasubramanian¹, Lan Zhang¹, Gauthami Chandanavelli¹, Divya Pasham¹, Robb Rowley⁶, Ken Wiley⁶, Maureen E Smith⁷, Adam Gordon⁷, Gail P Jarvik⁸, Patrick Sleiman⁹, Melissa A Kelly¹⁰, Harris T Bland¹¹, Mullai Murugan¹, Eric Venner¹, Eric Boerwinkle^{1

12}; eMERGE III consortium; Cynthia Prows¹³, Lisa Mahanta², Heidi L Rehm^{2

4}, Richard A Gibbs¹, Donna M Muzny¹⁴

Collaborators, Affiliations

Collaborators

eMERGE III consortium:
Debra J Abrams, Samuel E Adunyah, Ladia H Albertson-Junkans, Berta Almoguera, Paul S Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J Babb, Hana Bangash, Melissa A Basford, Meckenzie Behr, Barbara Benoit, Elizabeth J Bhoj, Sarah T Bland, Kenneth M Borthwick, Erwin P Bottinger, Deborah J Bowen, Mark Bowser, Murray Brilliant, Adam H Buchanan, Andrew Cagan, Pedro J Caraballo, David J Carey, David S Carrell, Victor M Castro, Rex L Chisholm, Wendy Chung, Christopher G Chute, Brittany B City, Ellen Wright Clayton, Beth L Cobb, John J Connolly, Paul K Crane, Katherine D Crew, David R Crosslin, Renata P da Silva, Jyoti G Dayal, Mariza De Andrade, Josh C Denny, Ozan Dikilitas, Alanna J DiVietro, Kevin R Dufendach, Todd L Edwards, Christine Eng, David Fasel, Alex Fedotov, Stephanie M Fullerton, Birgit Funke, Stacey Gabriel, Vivian S Gainer, Ali Gharavi, Joe T Glessner, Jessica M Goehringer, Adam S Gordon, Chet Graham, Heather S Hain, Hakon Hakonarson, John Harley, Margaret Harr, Andrea L Hartzler, Scott Hebbring, Jacklyn N Hellwege, Nora B Henrikson, Christin Hoell, Ingrid Holm, George Hripcsak, Alexander L Hsieh, Elizabeth D Hynes, Darren K Johnson, Laney K Jones, Yoonjung Y Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E Justice, Elizabeth W Karlson, Kenneth M Kaufman, Jacob M Keaton, Eimear E Kenny, Dustin L Key, Atlas Khan, H Lester Kirchner, Krzysztof Kiryluk, Terrie Kitchner, Barbara J Klanderman, David C Kochan, Emily Kudalkar, Benjamin R Kuhn, Iftikhar J Kullo, Philip Lammers, Eric B Larson, Matthew S Lebo, Ming Ta Michael Lee, Kathleen A Leppig, Chiao-Feng Lin, Jodell E Linder, Noralane M Lindor, Todd Lingren, Cong Liu, Yuan Luo, John Lynch, Bradley A Malin, Brandy M Mapes, Maddalena Marasa, Keith Marsolo, Elizabeth McNally, Frank D Mentch, Erin M Miller, Hila Milo Rasouly, Shawn N Murphy, Melanie F Myers, Bahram Namjou, Addie I Nesbitt, Jordan Nestor, Yizhao Ni, Janet E Olson, Aniwaa Owusu Obeng, Jennifer A Pacheco, Joel E Pacyna, Thomas N Person, Josh F Peterson, Lynn Petukhova, Cassandra Pisieczko, Siddharth Pratap, Megan J Puckelwartz, Alanna K Rahm, James D Ralston, Arvind Ramaprasan, Luke V Rasmussen, Laura J Rasmussen-Torvik, Dan M Roden, Elisabeth A Rosenthal, Maya S Safarova, Avni Santani, Juliann M Savatt, Daniel J Schaid, Steven Scherer, Baergen I Schultz, Aaron Scrol, Soumitra Sengupta, Gabriel Q Shaibi, Ning Shang, Himanshu Sharma, Richard R Sharp, Yufeng Shen, Rajbir Singh, Jordan W Smoller, Duane T Smoot, Ian B Stanaway, Justin Starren, Timoethia M Stone, Amy C Sturm, Agnes S Sundaresan, Peter Tarczy-Hornoch, Casey Overby Taylor, Lifeng Tian, Sara L Van Driest, Matthew Varugheese, Lyam Vazquez, David L Veenstra, Digna R Velez Edwards, Miguel Verbitsky, Kimberly Walker, Nephi Walton, Theresa Walunas, Firas H Wehbe, Wei-Qi Wei, Scott T Weiss, Quinn S Wells, Chunhua Weng, Marc S Williams, Janet Williams, Leora Witkowski, Laura Allison B Woods, Julia Wynn, Yanfei Zhang, Jodell Jackson

Affiliations

¹ Baylor College of Medicine, Human Genome Sequencing Center (HGSC), Houston, TX, USA.
² Laboratory for Molecular Medicine (LMM), Mass General Brigham, Cambridge, MA, USA.
³ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁶ Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
⁷ Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Medical Genetics, Department of Medicine, University of Washington Medical Center, Seattle, WA, USA.
⁹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Genomic Medicine Institute, Geisinger, Danville, PA, USA.
¹¹ Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁴ Baylor College of Medicine, Human Genome Sequencing Center (HGSC), Houston, TX, USA. donnam@bcm.edu.

PMID: 38433186
PMCID: PMC10910835
DOI: 10.1186/s13104-024-06723-w

Genetic sex validation for sample tracking in next-generation sequencing clinical testing

Jianhong Hu et al. BMC Res Notes. 2024.

. 2024 Mar 3;17(1):62.

doi: 10.1186/s13104-024-06723-w.

Authors

Collaborators

eMERGE III consortium:
Debra J Abrams, Samuel E Adunyah, Ladia H Albertson-Junkans, Berta Almoguera, Paul S Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J Babb, Hana Bangash, Melissa A Basford, Meckenzie Behr, Barbara Benoit, Elizabeth J Bhoj, Sarah T Bland, Kenneth M Borthwick, Erwin P Bottinger, Deborah J Bowen, Mark Bowser, Murray Brilliant, Adam H Buchanan, Andrew Cagan, Pedro J Caraballo, David J Carey, David S Carrell, Victor M Castro, Rex L Chisholm, Wendy Chung, Christopher G Chute, Brittany B City, Ellen Wright Clayton, Beth L Cobb, John J Connolly, Paul K Crane, Katherine D Crew, David R Crosslin, Renata P da Silva, Jyoti G Dayal, Mariza De Andrade, Josh C Denny, Ozan Dikilitas, Alanna J DiVietro, Kevin R Dufendach, Todd L Edwards, Christine Eng, David Fasel, Alex Fedotov, Stephanie M Fullerton, Birgit Funke, Stacey Gabriel, Vivian S Gainer, Ali Gharavi, Joe T Glessner, Jessica M Goehringer, Adam S Gordon, Chet Graham, Heather S Hain, Hakon Hakonarson, John Harley, Margaret Harr, Andrea L Hartzler, Scott Hebbring, Jacklyn N Hellwege, Nora B Henrikson, Christin Hoell, Ingrid Holm, George Hripcsak, Alexander L Hsieh, Elizabeth D Hynes, Darren K Johnson, Laney K Jones, Yoonjung Y Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E Justice, Elizabeth W Karlson, Kenneth M Kaufman, Jacob M Keaton, Eimear E Kenny, Dustin L Key, Atlas Khan, H Lester Kirchner, Krzysztof Kiryluk, Terrie Kitchner, Barbara J Klanderman, David C Kochan, Emily Kudalkar, Benjamin R Kuhn, Iftikhar J Kullo, Philip Lammers, Eric B Larson, Matthew S Lebo, Ming Ta Michael Lee, Kathleen A Leppig, Chiao-Feng Lin, Jodell E Linder, Noralane M Lindor, Todd Lingren, Cong Liu, Yuan Luo, John Lynch, Bradley A Malin, Brandy M Mapes, Maddalena Marasa, Keith Marsolo, Elizabeth McNally, Frank D Mentch, Erin M Miller, Hila Milo Rasouly, Shawn N Murphy, Melanie F Myers, Bahram Namjou, Addie I Nesbitt, Jordan Nestor, Yizhao Ni, Janet E Olson, Aniwaa Owusu Obeng, Jennifer A Pacheco, Joel E Pacyna, Thomas N Person, Josh F Peterson, Lynn Petukhova, Cassandra Pisieczko, Siddharth Pratap, Megan J Puckelwartz, Alanna K Rahm, James D Ralston, Arvind Ramaprasan, Luke V Rasmussen, Laura J Rasmussen-Torvik, Dan M Roden, Elisabeth A Rosenthal, Maya S Safarova, Avni Santani, Juliann M Savatt, Daniel J Schaid, Steven Scherer, Baergen I Schultz, Aaron Scrol, Soumitra Sengupta, Gabriel Q Shaibi, Ning Shang, Himanshu Sharma, Richard R Sharp, Yufeng Shen, Rajbir Singh, Jordan W Smoller, Duane T Smoot, Ian B Stanaway, Justin Starren, Timoethia M Stone, Amy C Sturm, Agnes S Sundaresan, Peter Tarczy-Hornoch, Casey Overby Taylor, Lifeng Tian, Sara L Van Driest, Matthew Varugheese, Lyam Vazquez, David L Veenstra, Digna R Velez Edwards, Miguel Verbitsky, Kimberly Walker, Nephi Walton, Theresa Walunas, Firas H Wehbe, Wei-Qi Wei, Scott T Weiss, Quinn S Wells, Chunhua Weng, Marc S Williams, Janet Williams, Leora Witkowski, Laura Allison B Woods, Julia Wynn, Yanfei Zhang, Jodell Jackson

Affiliations

¹ Baylor College of Medicine, Human Genome Sequencing Center (HGSC), Houston, TX, USA.
² Laboratory for Molecular Medicine (LMM), Mass General Brigham, Cambridge, MA, USA.
³ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁶ Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
⁷ Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Medical Genetics, Department of Medicine, University of Washington Medical Center, Seattle, WA, USA.
⁹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Genomic Medicine Institute, Geisinger, Danville, PA, USA.
¹¹ Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁴ Baylor College of Medicine, Human Genome Sequencing Center (HGSC), Houston, TX, USA. donnam@bcm.edu.

PMID: 38433186
PMCID: PMC10910835
DOI: 10.1186/s13104-024-06723-w

Abstract

Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.

Results: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

Keywords: Clinical testing; Next-generation sequencing (NGS); SNP genotyping; Sex concordance.

PubMed Disclaimer

Conflict of interest statement

JH, DM, MM, RAG, DMM disclose that the Baylor Genetics Laboratory is co-owned by Baylor College of Medicine. EV is cofounder of Codified Genomics, which provides variant interpretation services. DM has received consulting fees from Illumina. The remaining authors disclose they have no competing interests.

Figures

**Fig. 1**
eMERGE sample processing workflow. Steps indicating where aliquots of DNA are taken from samples that are presented to the Clinical DNA Sequencing Laboratory for accession, to test via the Fluidigm 96-SNP panel assay. Data from the Fluidigm 96-SNP panel assay are compared with DNA sequence data from the DNA sequencing pipeline as a quality control step, ahead of the Automated Clinical Reporting step

**Fig. 2**
Scatter plot analysis of 96-SNP panel reveals sample contamination. Scatter plot analysis from vendor software, showing a normal DNA male sample (A) or a contaminated sample containing a mixture of male and female DNAs (B). Panels 1–3 SNPs on X chromosome; panels 4–6 SNPs on Y chromosome; panels 7–9 autosomal SNPs. Each panel shows the data from a single SNP, as compared to clusters from all other SNPs. Clusters are shown as either homozygous (red or green), or heterozygous (blue) positions. In panels B2, 3, 7–9 single SNPS are represented as outside the expected (arrows) resulting in erroneous or ‘no-call’ from the software

See this image and copyright information in PMC

Update of

Genetic Sex Validation for Sample Tracking in Clinical Testing.
Hu J, Korchina V, Zouk H, Harden MV, Murdock D, Macbeth A, Harrison SM, Lennon N, Kovar C, Balasubramanian A, Zhang L, Chandanavelli G, Pasham D, Rowley R, Wiley K, Smith ME, Gordon A, Jarvik GP, Sleiman P, Kelly MA, Bland HT, Murugan M, Venner E, Boerwinkle E, Prows C, Mahanta L, Rehm HL, Gibbs RA, Muzny DM. Hu J, et al. Res Sq [Preprint]. 2023 Sep 11:rs.3.rs-3304685. doi: 10.21203/rs.3.rs-3304685/v1. Res Sq. 2023. Update in: BMC Res Notes. 2024 Mar 3;17(1):62. doi: 10.1186/s13104-024-06723-w. PMID: 37790445 Free PMC article. Updated. Preprint.

References

1. Norton N, Li D, Hershberger RE. Next-generation sequencing to identify genetic causes of cardiomyopathies. Curr Opin Cardiol. 2012;27(3):214–220. doi: 10.1097/HCO.0b013e328352207e. - DOI - PubMed
1. Ku CS, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R. Exome sequencing: dual role as a discovery and diagnostic tool. Ann Neurol. 2012;71(1):5–14. doi: 10.1002/ana.22647. - DOI - PubMed
1. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med. 2013;369(16):1502–1511. doi: 10.1056/NEJMoa1306555. - DOI - PMC - PubMed
1. Hayeems RZ, Dimmock D, Bick D, Belmont JW, Green RC, Lanpher B, Jobanputra V, Mendoza R, Kulkarni S, Grove ME, et al. Clinical utility of genomic sequencing: a measurement toolkit. NPJ Genom Med. 2020;5(1):56. doi: 10.1038/s41525-020-00164-7. - DOI - PMC - PubMed
1. Hammerling JA. A review of medical errors in laboratory diagnostics and where we are today. Lab Med. 2012;43(2):41–44. doi: 10.1309/LM6ER9WJR1IHQAUY. - DOI

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Genetic sex validation for sample tracking in next-generation sequencing clinical testing

Collaborators

Affiliations

Genetic sex validation for sample tracking in next-generation sequencing clinical testing

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

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