Genetic sex validation for sample tracking in next-generation sequencing clinical testing
Authors: Hu Jianhong , Korchina Viktoriya , Zouk Hana , Harden Maegan V. , Murdock David , Macbeth Alyssa , Harrison Steven M. , Lennon Niall , Kovar Christie , Balasubramanian Adithya , Zhang Lan , Chandanavelli Gauthami , Pasham Divya , Rowley Robb , Wiley Ken , Smith Maureen E. , Gordon Adam , Jarvik Gail P. , Sleiman Patrick , Kelly Melissa A. , Bland Harris T. , Murugan Mullai , Venner Eric , Boerwinkle Eric ,   the eMERGE III consortium, Abrams Debra J. , Adunyah Samuel E. , Albertson-Junkans Ladia H. , Almoguera Berta , Appelbaum Paul S. , Aronson Samuel , Aufox Sharon , Babb Lawrence J. , Bangash Hana , Basford Melissa A. , Behr Meckenzie , Benoit Barbara , Bhoj Elizabeth J. , Bland Sarah T. , Borthwick Kenneth M. , Bottinger Erwin P. , Bowen Deborah J. , Bowser Mark , Brilliant Murray , Buchanan Adam H. , Cagan Andrew , Caraballo Pedro J. , Carey David J. , Carrell David S. , Castro Victor M. , Chisholm Rex L. , Chung Wendy , Chute Christopher G. , City Brittany B. , Clayton Ellen Wright , Cobb Beth L. , Connolly John J. , Crane Paul K. , Crew Katherine D. , Crosslin David R. , da Silva Renata P. , Dayal Jyoti G. , De Andrade Mariza , Denny Josh C. , Dikilitas Ozan , DiVietro Alanna J. , Dufendach Kevin R. , Edwards Todd L. , Eng Christine , Fasel David , Fedotov Alex , Fullerton Stephanie M. , Funke Birgit , Gabriel Stacey , Gainer Vivian S. , Gharavi Ali , Glessner Joe T. , Goehringer Jessica M. , Gordon Adam S. , Graham Chet , Hain Heather S. , Hakonarson Hakon , Harley John , Harr Margaret , Hartzler Andrea L. , Hebbring Scott , Hellwege Jacklyn N. , Henrikson Nora B. , Hoell Christin , Holm Ingrid , Hripcsak George , Hsieh Alexander L. , Hynes Elizabeth D. , Johnson Darren K. , Jones Laney K. , Joo Yoonjung Y. , Jose Sheethal , Josyula Navya Shilpa , Justice Anne E. , Karlson Elizabeth W. , Kaufman Kenneth M. , Keaton Jacob M. , Kenny Eimear E. , Key Dustin L. , Khan Atlas , Kirchner H. Lester , Kiryluk Krzysztof , Kitchner Terrie , Klanderman Barbara J. , Kochan David C. , Kudalkar Emily , Kuhn Benjamin R. , Kullo Iftikhar J. , Lammers Philip , Larson Eric B. , Lebo Matthew S. , Lee Ming Ta Michael , Leppig Kathleen A. , Lin Chiao-Feng , Linder Jodell E. , Lindor Noralane M. , Lingren Todd , Liu Cong , Luo Yuan , Lynch John , Malin Bradley A. , Mapes Brandy M. , Marasa Maddalena , Marsolo Keith , McNally Elizabeth , Mentch Frank D. , Miller Erin M. , Rasouly Hila Milo , Murphy Shawn N. , Myers Melanie F. , Namjou Bahram , Nesbitt Addie I. , Nestor Jordan , Ni Yizhao , Olson Janet E. , Obeng Aniwaa Owusu , Pacheco Jennifer A. , Pacyna Joel E. , Person Thomas N. , Peterson Josh F. , Petukhova Lynn , Pisieczko Cassandra , Pratap Siddharth , Puckelwartz Megan J. , Rahm Alanna K. , Ralston James D. , Ramaprasan Arvind , Rasmussen Luke V. , Rasmussen-Torvik Laura J. , Roden Dan M. , Rosenthal Elisabeth A. , Safarova Maya S. , Santani Avni , Savatt Juliann M. , Schaid Daniel J. , Scherer Steven , Schultz Baergen I. , Scrol Aaron , Sengupta Soumitra , Shaibi Gabriel Q. , Shang Ning , Sharma Himanshu , Sharp Richard R. , Shen Yufeng , Singh Rajbir , Smoller Jordan W. , Smoot Duane T. , Stanaway Ian B. , Starren Justin , Stone Timoethia M. , Sturm Amy C. , Sundaresan Agnes S. , Tarczy-Hornoch Peter , Taylor Casey Overby , Tian Lifeng , Van Driest Sara L. , Varugheese Matthew , Vazquez Lyam , Veenstra David L. , Velez Edwards Digna R. , Verbitsky Miguel , Walker Kimberly , Walton Nephi , Walunas Theresa , Wehbe Firas H. , Wei Wei-Qi , Weiss Scott T. , Wells Quinn S. , Weng Chunhua , Williams Marc S. , Williams Janet , Witkowski Leora , Woods Laura Allison B. , Wynn Julia , Zhang Yanfei , Jackson Jodell , Prows Cynthia , Mahanta Lisa , Rehm Heidi L. , Gibbs Richard A. , Muzny Donna M. 
Published: March 2024

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.