Genetic Testing Reference Materials Coordination Program – GeT-RM

Reference and quality control (QC) materials are essential for many aspects of genetic testing. These materials, which are tested alongside patient samples, allow laboratories to detect errors due to test system failure or operator error. Reference materials are also useful for test development and validation, lot-testing of new reagent batches, and for profciency testing/external quality assessment programs (PT/EQA).

Genetic tests are currently ofered in clinical laboratories for over 10,000 human genetic disorders. However, for most of these tests, no characterized reference or QC materials are publicly available. Without publicly available materials, laboratories must adapt, and use limited genetic material and, in some cases, develop and run assays without adequate controls. Often DNA derived from residual patient specimens, which is not readily available or renewable, is used as a reference material. Laboratories also use synthetic DNA or DNA isolated from cell lines. This lack of reference materials may afect the quality of available tests and could inhibit the development of new genetic tests.

Since 1995, the Centers for Disease Control and Prevention (CDC) has been involved in eforts to develop appropriate and well characterized reference materials for use by the genetic testing community. In 2004, the Genetic Testing Reference Materials Coordination Program (GeT-RM) was established at the CDC in partnership with the genetic testing community. The goal of this program is to coordinate a self-sustaining community process to improve the public availability of characterized genomic DNA materials. The GeT-RM also facilitates information exchange between users and providers of reference materials. Although the GeT-RM Program is coordinated by the CDC, activities including decisions about reference material priorities, specimen collection, material development, and characterization occurs through voluntary collaborations with laboratories across the genetic testing community.

Cell lines with confrmed genotypes are considered the preferred type of control for DNA based genetic testing as they most closely resemble an actual patient specimen. Thus, the GeT-RM’s eforts focus on this material type. The GeT-RM program has characterized more than 5800 loci in over 450 cell line based genomic DNA reference materials for a number of genetic disorders including: fragile X1, disorders on the Ashkenazi Jewish Panel2 (Bloom syndrome, Canavan disease, Fanconi anemia, familial dysautonomia, Gaucher disease, mucolipidosis IV, Neimann Pick disease and Tay Sachs disease), cystic fbrosis3, Huntington disease4, MTHFR-related homocysteinemia, alpha1-antitrypsin defciency, multiple endocrine neoplasia, BRCA1 and BRCA2-related cancers5, Duchenne muscular dystrophy6, myotonic dystrophy8, Rett syndrome9, two large-scale studies of DNA from 244 cell lines for a number of polymorphisms in 28 pharmacogenetic loci7, 10, 108 samples for 11 HLA loci11, 179 samples for difcult and rare CYP2D6 variants12, and spinal muscular atrophy13. Each of the genomic DNA materials were tested by up to 10 clinical genetic laboratories using a variety of genetic assays including DNA sequence analysis. These materials are publicly available from the Coriell Cell Repositories.

The GeT-RM website has information for the genetic testing community about molecular genetic reference materials.

GeT-RM Publications:

1. Wilson JA, Pratt VM, Phansalkar A, Muralidharan K, Highsmith Jr WE, Beck JC, et al. Consensus Characterization of 16 FMR1 Reference Materials: A Consortium Study. J Mol Diagn. 2008, 10: 2-12.

2. Kalman LV, Amos Wilson J, Buller A, Dixon J, Edelmann L, Geller L, et al. Characterization of Genomic DNA reference materials for genetic testing of disorders common in people of Ashkenazi Jewish decent. J Mol Diagn. 2009, Nov;11(6): 530-536.

3. Pratt VM, Caggana M, Bridges C, Buller AM, DiAntonio L, Highsmith EW, et al. Development of Genomic Reference Materials for Cystic Fibrosis Genetic Testing. J Mol Diagn. 2009, May;11(3): 186-193.

4. Kalman L, Johnson MA, Beck J, Berry-Kravis E, Buller A, Casey B, et al. Development of genomic reference materials for Huntington disease genetic testing. Genetics in Medicine 2007, 9: 719-723.

5. Barker SD, Bale S, Buller A, Das S, Friedman K, Godwin AK, et al. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing J Mol Diagn. 2009 Nov;11(6): 553-561

6. Kalman L, Leonard J, Gerry N, Tarleton J, Bridges C, Gastier-Foster JM, et al. Quality Assurance for Duchenne and Becker Muscular Dystrophy Genetic Testing: Development of a Genomic DNA Reference Material Panel. J Mol Diagn. 2011, Mar;13(2): 167-174

7. Pratt VM, Zehnbauer B, Wilson JA, Baak R, Babic N, Bettinotti M, et al. Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1 and UGT1A1: A GeT-RM and Association for Molecular Pathology collaborative project. J Mol Diagn. 2010, 12(6): 835-846

8. Kalman L, Tarleton J, Hitch M, Hegde M, Hjelm N, Berry-Kravis E, et al. Development of a Genomic DNA Reference Material Panel for Myotonic Dystrophy type 1 (DM1) Genetic Testing. J Mol Diagn. 2013, 15: 518-525

9. Kalman L, Tarleton J, Percy A, Aradhya S, Bale S, Barker S, et al. Development of a genomic DNA reference material 1 panel for Rett Syndrome (MECP2-related disorders) Genetic Testing. J Mol Diagn. 2014, 16: 273-279

10. Pratt VM, Everts RE, Aggarwal P, Beyer BN, Broeckel U, Epstein-Baak R, et al. Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. J Mol Diagn. 2016,18: 109-123

11. Bettinotti MP, Ferriola D, Duke JL, Mosbruger TL, Tairis N, Jennings L, et al. Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen Loci: A GeT-RM Collaborative Project. J Mol Diagn. 2018, 20: 703-715

12. Gaedigk A, Turner A, Everts RE, Scott SA, Aggarwal P, Broeckel U, McMillin GA, Melis R, Boone EC, Pratt VM, Kalman LV. Characterization of Reference Materials for Genetic Testing of CYP2D6 Alleles: A GeT-RM Collaborative Project. J Mol Diagn. 2019, 21: 1034-1052

13. Prior TW, Bayrak-Toydemir P, Lynnes TC, Mao R, Metcalf JD, Muralidharan K, Iwata-Otsubo A, Pham HT, Pratt VM, Qureshi S, Requesens D, Shen J, Vetrini F, Kalman L. Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing: A Genetic Testing Reference Materials Coordination Program Collaborative Project. J Mol Diagn. 2021, 23: 103-110

For More Information: www.cdc.gov/labquality/GeT-RM