Using Genetic Testing: A Guide for Non-Geneticists

BY SUSAN E. HAHN, MS, CGC

In the past, the ability to understand genetic influence on health was limited by technology. This situation changed with the completion of the human genome project in 2003 and the onset of next-generation sequencing (NGS), which enabled sequencing of DNA at unprecedented speeds and sharply lower costs.

Now, more than 500 laboratories offer tests for more than 20,000 conditions. The Genetic Test Registry reports that there are nearly 75,000 tests available, 1 while a database compiled by the technology company Concert Genetics records more than 165,000 tests. 2 Most are laboratory-developed tests that are not subject to FDA oversight, although they are subject to regulations under the federal Clinical Laboratory Improvement Amendments of 1988 (CLIA) law. With only approximately 25,000 genes in the human genome, the substantial number of available tests can be attributed to differences in methods, sample type, variant assessment, and/or genes included in multigene assays.

Approximately 3.5% to 5.9% of individuals have a genetic variant associated with significant health implications. 3 Beyond diagnosis and risk assessment, genetic and molecular testing are used to evaluate drug response (pharmacogenetics); inform prognosis and treatment of solid tumors that result from acquired, or somatic, mutations that occur in cells; direct organ transplant decisions and management; and test for infection.

Although genetic testing is costly, it is highly effective when used appropriately. For example, quickly diagnosing babies with spinal muscular atrophy is paramount to avoid irrevocable damage that begins at birth. Asymptomatic patients with hereditary cancer syndromes such as Lynch or hereditary breast and ovarian cancer syndrome should receive enhanced and earlier cancer surveillance, chemoprevention, and/or prophylactic surgery.

In some instances, a genetic diagnosis ends the diagnostic odyssey, thus reducing unnecessary, costly, and time-consuming evaluations and procedures. 4 Knowledge of a specific gene or variant may also provide opportunities for families to connect to a support network, participate in research, enable family planning, and inform personal decisions.

The rapidly evolving and complex testing landscape can pose a challenge for non-genetics professionals looking to deliver value-based care.

This rapidly evolving and complex testing landscape can pose a challenge for non-genetics professionals looking to deliver value-based care. Many are not trained to assess genetic risk, order genetic tests, or interpret results. They also may be unfamiliar with referring patients to genetics professionals.

Consequently, genetic testing is both overused (20.6%) and underused (44.8%). 5 While overutilization is an economic and quality concern, underutilization is concerning from a health outcomes perspective.

There are three ways that non-geneticists can ensure they are appropriately and efficiently using genetic testing:

1. UTILIZE REPUTABLE LABORATORIES PRACTICING RESPONSIBLE GENOMICS

Because genomic medicine is new and emerging, there is tremendous variation in what laboratories offer. Competition has driven some labs to differentiate themselves with complex genetic test offerings that may lack sufficient evidence. For example, some boutique laboratories offer large panels containing genes where the relationship to the disease has not yet been fully validated. In this instance, more is not necessarily better. Other laboratories practice outright fraud. 6

The good news is that many reputable laboratories provide genetic counselors and other genetics professionals, who can provide training and consultations tailored to a practice’s clinical genetic testing needs; offer “just in time” consults with providers regarding orders and interpretation of results; flag potential duplicate or erroneous test orders; and receive clinician feedback on genetic testing offerings and services to better address their needs.

2. ACCESS PUBLICLY AVAILABLE RESOURCES

Many resources listed below provide accurate information about genetic disorders, including testing, treatment, and research opportunities:

• MedGen (ncbi.nlm.nih.gov/medgen) Search for genetic conditions by symptom or name. MedGen includes a link to professional practice guidelines, position statements, and recommendations.

• GeneReviews (ncbi.nlm.nih.gov/books/NBK1116) Provides clinically relevant information on inherited conditions, written by experts on the specific disorder

• Treatments for Genetic Disorders (rx-genes.com) Provides information about current treatments, as well as clinical trials that affect the underlying pathogenesis and progression of the disease

• Orphanet (orpha.net) Portal for rare diseases and orphan drugs

• Clinical Pharmacogenetics Implementation Consortium ® (cpicpgx.org) CPIC provides detailed gene/drug clinical practice guidelines free to the public. Guidelines focus on how to use available pharmacogenetic results.

• PharmGKB (pharmgkb.org) Resource regarding the impact of genetic variation on drug response

• National Human Genome Research Institute (NHGRI) Glossary of Genomic and Genetic Terms (genome.gov/genetics-glossary) Includes nearly 250 terms, explained in an easy-tounderstand way by NHGRI scientists and professionals

3. FIND SUPPORT FROM CLINICAL GENETICS PROFESSIONALS

Medical geneticists and genetic counselors are important members of the diagnostic and therapeutic team; they help close knowledge gaps to assure effective test utilization. These resources are available at many medical centers. Also, numerous companies offer remote genetic counseling services. Useful databases and directories include these:

• American College of Medical Genetics and Genomics: Genetics Clinics Database (https:// clinics.acmg.net)

• National Society of Genetic Counselors Directory (https://findageneticcounselor.nsgc.org)

In the end, the authority for ordering appropriate testing rests with the treating provider. APG members, America’s laboratories, and other professional organizations can work together to maximize the benefit of molecular and genetic testing while ensuring that non-value-added (and potentially detrimental) services are not ordered. o

Susan E. Hahn, MS, CGC, is Director of Health Economics and Outcomes Research and Payer Relations at Quest Diagnostics. You can follow the company on Twitter at @QuestDX.

Special thanks to Lee Hilborne, MD, MPH, and Terra E. White, PhD, both of Quest Diagnostics, for their contributions to this article.

References:

1 National Center for Biotechnology Information. National Library of Medicine Genetic Testing Registry. Accessed July 7, 2022. https:// www.ncbi.nlm.nih.gov/gtr/.

2 Hooker GW. Building an infrastructure to enable delivery of genomic medicine. Am J Med Genet C Semin Med Genet. 2021;187(1):95-99. doi:10.1002/ajmg.c.31881.

3 Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165-173. doi:10.1038/s41431-019-0508-0.

4 Incerti D, Xu XM, Chou JW, et al. Cost-effectiveness of genome sequencing for diagnosing patients with undiagnosed rare genetic diseases. Genet Med. 2022;24(1):109-118. doi:10.1016/j. gim.2021.08.015.

5 Zhi M, Ding EL, Theisen-Toupal J, et al. The landscape of inappropriate laboratory testing: a 15-year meta-analysis. PLoS One. 2013;8(11):e78962. doi:10.1371/journal.pone.0078962.

6 US Department of Health & Human Services Office of Inspector General. Data brief: Trends in genetic tests provided under Medicare Part B indicate areas of possible concern (A-09-20- 03027) pps. 13-14. Updated December 2021. Accessed July 7, 2022. https://oig.hhs.gov/oas/reports/region9/92003027.pdf.

Susan E. Hahn, MS, CGC, Director of Health Economics and Outcomes Research and Payer Relations, Quest Diagnostics