Special Focus: Genetic Counseling and the Laboratory: Genetic Counselors See Job Evolving: Further Changes Expected With Growth of Clinical Sequencing

While the majority of genetic counselors (GCs) report working in a direct clinical role, a growing number work in nonclinical capacities, primarily in laboratories. According to the National Society of Genetic Counselors 2014 Professional Status Survey, 16.6 percent of GCs work in a diagnostic laboratory (either commercial or academic), compared to 10.9 percent in 2010. “As the number and complexity of tests increase, more and more clinical decisions are dependent on the laboratory,” says Theresa Boomer, a clinical laboratory liaison at Sequenom Laboratories (San Diego). “While decisionmakers will always be in the clinic, they also need to be in the laboratory. General physicians have never really been educated [about molecular genetics], beyond straightforward tests.” GCs are in a unique position to bridge the clinical and laboratory environments, brining benefit to both. Utilization of GCs improves patient care with effective counseling and enhanced results interpretation, while optimizing health care spending through ensuring appropriate test ordering. “You can only fake it for so long—trying to do genetic counseling with other resources on board that are already paid for,” said Boomer. “But you get a heck of a lot of bang for the buck with a GC.” The “intangible value” that clinical geneticists provide has partially been responsible for the delay of laboratories in incorporating GCs as part of the molecular team, explains Boomer, who spoke at G2’s MDxNEXT conference (Baltimore; June 11-13) on what laboratories need to know about genetic counseling. “I have heard it said that GCs don’t make you money, but will save you money,” Boomer tells DTET. “But part of the benefit that a GC brings to a test is intangible. It is not black and white. Ninety-five percent of the value of a test is in accurate interpretation. GCs have the ability to put the whole testing process in context, and the value is in that end point. The value added by GCs may drive orders from Lab A to Lab B. The support may differentiate laboratories, and it is essential if you are paying $3,000 for a test.” GCs Improve Test Ordering Utilization of a genetic health care provider during the BRCA test ordering process improves the appropriateness of the test type ordered and significantly increases adherence to nationally recommended genetic counseling practices, according to a study published in Genetics in Medicine on June 12. A total of 473 enrollees in the Inherited Cancer Registry for whom BRCA testing had already been completed were surveyed to evaluate patients’ recall of pretest genetic counseling for hereditary breast and ovarian cancer. Additionally, BRCA test reports were assessed to determine appropriateness of the BRCA test type ordered and to determine type of ordering test provider (a master’s degree-trained GC, board-certified medical geneticist, or nongenetic provider). Among the cases in which a genetic health care provider placed the test order (58 percent of all cases), 97 percent of patients recalled a pretest discussion. In contrast, of the 42 percent of tests ordered without a genetic health care provider (i.e., obstetrician, gynecologist, oncologist, nurse practitioner) involved, only 59 percent of participants recalled a pretest discussion. Among the 385 total participants who recalled a pretest discussion, those with involvement of a genetic health care provider had higher adherence to eight recognized genetic counseling elements, four of which were statistically significant (family history assessment, discussing anti-discrimination laws, insurance impact, and being provided a session summary). Years since testing, personal cancer history, and BRCA status did not impact these results. In 266 patients, single-site testing (for a known familial BRCA gene mutation) or multisite-3 testing (for three BRCA mutations highly prevalent in Ashkenazi Jewish cases) would have been sufficient. Involvement of a genetic health care provider in these cases cut the chances that a comprehensive test was ordered by half. Unnecessary ordering of the comprehensive test is costly. The authors say that there is roughly a tenfold price difference between the comprehensive panel and the two more limited BRCA testing options (roughly $3,000 versus less than $400 per test). Recognizing the key role that GCs can play in improving appropriate test ordering, Cigna became the first national insurer to implement a policy whereby counseling by a certified genetics professional (either a board-certified genetic counselor or medical geneticist) is required prior to testing for BRCA, as well as testing for hereditary colorectal cancer and Long QT syndrome. It has been reported that this policy was implemented in response to the finding that 20 percent of these hereditary cancer tests are ordered inappropriately. In the BRCA study, the authors, led by Deborah Cragun, Ph.D., from the H. Lee Moffitt Cancer Center in Tampa, Fla., write that, “Our findings suggest that there may be potential cost-of-care implications associated with genetic health care provider involvement. ” NGS Further Impacts Counseling While the argument has been made that the declining cost of whole-genome sequencing (WGS) and whole-exome sequencing (WES) make it more cost-effective than single-mutation or small-panel analysis of genes, the comprehensive testing fails to incorporate the extended interpretation necessary for reporting of results back. Sequencing’s impact on the process of genetic counseling can already be seen. Although relevant, actionable incidental findings from WES appear from limited clinical experience to be rare, pretest and posttest genetic counseling are required as a small number of well-described disease-association mutations could have clinical consequences. Given that counseling a patient regarding every possible finding is not feasible, genetic counselors are shifting the context of pretest and consent discussions toward the big picture, rather than very disease-specific conversations. “The return of results discussion for WES is really about broad ideas about adult-onset and treatable conditions, Laura Amendola, a genetic counselor at the University of Washington Medical Center in Seattle, tells DTET. “There is not enough time to discuss every single condition, and really patients don’t have enough bandwidth to process that amount of information.” Amendola says that in her experience, primarily with WES testing of middle-aged research subjects, there have not been a lot of high-risk genetic conditions identified, but rather incidental findings are related to pharmacogenomic genes, which overall, patients are happy to learn about. “In returning results, patients expect more,” says Amendola. “We have to prepare them for what we actually get out of whole-exome and whole-genome testing. We have to manage expectations about what we do and do not know.” As genetic counselors reframe the counseling context in light of clinical application of WGS and WES, they are also involved in research to elucidate patient preferences for the return of incidental findings. Prelimary data, based on the first 200 families referred to Ambry Genetics (Aliso Viejo, Calif.) for diagnostic exome sequencing, suggest that families overwhelmingly opt to receive information on incidental or secondary findings. Although, it appears that current health status may influence patient decisions for disclosure of incidental findings, according to the study published online in October 2013 in Genetics in Medicine. While many participants in research studies want to receive secondary findings, these individuals are likely healthier or facing non–life-threatening disease, compared with those patients undergoing diagnostic exome sequencing who “represent an extreme end of the health spectrum,” the authors note. Ambry requires genetic counseling and consent in order for patients to accept or decline secondary findings disclosure. Ambry’s reportable secondary findings include “only medically reviewed and previously defined mutations in characterized genes.” During consent, secondary findings are characterized as carrier status of recessive disorders, predisposition to later-onset disease, predisposition to increased cancer risk, and early-onset disease (the only secondary findings category available for children). One the consent form adult patients can choose whether to receive secondary findings for the four categories. Among the first 200 diagnostic exome sequencing patients, the majority (93.5 percent) chose to receive secondary results in one or more categories. Of the patients tested, 162 were children (affected with complex diseases including severe cognitive impairment and a truncated life expectancy) and had an average age of 5 years. Minors were only eligible for reporting of early-onset secondary findings, and only seven guardians did not consent to this reporting. Adults tested (n = 38) had an average age of 38 years and milder disease manifestations than the children. Six of the 38 adults did not consent to reporting of at least one category. Among responses for blinding, preferences were evenly distributed among categories, which the authors say reflects “an intricate and complicated” decisionmaking process likely based on personal life experiences. “Individuals pursuing diagnostic exome sequencing may be more active in seeking medical information and therefore more receptive to obtaining secondary findings information than healthy individuals,” write the authors, led by Layla Shahmirzadi, from Ambry. GCs Work to Improve Lab Reports In addition to evaluating mechanisms of consenting patients and directly reporting results to them, genetic counselors are involved in research to optimize laboratory reports to return sequencing-based test results to ordering physicians, who may have limited genomics understanding. “Our process for the development of WES clinical reports has shown that accurate and open communication between the clinician and laboratory is ideally an ongoing process, both for individual reports and for general report formatting,” says Michael Dorschner, Ph.D., from the University of Washington in a paper published in the March issue of American Journal of Medical Genetics. As part of a research protocol, the researchers compared panels (25 genes) to sequencing for the clinical evaluation of genetic susceptibility to colorectal cancer/polyposis (CRCP). Exome sequencing evaluated the same 25 CRCP-related genes plus 96 non-CRCP genes that may contain actionable incidental findings and nine pharmacogenetic genes. Using an iterative process with feedback from clinical geneticists, genetic counselors, nongeneticist physicians, genomicists, bioethicists, molecular laboratory experts, and a research coordinator, the group ultimately developed a standard test report modeled after those used for targeted gene panels. “Non-geneticists, who are less comfortable communicating results of genetic testing, unanimously asked for clarity,” Dorschner reports. “Getting to the punch line early in the report and providing more guidance with respect to recommendations were among their requests. . . . Many clinicians are ill equipped to understand the limitations of complex WES/WGS testing and it is incumbent on the laboratory to provide guidance with respect to the completeness of testing.” Takeaway: As more data is gleaned on patient preferences, and professional organizations establish uniform standards for reporting of findings of whole-exome and whole-genome examinations, genetic counselors are positioned to play a key role in informing this ongoing discussion and in implementing effective strategies during this transition period.  Side Box: Nationally Recommended Elements of Pretest Counseling

• Family medical history
• Potential hereditary cancer syndromes
• Potential health care management impact
• Potential lack of conclusive test results
• Implications for other family members
• Impact of test results on insurance
• Take home educational tools or session summary

Source: Adapted from Cragun D, Camperlengo L, Robinson L, et al. “Differences in BRCA counseling and testing practices based on ordering provider type.” Genetics in Medicine. Published online 12 June 2014. Side Box: Reporting, Counseling Strategies Undertaken by eMERGE The electronic Medical Records and Genomics (eMERGE) network was established in 2007 to further genomic discovery by using biorepositories linked to the electronic health records (EHRs). According to a review published March 26 in Frontiers in Genetics, individual sites within the eMERGE network are exploring acceptable mechanisms, including reliance on genetic counseling, to address incidental findings.

• Northwestern University (Illinois) is returning potentially actionable findings (Factor V Leiden mutation and the hereditary hemochromatosis HFE mutations) by reconsenting 150 biobank participants who were genotyped during Phase I of eMERGE. Results will both be deposited in the EHR for physicians and sent (mail or online) to study participants. Participants can discuss the results during an appointment with the physician or be referred to a study genetic counselor.
• At the University of Washington-Group Health site (Seattle), 450 participants will be genotyped for pathogenic variants in six highly penetrant pharmacogenes (for malignant hyperthermia, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and LDLR for hyperlipidemia). The Department of Clinical Genetics will return results with appropriate counseling and subsequent EHR documentation.
• Geisinger Health System (Danville, Pa.) investigators are developing a laboratory report that summarizes results of WGS in individuals with intellectual disability and normal chromosomal microarray to identify an underlying genetic etiology. Causal variants and incidental findings (from the ACMG list) will be validated and all patients will be informed about the results and undergo counseling.

Side Box: Exome Sequencing-Based Lab Reports The most desired features identified by University of Washington researchers in optimizing comprehensive reports of WES data include:

• Two separate reports, one for indication-specific genes and one with incidental findings.
• Results and interpretation sections were placed at the beginning of the report, and the test methods were moved to the end.
• A mix of basic and higher-level information was needed to satisfy clinicians less comfortable with genetic testing and nongeneticist physicians with an interest or experience in genetics.
• Standard test report elements were supplemented with research study-specific language, which highlighted the limitations of exome sequencing and provided detailed, structured results and interpretations.