Family communication of cancer genetic test results in an ethnically diverse population: a qualitative exploration of more than 200 patients.

Previous research on family communication of cancer genetic test results has primarily focused on non-Hispanic White patients with high-risk pathogenic variants (PV). There are limited data on patient communication of moderate-risk PVs, variants of uncertain significance (VUS), and negative results. This qualitative study examined communication of positive, negative, and VUS hereditary cancer multi-gene panel (MGP) results in an ethnically and socioeconomically diverse population. As part of a multicenter, prospective cohort study of 2000 patients who underwent MGP testing at three hospitals in California, USA, free-text written survey responses to the question: "Feel free to share any thoughts or experiences with discussing genetic test results with others" were collected from participant questionnaires administered at 3 and 12-months post results disclosure. Content and thematic analyses were performed using a theory-driven analysis, Theory of Planned Behavior (TPB), on 256 responses from 214 respondents. Respondents with high perceived utility of sharing genetic test results often reported positive attitudes towards sharing test results and direct encouragement for genetic testing of others. Respondents with high self-efficacy in the sharing process were likely to report high perceived utility of sharing, whereas patients with low self-efficacy more often had VUS results and were more likely to report uncertainty about sharing. Consistent with TPB, our findings suggest that clinician reinforcement of the utility of genetic testing may increase intent for patients to communicate genetic information. Our findings suggest that clinicians should focus on strategies to improve patient understanding of VUS results.

The right not to know: Non-disclosure of primary genetic test results and genetic counselors' response.

As part of clinical genetic counseling practice, patients may request that their primary genetic test results be disclosed to someone else, such as a relative or referring provider, or request that results be disclosed to no one (non-disclosure). In making these requests, patients employ the ethical principle of the "right not to know," which argues that autonomous individuals can choose not to know relevant health information. Although the right not to know has been well-studied in medicine in general, and in the return of genomic secondary findings, we are not aware of other studies that have explored the return of primary genetic test results when patients request non-disclosure or disclosure to another individual. This study aimed to describe common clinical scenarios in which these requests occur, how genetic counselors respond, and what ethical considerations they employ in their decision-making process. We recruited participants from the National Society of Genetic Counselors' (NSGC) "Student Research Surveys and Reminders" listserv and conducted semi-structured interviews with 11 genetic counselors in the United States who described genetic counseling cases where this occurred. Interviews were transcribed and coded inductively, and themes were identified. Case details varied, but in our study data the requests for non-disclosure were most commonly made by patients with poor, often oncologic, prognoses who requested their test results be disclosed to a family member instead of themselves. Genetic counselors considered similar factors in deciding how to respond to these requests: patient autonomy, medical actionability of results for the patient and family, the relationship between the patient and the person to whom results might be disclosed, and legal or practical concerns. Genetic counselors often made decisions on a case-by-case basis, depending on how relevant each of these factors were. This study adds to the growing body of literature regarding patients' "right not to know" and will hopefully provide guidance for genetic counselors who experience this situation in clinical practice.

"I wish that there was more info": characterizing the uncertainty experienced by carriers of pathogenic ATM and/or CHEK2 variants.

Little is known about what uncertainties patients experience after being identified to carry a pathogenic variant in a moderate-risk cancer gene as a result of undergoing multigene panel testing for cancer susceptibility. Data regarding cancer risk estimates and effectiveness of risk management strategies for these variants continues to evolve, which has the potential to evoke uncertainty. Acknowledging uncertainty during pre- and post-test discussions is imperative to helping individuals to adapt to their results. A better understanding of this population's experience of uncertainty is needed to facilitate such discussions and is the aim of the current study. Semi-structured interviews (30-60 min in length), informed by Han and colleagues' taxonomy of uncertainty in clinical genomic sequencing, were conducted to assess motivations to pursue genetic testing, areas of perceived uncertainty, and strategies for managing uncertainty among 20 carriers of pathogenic variants in two moderate-risk genes, ATM and CHEK2. We found that participants pursue genetic testing with the expectation that results will clarify cancer risks and approaches to management. Participants experience uncertainties aligning with Han's taxonomy relating to the ambiguity of specific cancer risk estimates and effectiveness of certain risk management strategies. These uncertainties influenced decisions around the uptake of risk management strategies, which were additionally impacted by clinicians' uncertainty towards such strategies. Participants employ a variety of uncertainty management approaches to cope with their anxieties. Clinicians may wish to use these findings to facilitate patient adaptation to the implications of multigene panel testing for cancer susceptibility during both pre- and post-test counseling sessions.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Attitudes of people with inherited retinal conditions toward gene editing technology.

BACKGROUND: The views of people with genetic conditions are crucial to include in public dialogue around developing gene editing technologies. This qualitative study sought to characterize the attitudes of people with inherited retinal conditions (retinitis pigmentosa [RP] and Leber congenital amaurosis [LCA]) toward gene editing. METHODS: Individuals with RP (N = 9) and LCA (N = 8) participated in semi-structured qualitative interviews about their experience with and attitudes toward blindness, and their views about gene editing technology for somatic, germline, and enhancement applications. RESULTS: Participants saw potential benefits from gene editing in general, but views about its use for retinal conditions varied and were influenced by personal perspectives on blindness. Those who felt more negatively toward blindness, particularly those with later onset blindness, were more supportive of gene editing for retinal conditions. Concerns about both germline and somatic editing included: the importance of informed consent; impacts of gene editing on social attitudes and barriers affecting blind people; and worries about "eliminating" blindness or other traits. CONCLUSION: People with RP and LCA have diverse attitudes toward gene editing technology informed by their own lived experience with disability, and many have concerns about how the ways in which it is discussed and implemented might affect them.

Assessing genetic counselors' experiences with physician aid-in-dying and practice implications.

Physician aid-in-dying (PAD) is now legalized in more than half a dozen states across the United States yet remains controversial among health care providers and the general public. Previous studies have described physicians' and nurses' experiences with and attitudes about PAD; however, there is no data about PAD in the context of genetic counseling. This study explores genetic counselors' experiences, understanding, training, and perspectives about PAD. Fifteen participants were recruited to complete semistructured telephone interviews. Five participants had received patient inquiries about PAD. Most participants (n = 10) did not feel prepared to discuss PAD with patients and felt that they did not have adequate knowledge to answer patient questions about the practice. Participants described how the unique training, skills, and experiences of genetic counselors could be beneficial for discussing PAD with patients, in comparison to other providers. All participants supported training for genetic counselors about PAD, with many suggesting integration with education about palliative care and end-of-life planning. This is the first study to investigate PAD in the context of genetic counseling. Genetic counselors have had patients ask questions about PAD, want education and access to resources about PAD, and believe they can provide important support and guidance to patients considering PAD in some genetic counseling contexts.

Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.

PURPOSE: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians. METHODS: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics. RESULTS: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient. CONCLUSION: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.

Exploring the Medical and Psychosocial Concerns of Adolescents and Young Adults With Craniofacial Microsomia: A Qualitative Study.

OBJECTIVE: This study explores the experiences of adolescents and young adults with craniofacial microsomia, including the impact of growing up with this craniofacial condition on daily life and sense of self. The results may guide future research on optimally supporting individuals with craniofacial microsomia during this critical life phase. DESIGN AND SETTING: Participants were recruited through a craniofacial center, online patient support groups, and social media sites. Eleven individual semistructured interviews with participants between 12 and 22 years old were conducted by a single interviewer, transcribed, iteratively coded, and thematically analyzed. RESULTS: Five themes were evident in the data: (1) impact on personal growth and character development, (2) negative psychosocial impact, (3) deciding to hide or reveal the condition, (4) desire to make personal surgical decisions, and (5) struggles with hearing loss. CONCLUSIONS: We identified both medical and psychosocial concerns prevalent among adolescents with craniofacial microsomia. Although adolescents with craniofacial microsomia exhibit considerable resilience, the challenges they face impact their sense of self and should be addressed through psychosocial support and counseling. Further research should investigate the potential benefit of the wider use of hearing aids, as well as the involvement of patients in decision-making about reconstructive ear surgery.

Patient and provider perspectives on the development of personalized medicine: a mixed-methods approach.

While genetic testing gains adoption in specialty services such as oncology, neurology, and cardiology, use of genetic and genomic testing has yet to be adopted as widely in primary care. The purpose of this study is to identify and compare patient and primary care provider (PCP) expectations of genetics services in primary care. Patient and PCP perspectives were assessed through a mixed-method approach combining an online survey and semi-structured interviews in a primary care department of a large academic medical institution. A convenience sample of 100 adult primary care patients and 26 PCPs was gathered. The survey and interview questions focused on perceptions of genetic testing, experience with genetic testing, and expectations of genetic services in primary care. Patients felt that their PCP was knowledgeable about genetic testing and expected their PCP to be the first to recognize a need for genetic testing based on family history. Nonetheless, patients reported that PCPs rarely used family history information to discuss genetic risks or order testing. In contrast, PCPs felt uncertain about the clinical utility and scientific value of genetic testing. PCPs were concerned that genetic testing could cause anxiety, frustration, discrimination, and reduced insurability, and that there was unequal access to testing. PCPs described themselves as being "gatekeepers" to genetic testing but did not feel confident or have the desire to become experts in genetic testing. However, PCPs were open to increasing their working knowledge of genetic testing. Within this academic medical center, there is a gap between what patients expect and what primary care providers feel they are adequately prepared to provide in terms of genetic testing services.

Clinical interpretation and implications of whole-genome sequencing.

IMPORTANCE: Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES: To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS: An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES: Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS: Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE: In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

The views of Pakistani doctors regarding genetic counseling services - is there a future?

Pakistan is a densely populated country in South Asia with a high burden of genetic disease. A dearth of medical genetic services exists and master's level trained genetic counselors (GCs) are currently not a part of the healthcare system. This study is the first to determine the views of Pakistani medical doctors (MDs) towards genetic counseling services in Pakistan, including what manner a master's level genetic counselor might be incorporated into the healthcare system. Fifty-one MDs practicing in the city of Karachi completed a self-administered survey of twenty questions. Of the 49 respondents who answered a specific question, 100 % (49/49) felt that they would refer at least some, if not all, of their relevant patients to a genetic's clinic if one existed in Karachi. Overall, the respondents showed a positive attitude towards the provision of genetic counseling services as a part of the healthcare system of Pakistan. Some of the proposed roles identified specifically for GCs included: explaining how Down syndrome occurs (66.1 %), discussing genes associated with breast cancer (77.4 %), and explaining the inheritance pattern of ß-thalassemia (65.5 %). In contrast, the review of medical and family history and discussion of medical procedures such as ultrasound and amniocentesis were typically seen as the role of a physician. A majority of the respondents (98 %) were in favor of premarital carrier screening for thalassemia and would refer patients to a GC to describe the importance of carrier screening (84.3 %) and to help explain carrier screening results (94.1 %). Many respondents selected GCs as the ideal provider of education and support for people with inherited conditions (43.8 %), followed by specialist MDs (26 %) and general physicians (22.9 %). Considering the high burden of genetic disease in the country, we encourage the development of genetic counseling services in Pakistan.

Clinical assessment incorporating a personal genome.

BACKGROUND: The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context. METHODS: We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks. FINDINGS: Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported. INTERPRETATION: Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. FUNDING: National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

Attitudes of genetic counselors towards expanding newborn screening and offering predictive genetic testing to children.

There is movement to expand newborn screening (NBS) to include conditions that challenge the traditional public health screening criteria. Little is known about the attitudes of genetic counselors towards expanding NBS and offering predictive genetic tests to children. For our study genetic counselors completed an internet survey posted on the National Society of Genetic Counselors Listserv regarding five conditions: cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), glucose-6-phosphate dehydrogenase deficiency (G6PD), fragile X (FraX), and type 1 diabetes (T1D). The survey addressed attitudes towards: (1) testing high-risk infants; (2) mandatory NBS; (3) population screening beyond the newborn period; and (4) testing one's own child. Two hundred sixty-seven usable surveys were received. Over two-thirds of respondents supported testing high-risk infants for all conditions except T1D (22%). CF was the only condition for which there was majority support for both mandatory NBS (56%) and later population screening (60%). For all other conditions, later population screening was preferred over NBS (P

Marshall-Smith syndrome: natural history and evidence of an osteochondrodysplasia with connective tissue abnormalities.

The Marshall-Smith syndrome (MSS) is a distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. At least 33 cases have been reported in the literature, mostly as single case reports or small series. The purpose of the present study is to report on the clinical findings and natural history of MSS in five children and to review the features of three others previously reported, with particular attention to the skeletal and connective tissue findings. Our study demonstrates an increased rate of nontraumatic fractures and other bony and connective tissue abnormalities that support the hypothesis that MSS should be considered an osteochondrodysplasia. In addition, long-term survival beyond infancy is possible if respiratory problems are expectantly and aggressively managed.

Adjunct prenatal testing: patient decisions regarding ethnic carrier screening and fluorescence in situ hybridization.

Little has been reported regarding how women make decisions about genetic carrier screening for Ashkenazi Jewish genetic disease and cystic fibrosis (CF), and for fluorescent in situ hybridization (FISH) during pregnancy. Thirty-seven women who underwent genetic counseling and prenatal diagnosis were interviewed about their prenatal decision making. Respondents were largely Caucasian (95%), and undergoing prenatal diagnosis because of maternal age (78%). Sixty-three percent of those who reported having genetic carrier screening correctly defined it; 83% felt positively about it. Primary reasons reported for electing screening were: to get information, to be prepared, perception of risk, wanting peace of mind and percieved inability to care for an affected child. Women who declined screening felt they had very little or no risk, and some were deterred by cost. Ninety-five percent of respondents elected to have FISH; most were motivated by its speed in providing information and peace of mind or by timing of when the procedure was performed. Those who declined FISH reported being less concerned about having an affected child, receiving bad news, or waiting 2 weeks for results and slightly less affected by their "feelings toward medical testing" or physician's suggestion. These findings suggest decision-making factors differ between those electing and declining adjunct prenatal testing and increased knowledge about these factors may impact the way in which these services are offered by health care professionals. Prospective research with a larger population will be useful in further delineating the factors that influence prenatal decisions about adjunct testing measures.

Effect of family history on disclosure patterns of cystic fibrosis carrier status.

As general population screening becomes more common, an increasing number of cystic fibrosis (CF) carriers will be identified who do not have a family history of CF. Whether these carriers inform their relatives of their carrier status and whether their relatives are motivated to pursue carrier screening is unknown. We surveyed CF carriers with and without a family history of CF to understand whether and how information dissemination patterns differ, why information is or is not shared, and to what extent relatives are known to undergo testing. CF carriers were identified from a general population carrier screening clinic (group B = 18) or were parents of affected children followed at a CF clinic (group A = 30). CF carriers with a family history told essentially 100% of their living parents, siblings, and half-siblings, while those without a family history told 84% of living parents and 56% of siblings (P < 0.05). Despite the high rate of information dissemination in both groups, few siblings were known to have undergone carrier screening (14/74). Significantly fewer second- and third-degree relatives were informed about carrier status or were known to have undergone carrier screening. Group A was more likely to inform second- and third-degree relatives about carrier status. Our study documents that the frequency and reasons for disclosing CF carrier status differ between individuals with and without a family history of CF despite the fact that the reproductive risks for their relatives are the same.