Non-geneticist Clinicians Research Articles

Putting the Pieces Together: Clinically Relevant Genetic and Genomic Resources for Hospitalists and Neonatologists.

Genetic conditions are individually rare but are common in aggregate, and they often present in the neonatal and early pediatric periods. These conditions are often severe, can be difficult to diagnose and manage, and may heavily affect patients, families, health care systems, and society. Because of recent technological advances, the availability and uptake of genetic and genomic testing are increasing rapidly. However, there is a dearth of trained geneticists and genetic counselors to help guide and explain these conditions and relevant tests. To help hospitalists, neonatologists, and related practitioners navigate this complex and evolving field, we have compiled a list of free (mostly Web-based) resources relevant to the diagnosis and management of genetic conditions and related disorders. These resources, which we describe individually, can be useful for nongeneticist clinicians, and some also include material that can be used to explain concepts and conditions to patients or families. The resources presented are divided into the following categories (which overlap): general information, databases of genetic conditions, resources that can help generate differential diagnoses, databases of genetic testing laboratories (to help with logistics of ordering tests), information on newborn screening, and other resources. We also include a separate list of helpful textbooks and manuals. We conclude with 2 examples describing how some of these resources would be used by a pediatric hospitalist or neonatologist during the inpatient management of a child with a suspected genetic condition.

Genomic sequencing in clinical practice: applications, challenges, and opportunities

The development of massively parallel sequencing (or next-generation sequencing) has facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic sequencing (GS) is now an essential tool for evaluating rare disorders, identifying therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging applications, such as GS for preconception carrier screening and predisposition screening in healthy individuals, are being explored in research settings and utilized by members of the public eager to incorporate genomic information into their health management. The rapid pace of adoption has created challenges for all stakeholders in clinical GS, from standardizing variant interpretation approaches in clinical molecular laboratories to ensuring that nongeneticist clinicians are prepared for new types of clinical information. Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data enable further clinical innovation and complicated implementation questions continue to be resolved.

A Review on Spinal Muscular Atrophy: Awareness, Knowledge, and Attitudes.

Spinal Muscular Atrophy(SMA) is one of the most common genetic causes of infant death. There is presently no cure, but the therapeutic pipeline is promising. Given the prevalence of SMA coupled with the potential for new treatment options, universal carrier screening, and newborn screening, we conducted a literature review of the awareness, knowledge, and attitudes held by the public and non-geneticist clinicians about various aspects of SMA. We then identify recommendations for targeting additional research, training, and educational efforts to increase awareness. In the limited available literature, we found that the public is generally unfamiliar with SMA but has favorable views of carrier and newborn screening. Clinicians also had limited understanding of SMA. Further research into knowledge and attitudes of healthcare providers and the general public will help develop a better understanding of education gaps and inform outreach efforts. These educational efforts are needed to complement the momentum as treatments are being developed and tested. Furthermore, professional societies are proposing routine carrier screening and SMA may achieve newborn screening status, which will change the SMA landscape for genetics professionals and families. Thus, it is important to explore knowledge and attitudes about SMA to allow us to prepare for when SMA attains higher public and clinician recognition.

Genetic Test Results and Disclosure to Family Members: Qualitative Interviews of Healthcare Professionals' Perceptions of Ethical and Professional Issues in France.

The benefit of disclosing test results to next of kin is to improve prognosis and-in some cases-even prevent death though earlier monitoring or preventive therapies. Research on this subject has explored the question of intra-familial communication from the standpoint of patients and relatives but rarely, from the standpoint of healthcare professionals. The purpose of this study was to interview relevant healthcare professionals in France, where legislation framing the issue was recently passed. A qualitative study consisting of semi-structured interviews was set up to get a clearer picture of the challenges arising from this issue, its consequences in terms of medical care-service practices, and the positions that frontline professionals have taken in response to this new legal framework. The findings from eight interviews with 7 clinical geneticists and 1 genetic counselor highlight very different patterns of practices among care services and among the genetic diseases involved. It is equally crucial to investigate other issues such as the nature of genetic testing and its consequences in terms of disclosing results to kin, the question of the role of genetic counseling in the disclosure process, the question of prescription by non-geneticist clinicians, and practical questions linked to information content, consent and medical follow-up for patients and their relatives.

Jumping on the Train of Personalized Medicine: A Primer for Non-Geneticist Clinicians: Part 1. Fundamental Concepts in Molecular Genetics.

With the decrease in sequencing cost and the rise of companies providing sequencing services, it is likely that personalized whole-genome sequencing will eventually become an instrument of common medical practice. We write this series of three reviews to help non-geneticist clinicians get ready for the major breakthroughs that are likely to occur in the coming years in the fast-moving field of personalized medicine. This first paper focuses on the fundamental concepts of molecular genetics. We review how recombination occurs during meiosis, how de novo genetic variations including single nucleotide polymorphisms (SNPs), insertions and deletions are generated and how they are inherited from one generation to the next. We detail how genetic variants can impact protein expression and function, and summarize the main characteristics of the human genome. We also explain how the achievements of the Human Genome Project, the HapMap Project, and more recently, the 1000 Genomes Project, have boosted the identification of genetic variants contributing to common diseases in human populations. The second and third papers will focus on genetic epidemiology and clinical applications in personalized medicine.

Jumping on the Train of Personalized Medicine: A Primer for Non- Geneticist Clinicians: Part 3. Clinical Applications in the Personalized Medicine Area.

The rapid decline of sequencing costs brings hope that personal genome sequencing will become a common feature of medical practice. This series of three reviews aim to help non-geneticist clinicians to jump into the fast-moving field of personalized genetic medicine. In the first two articles, we covered the fundamental concepts of molecular genetics and the methodologies used in genetic epidemiology. In this third article, we discuss the evolution of personalized medicine and illustrate the most recent success in the fields of Mendelian and complex human diseases. We also address the challenges that currently limit the use of personalized medicine to its full potential.

Jumping on the Train of Personalized Medicine: A Primer for Non-Geneticist Clinicians: Part 2. Fundamental Concepts in Genetic Epidemiology

With the decrease in sequencing costs, personalized genome sequencing will eventually become common in medical practice. We therefore write this series of three reviews to help non-geneticist clinicians to jump into the fast-moving field of personalized medicine. In the first article of this series, we reviewed the fundamental concepts in molecular genetics. In this second article, we cover the key concepts and methods in genetic epidemiology including the classification of genetic disorders, study designs and their implementation, genetic marker selection, genotyping and sequencing technologies, gene identification strategies, data analyses and data interpretation. This review will help the reader critically appraise a genetic association study. In the next article, we will discuss the clinical applications of genetic epidemiology in the personalized medicine area.

Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance (VUS). In contrast to clearly pathogenic mutations, VUS do not firmly diagnose Lynch syndrome at the molecular level and cannot be used to identify with certainty any of the patients' asymptomatic relatives as Lynch syndrome mutation carriers. The International database that collects MMR gene variants ( www.insight-group.org/mutations ) already lists more than 1,000 different VUSs and these variants are likely the tip of the iceberg. This paper aims at introducing non-geneticist clinicians to the topic of clinical MMR gene variant interpretation. Many lines of evidence are being used to classify VUS. Some are already familiar to clinicians and others may be less familiar but are expected to become important in clinical genetics in the coming years. Clinicians can play an important role in collecting the data needed to interpret the MMR variants detected in their patients.

Hereditary breast and ovarian cancer: Referral source for genetic assessment and communication regarding assessment with nongenetic clinicians in the community setting

PurposeTo examine referral source to cancer genetic services; communication of results of genetic evaluation to clinicians; role of clinicians in postcounseling management; and use of alternative information sources after cancer genetic risk assessment/counseling in the community setting. MethodsRetrospective telephone survey. Setting: A community/private hospital-based cancer genetic counseling service. PatientsWomen, at least 21 years of age, who had undergone cancer genetic counseling with (1) at least a 10% predicted likelihood of carrying a BRCA1/2 mutation or (2) a documented BRCA1/2 mutation. InterventionA 121-item telephone survey. Main outcome measure: (1) initial referral source to cancer genetic services; (2) women's communication of results of cancer genetic assessment to primary and (nongenetic) specialist clinician(s); (3) education and support role played by subjects' physician(s); and (4) use of other hereditary breast and ovarian cancer (HBOC) information resources. ResultsOf 225 women eligible for study, 69 (31%) completed the survey. Sixty-two percent were referred by their medical oncologist; 13% by their primary care physician, and fewer by their surgeon (6%) or gynecologist (4%). Results of the cancer genetic assessment were not shared with 19% of primary care clinicians, 26% of primary gynecologists, 12% of oncologists, and 36% of surgeons. Twenty-six percent of participants noted that their primary care clinician had not been involved in their HBOC-related, cancer prevention decisions, 16% had not included their gynecologist, 2% had not involved their oncologist, and 20% replied that their surgeon had not been involved in these decisions. Overall, clinicians were perceived as supportive when it came to a participants' information and decision support needs. One exception was that 21% of respondents reported the use by clinicians of medical terms, without definition. Over two-thirds had sought alternative “self-help” HBOC-related materials, most Internet based. ConclusionsThese results have implications for interdisciplinary communication and decision support for those with or at risk for HBOC, cared for in the community setting.

Evolving perspectives on genetic discrimination in health insurance among health care providers

Previous studies have documented that concerns about genetic discrimination (GD) may influence access to and participation in medically necessary care. We sought to characterize how GD issues influence current cancer genetics professional (CGP) practice, determine if their attitudes regarding GD have changed over time, and compare their knowledge and attitudes regarding laws prohibiting GD to a contemporary cohort of non-genetics clinicians. Members of the National Society of Genetic Counselors Familial Cancer Special Interest Group were invited to complete a 39 item online survey, adapted from previously published instruments. The resulting data were compared to a survey of CGPs published in 2000 and to a contemporary cohort of non-genetics clinicians (n = 1,181). There were 153 qualified respondents. Compared to the historical CGP cohort (n = 163), a significantly greater proportion said they would bill insurance for the cost of genetic testing for themselves (P < 0.0001). Most CGPs (94%) considered the risk of GD to be low to theoretical, concordant with 64% who expressed confidence in existing federal laws prohibiting GD. The mean knowledge score of CGPs regarding GD protective laws was significantly greater than that of non-genetics clinicians (P < 0.001). As barometers of change, CGPs show a migration in opinion over the past 8 years, with decreased fear of GD and greater knowledge of laws prohibiting GD compared to non-genetics clinicians. Better knowledge of GD and protective legislation, may facilitate non-genetics clinician utilization of genetics and personalized medicine.

Influence of genetic discrimination perceptions and knowledge on cancer genetics referral practice among clinicians

PurposeTo describe nongenetics clinicians' perceptions and knowledge of cancer genetics and laws prohibiting genetic discrimination, attitudes toward the use of cancer genetic testing, and referral practices. MethodsInvitations to participate were sent to a random stratified sample of California Medical Association members and to all members of California Association of Nurse Practitioners and California Latino Medical Association. Responders in active practice were eligible and completed a 47-item survey. ResultsThere were 1181 qualified participants (62% physicians). Although 96% viewed genetic testing as beneficial for their patients, 75% believed fear of genetic discrimination would cause patients to decline testing. More than 60% were not aware of federal or California laws prohibiting health insurance discrimination—concern about genetic discrimination was selected as a reason for nonreferral by 11%. A positive attitude toward genetic testing was the strongest predictor of referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001) in stepwise logistic regression analyses. The higher the belief in genetic discrimination, the less likely a participant was to refer (odds ratio: 0.72 [95% confidence interval: 0.518-0.991], P < 0.05), whereas more knowledge of genetic discrimination law was associated with comfort recommending (odds ratio: 1.18 [95% confidence interval: 1.11-1.25], P < 0.001) and actual referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001). ConclusionConcerns about genetic discrimination and knowledge deficits may be barriers to cancer genetics referrals. Clinician education may help promote access to cancer screening and prevention.

Contending visions in the evolution of genetic medicine: The case of cancer genetic services in Ontario, Canada

Growth in genetic medicine has provoked debate about how new and emerging genetic services should be provided, and specifically, what roles non-genetic clinicians should assume. We address this question through a qualitative interview based case study of the program in genetic testing for the hereditary cancer syndromes (breast/ovarian and colorectal) in Ontario, Canada. We argue that two communities offer parallel visions of cancer genetic care: one “genetic,” the other “oncologic.” Both communities argue from precedent that cancer genetics is a natural extension of their work: it is “what we do.” Both communities also highlight the importance of their own expertise in providing core elements of cancer genetic care: it requires “what we know.” Further, both communities perceive the need for leadership by their own (or a related) community as genetic medicine expands to include a broader array of more common and complex diseases: it is expanding “where we're leading.” Yet, the “we's” articulating these visions are not reducible to professional identity; rather, both represent distinctive “communities of practice and discourse” that are constructed in relation to institutionalized professional roles, and interactions with the genetic technologies (both tests and counselling) themselves. Available literature on the role of diverse health care professionals in the provision of genetic health care presumes a fixed identity and set of approaches for each professional group that might play a role. Further, existing models tend to assume that genetic technologies are given as tools, and that service organization concerns primarily questions of who will have access to these tools and their powers, as well as the consequent professional and ethical responsibilities. Yet questions about who will control genetic technologies are not simply turf battles between the professions: they are also inescapably questions about what the genetic technologies should and will accomplish clinically.

Comparing genetic counseling with non-genetic health care interactions: Two of a kind?

Objective Increasingly clinicians other than genetic counselors will advise people with genetic risks. Although some express concerns about this development because of the need for non-genetic clinicians to have additional training, we argue that genetic counseling has more in common with other health care interactions than is generally assumed. Methods In this narrative review we investigate the health communication literature taking the perspective that all provider–patient/client interactions share the following goals: forming a relationship, the exchange of information, decision making, promoting health-related behavior and providing support. Results We found that both non-genetic and genetic ‘disciplines’ endorse an egalitarian relationship, based on a patient-centered approach and both have difficulties with attuning to the patients’ agendas and enhancing patient understanding. Shared decision making is increasingly the preferred model for geneticists and non-geneticists alike, and both need skills to constructively discuss patients’ risk-reducing behavior and provide emotional support. Conclusion Rather than developing separate vocabularies and research traditions, the discipline of genetic counseling may benefit by drawing on non-genetic patient–provider interaction research. Practice implications Since geneticists face the same challenges as non-geneticists, medical training should continue to improve basic consultation skills, regardless of whether the consultation involves genetic information.

Is it in your Genes? The Influence of Genes on Common Disorders and Diseases that affect you and your Family

Though Dr Reilly's book is targeted at scientifically literate laymen, I think it will be of greatest value to non-geneticist clinicians who occasionally face difficult questions about conditions that seem to run in a patient's family. An accompanying website promises to keep the information up to date and, if this commitment is sustained, this will be a really useful resource. As one might expect from a book from Cold Spring Harbor Laboratories, the examples provided are geared to healthcare delivery in the US. The British reader might have appreciated a list of contact numbers for NHS regional genetics centres who can be consulted by those in need of further guidance: such a list is obtainable from the British Society for Human Genetics [www.bshg.org.uk]. For the general public, I suspect this will be a work to consult rather than purchase. Those who do dip into it— and find information on the genetics of conditions ranging from homosexuality (2–3 times the background risk if you have a gay brother) and male pattern baldness to cancers and heart disease—will quickly realize that the deterministic view of genetics that is often conveyed by the media, with announcements of 'a gene for x or y' where these are complex behaviours or multifactorial diseases, is a gross oversimplification. If that message can be lodged in the reader's mind then the author will have done everyone a favour. For clinicians, the impact of genetics on clinical practice outside the specialist area of the rare single gene disorders (or the Mendelian subsets of some of the common ones) has so far been small, but this will soon start to change and they will have to master the complexities of genetic and environmental interactions. Whilst Reilly's book is no substitute for proper professional development programmes, its clarity and its easy and accessible style will help them meet this challenge and provide sensible advice.

Who gets the information about genetic testing for cancer risk? The role of race/ethnicity, immigration status, and primary care clinicians.

This study identified factors associated with awareness of genetic testing for cancer risk in the US general population. Multiple logistic regression analysis was used to analyze data from the 2000 National Health Interview Survey. The strong predictors were education, race/ethnicity, immigration status, health status, interaction with health professionals, controlling for socioeconomic status, cancer diagnosis, family history of cancer, and perceived personal cancer risk. The substantial lack of awareness of genetic testing among immigrant and ethnic populations warrants further research and tailored educational interventions. Ways to improve quality of patient interactions with non-genetic clinicians in promoting public knowledge of genetic testing for cancer risk are also worthy of further exploration.

National Confidential Enquiry into counselling for genetic disorders by non-geneticists: general recommendations and specific standards for improving care.

To assess genetic counselling by non-geneticists and to improve clinical practice. National retrospective review of casenotes. Antenatal, paediatric, medical, and surgical units. 1293 genetic events were identified, involving potentially avoidable cases of Down's syndrome, neural tube defect, cystic fibrosis, beta thalassaemia major and late onset medullary carcinoma of the thyroid (multiple endocrine neoplasia). Notes were available for review in 888 (69%) of these cases. Documented counselling, offers of relevant genetic screening and prenatal diagnosis. Clinical audit was frustrated by poor quality hospital records lacking evidence of counselling. Non-geneticist clinicians concentrate on the management of disease, and may overlook the need for counselling and recording data which patients will later need for decisions about reproduction or disease prevention. Counselling, screening and prenatal diagnosis were sometimes impossible because of late booking in pregnancy, or because of delayed diagnosis of an earlier affected child with cystic fibrosis. There are marked regional inequalities of access to genetic services, particularly for minority ethnic groups with increased risks of thalassaemia. Although patients were selected for this enquiry because they had known high risks of genetic disorders, on average less than half were referred to medical geneticists. General recommendations relevant for improvement of care for patients and families with medical genetic needs and those specific for each disorder are given. Assessment of the quality of genetic care becomes increasingly important as genetic counselling spreads beyond the narrow confines of specialist genetic services. Even though the events studied in this enquiry largely occurred between 1991 and 1995, there is little reason to believe that clinicians in general have become markedly better trained in medical genetics. The General Medical Council and Medical Royal Colleges should urgently consider the need for a national policy for improving undergraduate and postgraduate medical, nursing and midwifery education in genetics. Commissioners of clinical services should require that genetic management be at least as well-documented as surgical operations, drug records and informed consent, perhaps by using a nationally agreed pro-forma for prenatal diagnosis. Regular audit of counselling provided by non-geneticists is necessary to confirm that clinical improvements are occurring and standards are being met. The Confidential Enquiry provides data for a systematic approach to clinical governance of genetics in all specialities. This sets the scene for multi-speciality NHS genetic services capable of giving patients greater consistency both in access and in quality.

Assessment of quality of genetic counseling services by study of adverse events

Quality assessment of genetic counseling is rare in the 31 European nations of the Concerted Action on Genetic Services (CAGSE). Quality is here defined as the documented provision of genetic counseling in individual patient's records and adverse events are here defined as the occurrence of preventable genetic disorders when records suggest poor quality counseling has denied patients informed and unconstrained decisions. A lack of quality assessment is a matter of particular concern when counseling is provided by physicians who are not trained in medical genetics. In the UK a national audit has been successfully completed of adverse events associated with easily recognisable high-risk situations. Non-geneticists provided genetic counseling because only a minority of such cases is referred to clinical geneticists. The adverse events included within a defined period all Down syndrome pregnancies in women of 38 or more, all live born infants with neural tube defect, cystic fibrosis in a second sibling, beta thalassaemia major pregnancies and late onset medullary carcinoma of the thyroid (multiple endocrine neoplasia, MEN2). The overall findings were that non-geneticist clinicians concentrate on the management of disease and may overlook the need for counseling and recording data which patients will later need for decisions about reproduction or disease prevention. Counseling, screening and prenatal diagnosis were sometimes impossible because of late booking in pregnancy or because of delayed diagnosis of an earlier affected child with CF. There are marked regional inequalities of access to genetic services particularly for minority ethnic groups with increased risks of thalassaemia. Ongoing audit of adverse genetic events, including all cases of early onset breast and bowel cancer, is being developed as part of a national clinical governance strategy to improve the understanding and use of genetic counseling services.