Novel LOVD databases for hereditary breast cancer and colorectal cancer genes in the Chinese population

The Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP-China Node will build new and supplement existing databases of genetic diseases. As the first effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese search engines to collect all the variants of these genes in the Chinese population that have already been detected and reported. There are some differences in the gene variants between the Chinese population and that of other ethnicities. The database is available online at http://www.genomed.org/LOVD/. Our database will appear to users who survey other LOVD databases (e.g., by Google search, or by NCBI GeneTests search). Remote submissions are accepted, and the information is updated monthly.     

Carrier screening panels for Ashkenazi Jews: is more better?

PURPOSE: To describe the characteristics of Ashkenazi Jewish carrier testing panels offered by US Laboratories, including what diseases are included, the labels used to describe the panels, and the prices of individual tests compared to the prices of panels for each laboratory. METHODS: GeneTests (http://www.genetests.org) was searched for laboratories that offered Tay-Sachs disease testing. Information was obtained from laboratory web sites, printed brochures, and telephone calls about tests/panels. RESULTS: Twenty-seven laboratories offered up to 10 tests. The tests included two diseases associated with death in childhood (Niemann-Pick type A and Tay-Sachs disease), five with moderate disability and a variably shortened life span (Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia, and mucolipidosis type IV), and two diseases that are not necessarily disabling or routinely shorten the lifespan (Gaucher disease type I and DFNB1 sensorineural hearing loss). Twenty laboratories offered a total of 27 panels of tests for three to nine diseases, ranging in price from $200 to $2082. Of these, 15 panels cost less than tests ordered individually. The panels were described by 24 different labels; eight included the phrase Ashkenazi Jewish Disease or disorder and six included the phrase Ashkenazi Jewish Carrier. CONCLUSION: There is considerable variability in the diseases, prices, and labels of panels. Policy guidance for establishing appropriate criteria for inclusion in panels may be useful to the Ashkenazi Jewish community, clinicians, and payers. Pricing strategies that offer financial incentives for the use of "more tests" should be reexamined.     

The dawn of consumer-directed testing

As the public's interest in genetics and genomics has increased, there has been corresponding and unprecedented growth in direct-to-consumer genetic testing (DTC-GT). Although regulatory concerns have limited true DTC-GT available without a physician order, the paradigm has shifted to a model of consumer-directed genetic testing (CD-GT) in which patients are researching testing options and requesting specific genetic testing from their health-care providers. However, many nongenetics health-care providers do not have the background, education, interest, or time to order and/or interpret typical clinical genetic testing, let alone DTC-GT. The lines between CD-GT, DTC-GT, and traditional clinical genetic testing are also blurring with the same types of tests available in different settings (e.g., carrier screening) and tests merging medical and nonmedical results, increasing the complexity for consumer decision-making and clinician management. The genetics community has the training to work with CD-GT, but there has been a hesitancy to commit to working with these results and questions about what to do when consumers have more complicated asks, like interpretation of raw data. Additionally, at the rate with which CD-GT is growing, there are questions about having sufficient genetics professionals to meet the potential genetic counseling demand. While there are many complex questions and challenges, this market represents a chance for the genetics community to address and unmet need. We will review the history of the CD-GT/DTC-GT market and outline the issues and opportunities our profession is facing.     

The cypriot and Iranian National Mutation Frequency Databases

The National Mutation Frequency Databases are continuously updated mutation depositories, which contain extensive information over the described genetic heterogeneity of an ethnic group or population. Here, we report the construction of the Cypriot (http://www.goldenhelix.org/cypriot) and Iranian National Mutation Frequency Databases (http://www.goldenhelix.org/iranian), both derived from an academic effort to provide high quality and up-to-date information on the underlying genetic heterogeneity of inherited disorders in the Cypriot and Iranian populations, respectively. Both databases have been built and maintained online using ETHNOS platform, a specialized software, which provides the means for national mutation database construction and curation. Each database contains brief summaries of the various genetic disorders studied for each population, and an easy-to-use query interface provides, both to specialist as well as to non-specialist users (i.e. patients and their families), instant access to the list and frequencies of the different mutations responsible for the inherited disorders in these populations. Furthermore, numerous links to the respective Online Mendelian Inheritance in Man (OMIM) entries and, when available, to the locus-specific databases fruitfully integrate the databases content into a single Web site. Both databases can serve as valuable online tools for molecular genetic testing of inherited disorders in these populations and could potentially motivate further investigations of yet unknown genetic diseases in the Cypriot and Iranian populations.     

Gastrointestinal polyposis syndromes

Numerous polyposis syndromes involve the gastrointestinal (GI) tract, including both non-hereditary and hereditary types. Causative genes are now known for the seven major syndromes. Genetic and clinicopathologic features are reviewed here and cancer predisposition is emphasized. Genetic testing is available for the GI polyposis syndromes, and can be accessed through GeneTests-GeneClinics on the Internet at http://www.genetests.org/. The website is available at no cost and is a publicly funded medical genetics resource for health care providers and researchers.     

Knowledge of genetics and attitudes toward genetic testing in two hereditary ataxia (SCA 1) Kindreds

Molecular genetic predictive or prenatal genetic testing is now possible in families with one form of adult-onset, autosomal dominant ataxia (SCA 1). Before the SCA 1 gene was isolated, we began a study of the knowledge of genetics, the perception of the disease, and the intended use of genetic testing among members of two large SCA 1 kindreds. Questionnaires were sent to 210 consenting affected, at-risk, and spouse members of two SCA 1 kindreds; data from the 117 respondents were analyzed on a personal computer. Sixty-nine percent of respondents thought predictive testing (by genetic linkage) should be made available immediately, and 42% thought prenatal testing should be made available. The kindreds differed in several important aspects: knowledge of genetic concepts, family size, and anticipated emotional responses to genetic testing. No respondent had obtained individualized genetic counseling. There is moderate interest in genetic testing for this fatal neurodegenerative disease of adulthood. Members of our kindreds have not received genetic counseling outside of the research setting. Finally, factors specific to a particular kindred may influence or predict individual responses to genetic testing. © 1994 Wiley-Liss, Inc.     

Novel LAMB3 mutations cause non‐syndromic amelogenesis imperfecta with variable expressivity

The field of genetics is evolving rapidly, significantly expanding the number of clinically useful genetic tests. The cost of genetic testing has created an increasing burden on public health care budgets. In Canada, funding bodies have responded by developing independent systems. Key individuals in each province and territory participated in a semi‐structured interview regarding the process in their jurisdiction to approve funding for referred out genetic testing and their decision‐making criteria. Two themes were identified: the importance of clinical utility in decision‐making and the utilization of genetic specialists as gate keepers. Allocation of a specific budget appears to be associated with some fiscal responsibility. Collaboration between provincial and territorial bodies may lead to a more unified approach across Canada.     

Investigating genetic discrimination in Australia: a large-scale survey of clinical genetics clients

We report first results from the Australian Genetic Discrimination Project of clinical genetics services clients' perceptions and experiences regarding alleged differential treatment associated with having genetic information. Adults (n = 2667) who had presented from 1998 to 2003 regarding predictive or presymptomatic testing for designated mature-onset conditions were surveyed; 951/1185 respondents met inclusion criteria for current asymptomatic status. Neurological conditions and familial cancers were primary relevant conditions for 87% of asymptomatic respondents. Specific incidents of alleged negative treatment, reported by 10% (n = 93) of respondents, occurred in life insurance (42%), employment (5%), family (22%), social (11%) and health (20%) domains. Respondents where neuro-degenerative conditions were relevant were more likely overall to report incidents and significantly more likely to report incidents in the social domain. Most incidents in the post-test period occurred in the first year after testing. Only 15% of respondents knew where to complain officially if treated negatively because of genetics issues. Recommendations include the need for increased community and clinical education regarding genetic discrimination, for extended clinical genetics sector engagement and for co-ordinated monitoring, research and policy development at national levels in order for the full benefits of genetic testing technology to be realised.     

Knowledge About Genetic Risk for Breast Cancer and Perceptions of Genetic Testing in a Sociodemographically Diverse Sample

Informed consent for genetic testing for breast–ovarian cancer susceptibility requires that women understand basic concepts about the inheritance of cancer susceptibility and the benefits and risks associated with genetic testing. Women awaiting routine medical services (N = 220) were surveyed about their knowledge of breast cancer and cancer genetics and their perceptions of genetic testing and personal risk. There were no racial differences in median income or mean level of education. Compared to Caucasian women, African American women knew significantly less about breast cancer and about genetic risk for breast cancer. African American women had different psychological, social, and economic concerns as evidenced by how they weighted the benefits and risks of genetic testing. This study is the first to assess several dimensions of informed consent for genetic testing among a sociodemographically diverse group. The findings should enable health professionals to target the African American and lower-income populations with the appropriate education and counseling.     

Impact of direct-to-consumer genetic testing on Australian clinical genetics services

The increasing popularity of direct-to-consumer genetic testing (DTCGT) is thought to be creating a burden on clinical genetic services worldwide. However, no Australian studies have collected recent evidence regarding this impact. We surveyed Australian clinical genetics services about DTCGT-related referrals over the past 10 years. Eleven publicly-funded services reported over 100 DTCGT-related referrals. Most (83%) involved general practitioners seeking interpretation of DTCGT results. More than 30% involved imputed risk estimates from third-party software tools. Services reported low validation rates for DTCGT results (<10%), and variable procedures for managing DTCGT referrals, with most (8/11) lacking specific procedures. Our study helps quantify the impact of DTCGT on clinical genetics services, and highlights the impact of imputed risk estimates.     

The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates

Background: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability.

Objective: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa.

Approach: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women.

Methods: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses.

Conclusions: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub-Saharan Africa. We anticipate the results will directly inform HIV policy in sub-Saharan Africa to optimize care for HIV-infected patients.     

Evaluating empowerment in genetic counseling using patient-reported outcomes

Data about patient reported outcomes from cancer genetics services (CGS) are lacking but are essential to guide service evaluation and improvements. We measured improvement in empowerment, following genetic counseling in Singapore using a culturally-adapted version of the Genetic Counseling Outcome Scale (GCOS-24); and sought to identify factors associated with change in empowerment. The GCOS-24 was administered to 155 patients of the CGS, at pre- and post-counseling or testing timepoints. Of which, 110 patients underwent genetic testing. Individual pre- and post-counseling responses were subjected to Rasch analysis; the scale was subsequently split into cognitive control (CC) and emotional control (EC) domains. Associations of baseline characteristics with changes in pre- and post-CC and EC scores were assessed using multiple regression analysis. Both CC and EC scores showed significant improvement following genetic counseling and testing. While all items in the CC domain of being showed increases at follow-up, aspects of EC related to alleviating negative emotions (P = .88) and hopelessness (P = .2) did not show significant improvement. Our study revealed significant improvement in empowerment in patients who have received cancer genetic counseling, while revealing a need to cultivate hope and facilitate the alleviation of negative emotions in patients during genetic counseling.     

eyeGENE®: a vision community resource facilitating patient care and paving the path for research through molecular diagnostic testing

Molecular genetics and genomics are revolutionizing the study and treatment of inherited eye diseases. In recognition of the impact of molecular genetics on vision and ophthalmology, the National Eye Institute established the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE®) as a multidirectional research initiative whereby a clinical component for patients diagnosed with inherited eye disease fosters research into the causes and mechanisms of these ophthalmic diseases. This is accomplished by broadening access to genetic diagnostic testing and maintaining a repository of DNA samples from clinically characterized individuals and their families to allow investigations of the causes, interventions, and management of genetic eye disorders. The eyeGENE® Network currently includes Clinical Laboratory Improvement Amendments (CLIA)‐certified diagnostic laboratory partners, over 270 registered clinical organizations with 500 registered users from around the United States and Canada, and is now testing approximately 100 genes representing 35 inherited eye diseases. To date, the Network has received 4400 samples from individuals with rare inherited eye diseases, which are available for access by the vision research community. eyeGENE® is a model partnership between the U.S. federal government, eye health care providers, CLIA‐approved molecular diagnostic laboratories, private industry, and scientists who represent a broad research constituency.     

Psychosocial implications of living with familial risk of a psychiatric disorder and attitudes to psychiatric genetic testing: A systematic review of the literature

The aim of this systematic review was to synthesize the existing evidence documenting the psychosocial implications of living with a familial risk of an adult‐onset psychiatric disorder. Six databases were searched systematically to identify qualitative and quantitative studies, which explored perspectives of those at increased risk for psychiatric disorders, as well as the general public. Thematic analysis was used to identify major themes. Thirty‐five articles met the eligibility criteria and reported on the views of 4,896 participants. The literature demonstrates strong interest in psychiatric genetic testing of adults as well as children, whereas attitudes toward prenatal testing were much less positive. Predictors of interest in testing, as well as perceived advantages and disadvantages were identified. Very few studies are available on anticipated and actual reactions to receiving results. Studies show that the majority of participants feel that having a genetic explanation would alleviate some of the stigma associated with mental illness. This review shows that interest in, and predictors of attitudes toward, psychiatric genetic testing are well researched, but the extent to which attitudes will translate into actual testing uptake is unknown. Future research also needs to assess the actual behavioral and psychological impact of genetic testing.     

Public interest in predictive genetic testing, including direct-to-consumer testing, for susceptibility to major depression: preliminary findings

The past decade has seen rapid advances in the identification of associations between candidate genes and a range of common multifactorial disorders. This paper evaluates public attitudes towards the complexity of genetic risk prediction in psychiatry involving susceptibility genes, uncertain penetrance and gene–environment interactions on which successful molecular-based mental health interventions will depend. A qualitative approach was taken to enable the exploration of the views of the public. Four structured focus groups were conducted with a total of 36 participants. The majority of participants indicated interest in having a genetic test for susceptibility to major depression, if it was available. Having a family history of mental illness was cited as a major reason. After discussion of perceived positive and negative implications of predictive genetic testing, nine of 24 participants initially interested in having such a test changed their mind. Fear of genetic discrimination and privacy issues predominantly influenced change of attitude. All participants still interested in having a predictive genetic test for risk for depression reported they would only do so through trusted medical professionals. Participants were unanimously against direct-to-consumer genetic testing marketed through the Internet, although some would consider it if there was suitable protection against discrimination. The study highlights the importance of general practitioner and public education about psychiatric genetics, and the availability of appropriate treatment and support services prior to implementation of future predictive genetic testing services.     

An evaluation of clinical presentation and genetic testing approaches for patients with neuromuscular disorders

Inherited neuromuscular disorders (NMDs) are a large group of genetic conditions characterized by impaired peripheral nerve, motor neuron, neuromuscular junction, or skeletal muscle function. These conditions are also known to have clinical and genetic heterogeneity and variable ages of onset. Clinical evaluation for NMDs has increasingly incorporated molecular genetics. However, genetic testing is complicated by the variety of testing options and the ambiguity of NMD phenotypes. Examining test selection and yield may elucidate testing recommendations and improve the diagnostic journey for these patients. This retrospective chart review evaluated the clinical presentations, genetic testing approaches, and diagnostic outcomes of 155 patients with suspected NMDs at Cincinnati Children's Hospital Medical Center. A total of 262 individual tests were ordered, averaging 1.7 tests per patient. The clinic utilized 26 separate genetic tests, with test yields ranging from 0% to 66%. Overall, 21% of patients received a genetic diagnosis. Of all the clinical findings evaluated, elevated CPK levels with or without muscle weakness were the most informative symptoms correlated with a diagnostic result. This study highlights several genetic testing considerations for NMDs, including the variability of diagnostic outcomes. This knowledge is relevant to clinicians and patients, especially during the pretest counseling and consenting process.     

Pediatric psychology training and genetics: what will twenty-first-century pediatric psychologists need to know?

OBJECTIVE: To demonstrate the importance of genetic knowledge in coming decades and to outline necessary areas of genetic education. METHOD: This article reviews research involving genetic testing of children for cancer syndromes, development disabilities, psychiatric problems, and other conditions. RESULTS: The developmental, clinical, research, and consultation skills of well-trained pediatric psychologists will make them valuable collaborators with genetics professionals. Pediatric psychologists study the genetic etiology of psychiatric conditions and outcomes of genetic testing for physical disease. CONCLUSIONS: Pediatric psychologists will need training in the concepts and methods of the New Genetics. They should understand the implications of risk notification and genetic test disclosure and should be aware of related ethical concerns.