Genetic Risk Screening Research Articles

Implementation of type 1 diabetes genetic risk screening in children in diverse communities: the Virginia PrIMeD project

BackgroundPopulation screening for risk of type 1 diabetes (T1D) has been proposed to identify those with islet autoimmunity (presence of islet autoantibodies). As islet autoantibodies can be transient, screening with a genetic risk score has been proposed as an entry into autoantibody testing.MethodsChildren were recruited from eight general pediatric and specialty clinics across Virginia with diverse community settings. Recruiters in each clinic obtained informed consent/assent, a medical history, and a saliva sample for DNA extraction in children with and without a history of T1D. A custom genotyping panel was used to define T1D genetic risk based upon associated SNPs in European- and African-genetic ancestry. Subjects at “high genetic risk” were offered a separate blood collection for screening four islet autoantibodies. A follow-up contact (email, mail, and telephone) in one half of the participants determined interest and occurrence of subsequent T1D.ResultsA total of 3818 children aged 2–16 years were recruited, with 14.2% (n = 542) having a “high genetic risk.” Of children with “high genetic risk” and without pre-existing T1D (n = 494), 7.0% (34/494) consented for autoantibody screening; 82.4% (28/34) who consented also completed the blood collection, and 7.1% (2/28) of them tested positive for multiple autoantibodies. Among children with pre-existing T1D (n = 91), 52% (n = 48) had a “high genetic risk.” In the sample of children with existing T1D, there was no relationship between genetic risk and age at T1D onset. A major factor in obtaining islet autoantibody testing was concern over SARS-CoV-2 exposure.ConclusionsMinimally invasive saliva sampling implemented using a genetic risk score can identify children at genetic risk of T1D. Consent for autoantibody screening, however, was limited largely due to the SARS-CoV-2 pandemic and need for blood collection.

Diagnostic yield of genetic screening in a diverse, community-ascertained cohort

BackgroundPopulation screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines.MethodsWe sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population. We developed a low-cost, short-read next-generation sequencing panel of 25 genes that had 98.4% sensitivity and 99.98% specificity compared to diagnostic panels. We used email invitations to recruit a diverse cohort of patients in the University of Washington Medical Center system unselected for personal or family history of hereditary disease. Participants were sent a saliva collection kit in the mail with instructions on kit use and return. Results were returned using a secure online portal. Enrollment and diagnostic yield were assessed overall and across race and ethnicity groups.ResultsOverall, 40,857 people were invited and 2889 (7.1%) enrolled. Enrollment varied across race and ethnicity groups, with the lowest enrollment among African American individuals (3.3%) and the highest among Multiracial or Other Race individuals (13.0%). Of 2864 enrollees who received screening results, 106 actionable variants were identified in 103 individuals (3.6%). Of those who screened positive, 30.1% already knew about their results from prior genetic testing. The diagnostic yield was 74 new, actionable genetic findings (2.6%). The addition of more recently identified cancer risk genes increased the diagnostic yield of screening.ConclusionsPopulation screening can identify additional individuals that could benefit from prevention, but challenges in recruitment and sample collection will reduce actual enrollment and yield. These challenges should not be overlooked in intervention planning or in cost and benefit analysis.

Improving access to cancer genetic testing for underserved women in southeast Texas.

6548 Background: Hereditary breast cancer accounts for 5-10% of all cases, but only 20% of eligible women undergo NCCN guideline-concordant screening. We demonstrated previously that our simple genetic risk screening tool (GRST) and telegenetics improved adherence to genetic testing guidelines and increased high-risk cancer surveillance. Our objective was to identify women eligible for genetic testing using breast cancer screening clinics in underserved communities as entry points, reach them with our tailored program, and measure impact. Methods: This is a prospective study in women presenting for breast cancer screening at The Rose, which provides breast imaging to underserved patients in Houston, TX. Women who consented to participate filled out the GRST and provided socio-demographic information. Those at high risk for hereditary cancer after GRST scoring were provided with educational materials and sent a saliva-based genetic testing kit. When results included a pathogenic variant (PV) or variant of uncertain significance (VUS), individuals received telegenetic counseling and risk reduction resources. Others were notified of negative results by phone. The program included education for providers about importance of genetic testing. Socio-demographic characteristics were analyzed using descriptive statistics. All statistical tests were two-sided. Results: 501 women filled out the GRST. Median age was 52. Median annual salary was $45,000 (IQR 21-75K). 151 (36.3%) were uninsured. 252 (50.3%) identified as White, 230 (45.9%) as Hispanic/Latino, and 106 (21.2%) as Black/African American. 150 (33%) were eligible for genetic testing; 100 could be contacted. Of the 100, 41 declined testing, 40 were lost to follow-up, 19 agreed, and 15 (10% of those eligible) returned the kits. Results included 11 negative, 2 VUS, 1 PV (NF1). Among 41 who declined testing, reported reasons included not wanting to know the results or preference to follow-up with their primary care doctor in 11 (26.8%) each, not enough time or prior genetic testing in 6 (14.6%) each, no reason given by five, and perception that testing was unnecessary in two. Completion of genetic testing was not associated with insurance, salary, family history, or race/ethnicity (p > 0. 05). Conclusions: Our study was successful in identifying underserved women at high risk of hereditary cancer who have not previously undergone genetic testing using a simple screening tool. We reduced barriers to genetic testing by working with a trusted community organization and using remote testing and telegenetics. We did not find any factors associated with genetic testing completion, though results are limited by small sample size. Given the low proportion of patients who completed testing, the next project phase will focus on improving convenience for patients and exploring patient and program-related reasons for non-completion of testing and strategies to overcome these.

Abstract P3-01-16: Screening for genetic risk at the time of mammography

Abstract Introduction: Approximately, 10-15% of breast cancers may be hereditary. Early identification of elevated genetic risk may decrease morbidly and mortality associated with breast cancer for this population by enabling timely implantation of optimized screening techniques. Reaching out to women with breast cancer risk assessment at the time of mammography may provide an opportunity to connect risk perception with risk reduction action. We hypothesized that women receiving a high-risk assessment at the time of mammography would facilitate entry to genetic counseling. Methods: In September 2019, Jefferson Health New Jersey (JHNJ) started utilizing a tool to screen individuals for an increased risk for hereditary breast cancer syndromes (family history screening 7; FHS-7) to all women presenting for mammography at its three breast imaging centers. The FHS-7 tool was embedded into the electronic medical record system and would generate a score based on 7 questions related to a patient’s family history of breast, ovarian and bowel cancer. Women who were identified at elevated risk (FHS-7 scores ≥1) were asked by the mammography technician prior to performing the screening mammogram for their permission to be contacted by a high-risk counselor for a formal high-risk assessment and potential genetic counseling/testing. In March 2020, nearly all cancer screening services shut down with the COVID-19 pandemic. Services re-opened in June 2020. We report on our experience in three-time frames: September 2019-February 2020; March 2020-May 2020, and June 2020-present. Results: From September 2019-February 2020: 3,169 mammograms and FHS-7 screenings were performed. 44 had scores ≥1 (1.4%). 4 (9%) agreed to be contacted for an appointment with a high-risk counselor. Of these, 2 had previously met with genetics. No additional appointments were scheduled. From March 2020-May 2020, 576 mammograms and FHS-7 screenings were performed. 9 had scores ≥1 (1.6%). None agreed to be contacted for an appointment with a high-risk counselor. Two appointments had previously been completed. From June 2020-June 2021, 9,131 mammograms and FHS-7 screenings were performed. 240 had scores ≥1 (2.6%). 22 (9%) agreed to be contacted for an appointment with genetics. 11 appointments had previously been completed. 8 (73%) were completed as a consequence of this direct outreach. Conclusion: Although our work was interrupted by the COVID-19 pandemic, screening for hereditary risk at the time of mammography may be an effective way of facilitating referrals for genetic counseling/testing for high-risk patients. Consent to be contacted for a formal high-risk assessment was consistent at 9% pre-mammography closure and post-mammography re-opening. Consent to be contacted for genetics is likely to be associated with breast cancer risk perception. Future Directions: We are planning an educational intervention regarding the FSH-7 risk assessment tool and a positive score’s association with the risk of hereditary breast cancer syndromes, as well as the benefits of optimized screening techniques depending on a patient’s life-time risk of developing breast cancer. We anticipate that this will likely result in greater acceptance of a formal high-risk assessment for this at-risk population. Citation Format: Jason Shames, Dina Alnabulsi, Olivia Trachtenberg, AnaMaria Lopez. Screening for genetic risk at the time of mammography [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-16.

An Electronic Health Record Tool Increases Genetic Counseling Referral of Individuals at Hereditary Cancer Risk: An Intervention Study

Introduction: There is widespread under-identification of individuals at hereditary cancer risk despite national guidelines calling for screening. We evaluated the utilization of a tool embedded in the electronic health record (EHR) to assist primary care providers in screening patients for cancer genetic counseling referral. Methods: We designed BestPractice Advisories linked to a Genetic Cancer Screening Tool (GCST) in EpicCare Ambulatory. The GCST identifies individuals for evaluation for BRCA1/2, Lynch syndrome, and other risk mutations due to personal and family history. We tested the tool in a 7-week intervention in adult wellness visits at two clinics, one urban and one rural. Results: Out of 687 eligible patients, the screening survey was completed for 469 (67%), and of these, 150 (32%) screened positive for a personal and/or family history meeting genetic counseling referral criteria. Of individuals screening positive, a referral order was placed for 20 (13%). GCST screen-positive rate varied by patient gender but not race or age. Referral rate varied by provider and clinic but was not significantly affected by patient demographics. In the previous year over an equivalent date range, 0.1% of wellness visits (1 of 1,086) led to a referral, and this rate increased to 2.1% (22 of 1,062) during the intervention. The proportion of providers referring patients also increased, from 3.8% (1 of 26) to 42.3% (11 of 26). Discussion/Conclusion: Genetic counseling referral of individuals at hereditary cancer risk was increased by use of an EHR-integrated tool. These findings add evidence for the benefit of clinical decision support for cancer genetic risk screening in primary care.

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum’s group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case –controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case –control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data –a work in progress.

A feasibility study of breast cancer genetic risk assessment in a federally qualified health center.

The US Preventive Services Task Force (USPSTF) endorses routine screening for genetic risk of breast and/or ovarian cancer as a component of primary health care. Implementation of this recommendation may prove challenging, especially in clinics serving disadvantaged communities. The authors tested the feasibility of implementing the USPSTF mandate at a federally qualified health center (FQHC) to identify women who were eligible for genetic counseling (GC). A 12-month usual-care phase was followed by a 12-month intervention phase, during which time cancer genetic risk assessment (CGRA) was systematically performed for all women aged 25 to 69 years who presented for an annual examination. Women who were eligible for GC were recruited to participate in the study. After initiating CGRA, 112 women who were eligible for GC consented to study participation, and 56% of them received a referral for GC from their primary care physician. A subgroup of 50 participants were seen by the same primary care physician during both the usual-care and intervention phases. None of these patients was referred for GC during usual care, compared with 64% after the initiation of CGRA (P < .001). Only 16% of referred participants attended a GC session. Implementing USPSTF recommendations for CGRA as a standard component of primary health care in FQHCs is feasible and improves referral of minority women for GC, but more work is needed to understand the beliefs and barriers that prevent many underserved women from accessing cancer genetic services.

Marshaling the Translational Potential of MC1R for Precision Risk Assessment of Melanoma.

Melanoma rates have been increasing in the United States, and neither primary (sun protection and avoidance) nor secondary (skin examination) prevention is practiced consistently, even by those with melanoma risk factors. Inherited variation at MC1R is a robust marker for increased risk of melanoma, even among individuals with "sun-resistant" phenotypes. Although MC1R conveys important information about inherited melanoma risk for a broad spectrum of individuals, concerns that MC1R feedback could have negative consequences, including increased distress about melanoma, inappropriate use of health services, and development of a false sense of security, are valid and require empirical examination. The time is right for high-quality research focusing on the translation of MC1R genotype into clinical and public health practice. If studies show MC1R genetic risk screening is effective at motivating behavior change, more melanomas may be detected at earliest stages for which surgical excision is highly curative or a large number of melanomas may be prevented altogether. While other genetic markers for melanoma susceptibility may emerge in the coming years, the burgeoning research agenda on the public health translational potential of MC1R genetic risk screening will inform and usefully advance current and future precision risk assessment of melanoma. Cancer Prev Res; 11(3); 121-4. ©2017 AACR.

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.

Community attitudes to genetic susceptibility-based mental health interventions for healthy people in a large national sample

Despite an apparent high interest in predictive genetic testing for common multifactorial disorders, few data describe anticipated health behaviour as a consequence of such testing. A large population-based public survey with community dwelling adults (N = 1046) ascertained through random digit dialling. Attitudes were assessed via structured interviews. Intention to start therapies or courses to learn to develop better strategies to cope with stress (80%) was significantly and positively associated with self-estimation of risk for major depressive disorder as higher than average (ß = 0.12, p = 0.001); endorsement of family environment as a causal attribution (ß = 0.11, p < 0.001); and endorsement of gene-environment interaction as a causal mechanism of mental illness (ß = 0.12, p = 0.017). Intention to modify potential life stressors (84%) was significantly and positively associated with self-estimation of risk for depression as higher than average (ß = 0.07, p = 0.029); endorsement of 'abuse' as a causal attribution (ß = 0.10, p = 0.003); and endorsement of 'gene-environment interaction' as a causal mechanism (ß = 0.10, p = 0.002). The hypothetical nature of the genetic risk scenario may have weakened participants' sensitivity to the potential personal impact of such a genetic test result. Perceptions that modifiable environmental factors strongly contribute to overall risk of major depressive disorder appeared to drive willingness to engage in risk-modifying interventions in the hypothetical scenario of a genetic predisposition. Our results suggest that screening for genetic risk in consort with environmental risk factor assessment has potential community acceptability and clinical value as an early intervention and preventive tool for high risk groups.

Experiencing genetic counselling for hereditary cancers: the client's perspective

As genetic health care expands and genetic testing becomes more widely available, it becomes relevant to understand how individuals involved in genetic counselling are integrating this new information in health management and into their lives. This article examines the client's experiences of genetic counselling for hereditary cancers, which definitely play a major role in the assessment of their needs and also lead to improvement of the psychosocial focus in genetic counselling protocols. Methods include a semi-structured interview, administered in two focus groups, comprising 10 (5 + 5) participants after attending genetic counselling for hereditary cancers at a Portuguese public hospital. Findings suggest an experience embedded in two dimensions: (1) instrumental (goals, needs and decision making); and (2) emotional (uncertainty regarding genetic risk screening and an emotional complex). Ambiguity plays a crucial role, especially in two moments: (1) the hiatus between genetic testing and the screening results; and (2) after being confirmed as carrying a cancer susceptibility gene mutation. The spectrum of genetic illness comprises an intensely complex emotional experience that challenges individuals and their families in terms of health management, and personal and family planning. Recommendations are included in order to enhance the services available by expanding psychosocial support.

Molecular genetic risk screening.

Under the impetus of the Human Genome Project, new disease-associated genes are being discovered at a rapid pace. Mutations in many of these genes are present in a high enough proportion of the general population, or of particular ethnic groups, that global or targeted population screening can be contemplated. If performed early enough, identification of these mutations by molecular genetic testing can be used not merely to diagnose disease but to predict risk of future disease, either in the individual being tested or in his or her offspring. In some cases this knowledge can be the rationale for heightened surveillance and/or preventive or therapeutic interventions. Mass screening has already commenced for cystic fibrosis mutations and has been discussed for such diverse diseases as hereditary hemochromatosis, thrombophilias, familial cancer predispositions, and pharmacogenetic risk factors. However, implementation of such programs is often impeded by the complexity of the gene mutations, by incomplete penetrance, and by thorny ethical and social issues. This chapter reviews the basic criteria to be considered before embarking on population genetic risk screening, and examines multiple disease-screening examples representing a variety of modes of inheritance and technical challenges.

Delivering Genetic Screening to the Community

Concern is often expressed that, in the future, screening for genetic risk will become too widespread. Haemoglobin disorders (the thalassaemias and sickle cell disorders) offer an excellent model for genetic screening, because they are common and severe. They are recessively inherited. Carriers can be detected by conventional blood tests with an accuracy of 99%, so couples at risk can be identified before they have children and offered genetic counselling and prenatal diagnosis. Carrier-screening programmes have been in place in several countries for over 20 years and now offer extensive practical experience of the problems of delivering the service equitably to entire populations. This experience suggests that the main risk is of too tittle rather than too much genetic screening, and of doing it badly, and demonstrates the need for a discipline of 'community genetics'. Here I propose that modern information technology has a central role in providing communities with adequate access to correct genetic information.

Angiotensin I converting enzyme gene polymorphism and coronary heart disease.

Genetic variations in the renin-angiotensin and kallikrein-kinin systems could prove to be significant pathophysiological mechanisms affecting coronary heart disease (CHD), particularly given the powerful vasoactivity of products such as angiotensin II and bradykinin. Indeed, studies show that angiotensin converting enzyme (ACE) gene polymorphism is associated with an increased risk of myocardial infarction and death, even in otherwise low-risk subjects. Genetic differences do not appear to be a risk factor for atherosclerosis or hypertension, however. Because ACE polymorphism modulates local production of angiotensin II, a powerful coronary vasoconstrictor, it may influence left ventricular mass in general as well as in coexisting disease states such as hypertension and cardiomyopathy. However, further study is needed to clarify the implications of ACE polymorphism in patients with left ventricular hypertrophy. Interactions between ACE and angiotensin II type-1 receptors may have clinical implications for preventing and managing CHD. Screening for genetic risk, as evidenced by certain variants in receptor coding sequence, may prove worthwhile if detrimental effects can be countered by drugs such as ACE inhibitors and angiotensin II receptor blockers. Given the important roles of angiotensin II and bradykinin as modulators of cellular growth and of vasoactivity, deleterious and beneficial effect at different stages of the atherosclerotic process and during acute events leading to myocardial infarction or sudden death can be suspected.

Preconceptional family health evaluation: A regional education program for family planning clients and health professionals

The Preconceptional Family Health Evaluation Program was a regional project developed and funded for 2 years by the New England Regional Genetics Group (NERGG) to educate family planning health professionals about genetics, and to offer family planning clients preconceptional identification of genetic and environmental exposure risks. To meet these goals, genetic education was provided on a regional basis to 45 family planning professionals. A self-administered family health risk questionnaire adaptable to individual family planning settings was developed. Five hundred and twenty-nine family planning clients voluntarily completed the questionnaire. Cigarette smoking (35%) and alcohol use (57%) were two major categories of risks identified. The Preconceptional Family Health Evaluation Program was well received by all participants and provided an effective means for regional education of family planning health professionals. As a result of the program, state program planners, clinical genetics services, and family planning health professionals developed a strong relationship that will serve future educational and genetic risk screening efforts.