Recontact to return new or updated PALB2 genetic results in the clinical laboratory setting.

OBJECTIVE: The purpose of this study was to recontact individuals with clinically actionable test results identified through a retrospective research study and to provide a framework for laboratories to recontact patients. METHODS: Genetic testing was conducted on 2977 individuals originally referred for BRCA1 and BRCA2 hereditary breast and ovarian cancer testing that had a negative genetic test result. A gene panel was used to identify pathogenic variants in known or newly discovered genes that could explain the underlying cause of disease; however, analysis was restricted to PALB2 for the purposes of this study. A patient recontact decision tree was developed to assist in the returning of updated genetic test results to clinics and patients. RESULTS: Novel clinically actionable pathogenic variants were identified in the PALB2 gene in 18 participants (0.6%), the majority of whom were recontacted with their new or updated genetic test results. Eight individuals were unable to be recontacted; five individuals had already learnt about their new or updated findings from genetic testing outside the context of this study; three individuals prompted cascade testing in family members; two individuals were deceased. CONCLUSION: Novel pathogenic variants in PALB2 were identified in 18 individuals through retrospective gene panel testing. Recontacting these individuals regarding these new or updated findings had a range of outcomes. The process of conveying genomic results within this framework can be effectively accomplished while upholding patient autonomy, potentially leading to advantageous outcomes for patients and their families.

Germline whole genome sequencing in adults with multiple primary tumors.

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.

HLA Variation and SARS-CoV-2 Specific Antibody Response.

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Exploring the role of a multidisciplinary hereditary gynecologic oncology clinic in epithelial ovarian cancer risk-reducing surgical decision-making practices: A mixed-methods study.

Individuals that have gynecologic reproductive organs with pathogenic variants in BRCA1 or BRCA2 ("BRCA-positive") have an increased risk of developing high-grade serous ovarian cancer (HGSOC). The majority of HGSOC develops in the fallopian tubes and later spreads to the ovaries and peritoneal cavity. Therefore, risk-reducing salpingo-oophorectomy (RRSO) is recommended for those who are BRCA-positive to preventatively remove their ovaries and fallopian tubes. The Hereditary Gynecology Clinic (HGC) is a provincial program in Winnipeg, Canada, that specifically targets care to the unique needs of such individuals through an interdisciplinary team of gynecological oncologists, menopause specialists, and registered nurses. A mixed-methods study design was used to explore the decision-making processes of these BRCA-positive individuals who have been recommended (or who completed) RRSO and experiences with healthcare providers at the HGC influenced this decision. Individuals who are BRCA-positive without a previous diagnosis of HGSOC and who had previously received genetic counselling were recruited from the HGC and the provincial cancer genetics program (Shared Health Program of Genetics & Metabolism). Forty-three people completed a survey and 15 participated in an in-depth interview about their experiences and decisions surrounding RRSO. Surveys were analyzed to compare scores on validated scales related to decision-making and cancer-related worry. Qualitative interviews were transcribed, coded, and analyzed using interpretive description. Participants described the complex decisions faced by those who are BRCA-positive, which are intertwined with life experiences and circumstances including age, marital status, and family disease history. Participants interpreted their HGSOC risk through a personalized "lens" of contextual factors that impacted perceptions about the practical and emotional implications of RRSO and the need for surgery. Mean scores on validated scales evaluating the HGC's impact on decisional outcomes and preparedness for decision-making about RRSO were not significant, indicating that the HGC played a supportive role, rather than helping with decision-making itself. Therefore, we present a novel framework that consolidates the various influences on decision-making and connects them to the psychological and practical implications of RRSO in the context of the HGC. Strategies for improving support, decisional outcomes, and the overall experiences of individuals who are BRCA-positive attending the HGC are also described.

Genome Reporting for Healthy Populations-Pipeline for Genomic Screening from the GENCOV COVID-19 Study.

Genome sequencing holds the promise for great public health benefits. It is currently being used in the context of rare disease diagnosis and novel gene identification, but also has the potential to identify genetic disease risk factors in healthy individuals. Genome sequencing technologies are currently being used to identify genetic factors that may influence variability in symptom severity and immune response among patients infected by SARS-CoV-2. The GENCOV study aims to look at the relationship between genetic, serological, and biochemical factors and variability of SARS-CoV-2 symptom severity, and to evaluate the utility of returning genome screening results to study participants. Study participants select which results they wish to receive with a decision aid. Medically actionable information for diagnosis, disease risk estimation, disease prevention, and patient management are provided in a comprehensive genome report. Using a combination of bioinformatics software and custom tools, this article describes a pipeline for the analysis and reporting of genetic results to individuals with COVID-19, including HLA genotyping, large-scale continental ancestry estimation, and pharmacogenomic analysis to determine metabolizer status and drug response. In addition, this pipeline includes reporting of medically actionable conditions from comprehensive gene panels for Cardiology, Neurology, Metabolism, Hereditary Cancer, and Hereditary Kidney, and carrier screening for reproductive planning. Incorporated into the genome report are polygenic risk scores for six diseases-coronary artery disease; atrial fibrillation; type-2 diabetes; and breast, prostate, and colon cancer-as well as blood group genotyping analysis for ABO and Rh blood types and genotyping for other antigens of clinical relevance. The genome report summarizes the findings of these analyses in a way that extensively communicates clinically relevant results to patients and their physicians. © 2022 Wiley Periodicals LLC. Basic Protocol 1: HLA genotyping and disease association Basic Protocol 2: Large-scale continental ancestry estimation Basic Protocol 3: Dosage recommendations for pharmacogenomic gene variants associated with drug response Support Protocol: System setup.

Quality of life drives patients' preferences for secondary findings from genomic sequencing.

There is growing impetus to include measures of personal utility, the nonmedical value of information, in addition to clinical utility in health technology assessment (HTA) of genomic tests such as genomic sequencing (GS). However, personal utility and clinical utility are challenging to define and measure. This study aimed to explore what drives patients' preferences for hypothetically learning medically actionable and non-medically actionable secondary findings (SF), capturing clinical and personal utility; this may inform development of measures to evaluate patient outcomes following return of SF. Semi-structured interviews were conducted with adults with a personal or family cancer history participating in a trial of a decision aid for selection of SF from genomic sequencing (GS) ( www.GenomicsADvISER.com ). Interviews were analyzed thematically using constant comparison. Preserving health-related and non-health-related quality of life was an overarching motivator for both learning and not learning SF. Some participants perceived that learning SF would help them "have a good quality of life" through informing actions to maintain physical health or leading to psychological benefits such as emotional preparation for disease. Other participants preferred not to learn SF because results "could ruin your quality of life," such as by causing negative psychological impacts. Measuring health-related and non-health-related quality of life may capture outcomes related to clinical and personal utility of GS and SF, which have previously been challenging to measure. Without appropriate measures, generating and synthesizing evidence to evaluate genomic technologies such as GS will continue to be a challenge, and will undervalue potential benefits of GS and SF.

Primary care provider perspectives on using genomic sequencing in the care of healthy children.

Genome sequencing (GS) studies involving healthy children can advance scientific knowledge of genetic variation. Little research has examined primary care providers' views on using GS in this context. This study explored primary care provider perspectives on the use of GS in research and the care of healthy children. We conducted semi-structured interviews with 16 providers discussing their views on GS research and receiving results. Interviews were analyzed by thematic analysis and constant comparison. Participants were family physicians (11/16) and primary care pediatricians (5/16) in practice for >10 years (11/16). Participants valued GS in healthy children for research purposes; however, opinions diverged on using the results in primary care. Proponents valued using results for surveillance and prevention in healthy children. Skeptics questioned the clinical utility of results and the appropriateness of applying research data in primary care. Both groups shared concerns over opportunistic screening, validity, and interpretation of results, increased health system costs and inequities, and genetic discrimination. Primary care providers were ambivalent about the appropriateness and utility of GS in the care of healthy children. Providers feel unprepared and unsure of their obligations in disclosing these results. Providers do not feel they are equipped with the necessary resources and training to support their patients in using GS results in their care.

Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial.

INTRODUCTION: Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results. METHODS AND ANALYSIS: We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results. ETHICS AND DISSEMINATION: This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice. TRIAL REGISTRATION NUMBER: NCT03244202; Pre-results.