Updated Stroke Gene Panels: Rapid evolution of knowledge on monogenic causes of stroke.

This article updates our previous Stroke Gene Panels (SGP) from 2017. Online Mendelian Inheritance in Man and PubMed were searched. We divided detected genes into two SGP groups, SGP1: genes reported in at least one person with stroke and associated with one or more clinical subgroups: large artery atherosclerotic, large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection or occlusion), cerebral small vessel diseases, cardio-embolic (arrhythmia, heart defect, cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma, arteriovenous malformations) and metabolism disorders; and SGP2: genes related to diseases that may predispose to stroke. We identified 168 SGP1 genes, 70 of these were validated for clinical practice. We also detected 72 SGP2 genes. Nine genes were removed because of conflicting evidence. The number of genes increased from 168 to 240 during 4.5-years, reflecting a dynamic evolution and the need for regular updates for research and clinical use.

Genetic testing in women with early-onset breast cancer: a Traceback pilot study.

PURPOSE: In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. METHODS: Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. RESULTS: Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. CONCLUSION: The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients.

Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.

A century of Hereditas: from local publication to international journal.

BACKGROUND: The Mendelian Society of Lund launched Hereditas in 1920. The purpose of this article is to give an overview of Hereditas's hundred-year existence, focusing on the conditions for a learned society to publish a scientific journal, and the journal's importance for the publication and dissemination of genetic research. The article focuses on the historical development of the journal and analyses how the content and orientation of research published in Hereditas have changed over the years. METHODS: The historical study is based on the collation and interpretation of archival material, mainly held in the Mendelian Society's archive, which includes the Hereditas archive. The bibliometric analyses are based on bibliographic metadata from Web of Science (WoS). Together with descriptive statistics, co-citation analyses were performed by using BibExcel, in combination with the clustering and visualisation tool VOSviewer. Journals with articles citing Hereditas articles were identified as a complement to the co-citation analyses. RESULTS: The history of the journal falls into three main periods: a local period, 1920-1959, when Hereditas was primarily intended for Swedish geneticists; a Scandinavian period, 1960-1988, when Hereditas was the official journal of the Scandinavian Association of Geneticists; and an international period from 1989 onwards. The original decision that Hereditas should cover genetic research with no particular specialisation was retained throughout. Its publications demonstrate the continuing presence of genetic research on plants and animals, albeit with a shifting focus, while human genetics emerged slowly and reached its peak in the period 1960-1988. CONCLUSION: In the hundred years of Hereditas's existence, the publishing landscape has changed dramatically, including a far greater number of specialist journals, changes to the academic merit system, new commercial models for publishing, and digitalisation. Over the years, the journal's survival has therefore been dependent on the strong commitment of its owners and an ability to adapt to changing conditions.

Increased Cancer Risk in Families with Pediatric Cancer Is Associated with Gender, Age, Diagnosis, and Degree of Relation to the Child.

BACKGROUND: Studies of cancer risk among relatives of children with cancer beyond parents and siblings are limited. We have investigated the cancer risk up to the third degree of relation in families with pediatric cancer to reveal patterns of inheritance. METHODS: A single-center cohort of 757 patients with pediatric cancer was linked to the Swedish National Population Register, resulting in 16,137 relatives up to the third degree of relation. All relatives were matched to the Swedish Cancer Register, and standard incidence ratios (SIR) were calculated to define relatives at risk. RESULTS: Children and adults up to the third degree of relation had increased cancer risk, with SIRs of 1.48 (P = 0.01) and 1.07 (P < 0.01), respectively. The SIRs for first- and third-degree adult relatives were 1.22 and 1.10, respectively, but no increased risk was observed in second-degree relatives. Male relatives had a higher risk than females, especially when related to a girl and when the child had leukemia. The risk was mainly increased for lung, prostate, and gastrointestinal cancer. When excluding 29 families of children with known pathogenic germline variants, the increased risk remained. CONCLUSIONS: Relatives to children with cancer up to third degree of relation have an increased cancer risk. Known pathogenic germline variants do not explain this increased risk. IMPACT: The overall increased cancer risk among relatives of children with cancer in this population-based cohort strengthens the importance of surveillance programs for families with pediatric cancer.

Variations in the Referral Pattern for Genetic Counseling of Patients with Early-Onset Breast Cancer: A Population-Based Study in Southern Sweden.

Swedish national breast cancer guidelines recommend that all women diagnosed with breast cancer (BC) at the age of 35 years or younger should be referred to their regional oncogenetic clinic for genetic counseling and testing, regardless of family history of cancer. The main objective of this study was to evaluate whether place of residence at BC diagnosis and treating hospital were associated with the fact that not all BC patients diagnosed at ≤35 years in the southern part of Sweden have attended genetic counseling and testing. Between 2000 and 2013, 279 women in the South Swedish Health Care Region were diagnosed with BC at ≤35 years. Information regarding place of residence at BC diagnosis, treating hospital, time of registration and first meeting at the Oncogenetic Clinic in Lund, and genetic testing was collected. With a follow-up period until August 2018, 64% were registered at the clinic (60% underwent genetic testing) and 36% were not. BC patients from 2 counties and from rural settings with a population of <10,000 inhabitants were significantly less likely to be registered at the clinic. Our results suggest that place of residence at BC diagnosis and treating hospital were associated with the probability of referral for genetic counseling and testing for women diagnosed with BC at ≤35 years in the South Swedish Health Care Region. We propose, as a generalizable finding, that further educational and outreach activities within the health care system and the community may be needed to ensure that all women diagnosed with early-onset BC receive proper genetic counseling.

Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke.

Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.

A stroke gene panel for whole-exome sequencing.

Extensive analyses of known monogenic causes of stroke by whole-exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of stroke for use in clinical and research situations. We systematically searched the publically available database Online Mendelian Inheritance in Man, and validated the entries against original peer-reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with stroke, and classified the stroke phenotype for each gene into eight subgroups: (1) large artery atherosclerotic, (2) large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection, occlusion), (3) cerebral small-vessel diseases, (4) cardioembolic (arrhythmia, heart defect, cardiomyopathy), (5) coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), (6) intracerebral hemorrhage, (7) vascular malformations (cavernoma, arteriovenous malformations), and (8) metabolism disorders. Second, we selected other genes that may plausibly cause stroke through diseases related to stroke, but without any documented stroke patient description. A third section comprised SNPs associated with stroke in genome-wide association studies (GWAS). We identified in total 214 genes: 120 associated with stroke, 62 associated with diseases that may cause stroke, and 32 stroke-related genes from recent GWAS. We describe these 214 genes and the clinical stroke subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic stroke. Based on the panel's clinical phenotype description, the pathogenicity of novel variants in these genes may be evaluated in specific situations.

Utvidgad anlagsbärartestning kan bredda fosterdiagnostiken - Recessiva sjukdomsanlag kan kartläggas hos friska personer inför planerad graviditet.

A new genetic test - expanded carrier screening Due to recent advances in molecular genetic testing, massive parallel sequencing has become possible at an affordable cost for health care. Thus, it is now possible to test healthy young persons for carriership of mutations in many genes for severe recessive genetic conditions - extended genetic carrier testing. The introduction of this test in Swedish health care must be accompanied by ethical considerations, education of stakeholders, health care staff and the public.

BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer.

PURPOSE: To evaluate a simplified method of pre-test information and germline BRCA1/2 mutation testing. METHODS: In a prospective, single-arm study, comprehensive BRCA1/2 testing was offered to unselected patients with newly diagnosed breast cancer at three hospitals in south Sweden (BRCAsearch, ClinicalTrials.gov Identifier: NCT02557776). Pre-test information was provided by a standardized invitation letter, but the patients could contact a genetic counselor for telephone genetic counseling if they felt a need for that. Noncarriers were informed about the test result through a letter. Mutation carriers were contacted and offered an appointment for in-person post-test genetic counseling. RESULTS: During the period Feb 2, 2015-Aug 26, 2016, eight hundred and eighteen patients were invited to participate in the study. Through Jan 31, 2017, five hundred and forty-two (66.2%) of them consented to analysis of BRCA1 and BRCA2. Eleven pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9), corresponding to a mutation prevalence of 2.0%. Six out of 11 fulfilled the Swedish BRCA testing criteria, and 9 out of 11 fulfilled the NCCN testing criteria. None of the BRCA-associated tumors were of the luminal A-like subtype. Very few patients contacted us for telephone genetic counseling or practical questions, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. CONCLUSIONS: Streamlining the process of pre-test information, genetic testing, and delivery of test results was feasible and was associated with an uptake of genetic testing in 2/3 of the breast cancer patients.

Accuracy of self-reported family history of cancer, mutation status and tumor characteristics in patients with early onset breast cancer.

BACKGROUND: The main objectives of this study were to evaluate the concordance between self-reported and registry-reported information regarding family history of breast cancer (BC), ovarian cancer (OvC) and other types of cancer in first-degree relatives of patients with early onset BC, and to determine the frequency of mutation carriers and non-mutation carriers. The secondary objective was to describe tumor characteristics for each mutation group. MATERIAL AND METHODS: Between 1993 and 2013, 231 women who were ≤35 years old when diagnosed with BC were registered at the Oncogenetic Clinic at Skåne University Hospital in Lund, Sweden. Self-reported and registry-reported information regarding first-degree family history of cancer was collected together with information regarding tumor characteristics. RESULTS: Almost perfect agreement was observed between self-reported and registry-reported information regarding first-degree family history of BC (κ = 0.92) and OvC (κ = 0.86). Lesser agreement was observed between reports regarding family history of other types of cancer (κ = 0.51). Mutation screening revealed pathogenic germline mutations in 30.4%; 18.8% in BRCA1, 7.1% in BRCA2 and 4.5% in other genes. Compared with other mutation groups, BRCA1 mutation carriers were more likely to be diagnosed with high-grade, ER-, PR- and triple-negative tumors. CONCLUSIONS: Our results demonstrate that physicians and genetic counselors can rely on self-reported information regarding BC and OvC in first-degree relatives. However, self-reported information regarding other types of cancer is not communicated as effectively, and there should be more focus on retrieving the correct information regarding family history of all tumor types. Furthermore, we observed that even though all BC patients fulfilled the criteria for genetic counseling and testing, a large number of patients diagnosed at ≤35 years of age did not receive genetic counseling at the Oncogenetic Clinic. This finding merits further elucidation.

Germline mutations in BRCA1 and BRCA2 incidentally revealed in a biobank research study: experiences from re-contacting mutation carriers and relatives.

Once an incidental finding (IF) is discovered in the course of genomic research, the researchers are faced with the question of whether or not that finding should be reported back to the study participant. A large number of hypothetical studies and policy documents on this issue have been published, but there are very few empirical studies to inform the bioethics debate. Within a biobank research study of somatic mutations in breast carcinomas, ten germline BRCA1/2 mutations were incidentally detected. After thorough discussions within a group of experts, the mutation carriers (n = 7) or relatives of deceased carriers (n = 3) were re-contacted and informed about the findings. Eight out of ten accepted to receive the information and underwent confirmatory testing. One year later, semi-structured interviews were undertaken with three of the study participants. All of them felt that BRCA mutations discovered in the course of research should be reported back to the individual study participants. In this paper, we report our step-by-step experiences of the re-contacting process. We hope that our detailed reporting will be helpful for other researchers and clinicians that are faced with similar situations. The results of our study lend empirical support to opinion that IFs that meet the three baseline criteria of analytic validity, clinical significance, and actionability should be reported back to the individual study participants.

Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer.

Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast cancer patients from the well-characterized, population-based, single-site All Breast Cancer in Malmö (ABiM) study. The patients were diagnosed with breast cancer during the years 2007 through 2009. Out of 20 mutation carriers identified, 13 fulfilled Swedish criteria at time of diagnosis. Thus, the efficacy of these criteria was 65%. Excluding three patients in whom a mutation was already known at time of diagnosis, only 3/17 had been identified in the clinical routine, corresponding to an effectiveness of 18%. Here we detail the reasons why mutation carriers in our cohort were not detected though routine health care. In conclusion, effectiveness of BRCA testing criteria was much lower than efficacy. Our results indicate that current testing criteria and procedures associated with BRCA1 and BRCA2 testing are insufficient. There is room for improvement of their efficacy, but even more so regarding effectiveness. Clinical BRCA testing routines need to be critically revised.

Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer.

The purpose of the study was to compare breast-conserving therapy (BCT) and mastectomy (M) in BRCA1/2 mutation carriers. Women with invasive breast cancer and a pathogenic mutation in BRCA1 or BRCA2 were included in the study (n = 162). Patients treated with BCT (n = 45) were compared with patients treated with M (n = 118). Endpoints were local recurrence as first recurrence (LR), overall survival (OS), breast cancer death, and distant recurrence. Cumulative incidence was calculated in the presence of competing risks. For calculation of hazard ratios and for multivariable analysis, cause-specific Cox proportional hazards regression was used. Compared to M, BCT was associated with an increased risk of LR in univariable analysis (HR 4.0; 95 % CI 1.6-9.8) and in multivariable analysis adjusting for tumor stage, age, and use of adjuvant chemotherapy (HR 2.9; CI 1.1-7.8). Following M, all local recurrences were seen in the first 5 years after breast cancer diagnosis. Following BCT, the rate of LR continued to be high also after the first 5 years. The cumulative incidence of LR in the BCT group was 15, 25, and 32 % after 5, 10, and 15 years, respectively. There were no significant differences between BCT and M for OS, breast cancer death, or distant recurrence. BRCA1/2 mutation carriers treated with BCT have a high risk of LR, many of which are new primary breast cancers. This must be thoroughly discussed with the patient and is an example of how rapid treatment-focused genetic testing could influence choice of treatment.

Developing a framework for implementation of genetic services: learning from examples of testing for monogenic forms of common diseases.

Genetics in health care is shifting, and responsibilities of genetic and nongenetic specialists are changing, requiring new guidance on how to adapt health care to advances in genetic services. This paper explores facilitators and barriers in the process of implementation of innovations in genetic health care. Furthermore, lessons learnt for optimizing development of new genetic services are summarized. Barriers and facilitators in transition processes were identified using mixed methods, including an online open-ended questionnaire among professionals and an international expert meeting. A multi-case study approach was used to explore recent experiences with innovations in genetic services in different phases of implementation. Barriers encountered in transitions in genetic service provision include the following: lack of genetic knowledge and skills among nongenetic health care providers, resistance to new divisions of responsibilities, and a need for more close collaboration and communication between geneticists and nongeneticists. Facilitating factors include the following: statutory registration of genetic specialists, availability of essential staff and equipment, and existence of registries and guidelines. Other challenges are experienced in the establishment of the appropriate legal and financial structures. A set of points to consider for genetic innovation processes is proposed, addressing, e.g., transition management and cooperation and communication strategies.

Long-term prognosis of early-onset breast cancer in a population-based cohort with a known BRCA1/2 mutation status.

All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2-7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9-18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy.