Difficulties in disclosing secondary findings by facilities performing comprehensive germline genetic testing for rare diseases in Japan.

In Japan, a limited number of laboratories perform comprehensive genetic testing for rare diseases; this study investigated the attitudes of these laboratories toward the disclosure of secondary finding (SF). Following a preliminary survey, we identified laboratories conducting comprehensive genetic testing for participation. Subsequently, an online survey involving 20 selected facilities was conducted. The response rate was 80% (16/20). Of the 14 facilities, 71.4% had SFs. While 42.9% of them had a policy to disclose SFs with clinical utility, only 14.3% actively searched for actionable variants that could be included in the American College of Medical Genetics and Genomics list. Japan was less enthusiastic than the USA regarding SF disclosure. With regard to the reasons for not disclosing SFs, the factors "the thought that participants may have a low desire for SFs" and "uncertainty regarding their wish" were considered more important than in the USA. A content analysis of what was sought as a solution to this difficulty revealed a need to improve databases on pathogenicity and actionability and collect public thoughts on the issue. The factor "to promote entry in research" was not considered a critical reason for disclosing SFs, indicating that the thirst for information was not possibly due to anxiety but rather due to scientific interest. Japanese medical professionals may not be confident that society requires the disclosure of SFs. To improve the environment, it is necessary to survey the public regarding their thoughts on SF disclosure and discuss this issue in society.

Decision-making processes behind seeking regular cardiac checkups for individuals with Marfan syndrome: A grounded theory study.

Patients with Marfan syndrome (MFS) present with various symptoms, such as aortic aneurysm/dissection, tall stature, and lens deviation. Among them, acute aortic dissection is a complication that leads to sudden death. Some individuals with MFS are reluctant to see a cardiologist and discontinue regular checkups until they develop life-threatening complications. We conducted a grounded theory study to investigate how individuals with MFS decided whether to adhere to healthcare recommendations, specifically to attend cardiology appointments. The study recruited individuals with a clinical or genetic diagnosis of MFS from a Japanese university hospital and individuals from a support group. Semi-structured interviews were conducted with 28 consenting participants. In this study, we identified the decision-making processes of individuals with MFS concerning their cardiology visits. We extracted "perception of the gap between their health status and medical recommendations" as the central category. This decision-making process consisted of three parts: (A) the process by which an individual with MFS sees a cardiologist for the first time, (B) the process by which an individual with MFS keeps up with cardiology checkups, and (C) the process by which parents bring their children with MFS to the cardiologist. Individuals who learned of the possibility of MFS decided whether to adhere to medical recommendations depending on how they perceived the gap between their health status and the medical recommendations. In addition to medical information and treatment experience, adaptation to MFS, which changed through interactions with others, influenced the perception of the gap. This study suggests the role of genetic counseling and molecular genetic diagnosis as factors that may facilitate adaptation to MFS. The involvement of genetic counselors is important for helping individuals with MFS keep up with regular checkups while affirming their own experiences. These results provide insight into adherence to medical recommendations for individuals with MFS.

When and how to enlighten citizens on genetics and hereditary cancer: a web survey of online video viewers.

With the rapid expansion of genomic medicine, more citizens are compelled to think about genetics in their daily lives. This study aims to explore appropriate types of educational media and methods to enlighten activities for genetics and hereditary cancer. We presented an 18-min YouTube video on genetics and hereditary cancer to participants at a scientific event, Science Agora 2020, and administered a web questionnaire to investigate their opinions about when and how citizens should start learning about genetics and hereditary cancer. We recruited 133 participants who watched the video, and 26.3% (35/133) responded to the questionnaire. Most of them were evaluated to understand and appreciate the contents of the video. They identified websites, or videos as suitable learning media, irrespective of their sex, age, or profession. They highlighted upper elementary school or junior high school as appropriate educational stages to start learning about genetics and hereditary cancer to facilitate collecting their own genetic information by themselves. Our findings show that educational institutions should provide opportunities to learn about genetics and hereditary cancers, especially for upper elementary school and junior high school students, using learning media, such as videos, depending on their level or demand.

Reproductive decision-making following the diagnosis of an inherited metabolic disorder via newborn screening in Japan: a qualitative study.

Introduction: The aim of the study was to describe the factors influencing the reproductive decision-making of carrier parents after the diagnosis of an inherited metabolic disorder in newborn screening in Japan. Methods: We conducted a semi-structured interview with 12 parents and analyzed data based on content analysis methodology. Results: We identified 11 factors, including personal evaluation of recurrence risk, understanding of hereditary phenomena, concerns and desires for future planned children, concerns for older siblings, perceptions of diseases, degree of acceptance and denial of diseases, the opinions of others on having another child, optimism/faith in positive outcomes, self-evaluation of parental capability, factors unrelated to the disease, and the "right" time to expand the family. Discussion: Perceptions and acceptance of disease are both important factors in reproductive decision-making, though these factors fluctuate continuously during the childbearing period. Therefore, effective reproductive genetic counseling will be considerate of the parents' fluctuating perceptions on reproduction. To ensure that the decision-making process is for the benefit of the parents and future children, long-term involvement of health care professionals is needed to assess the client's acceptance of the disease and their understanding of genetic phenomena and recurrence rates.

Fundamental knowledge taught in compulsory education for effective genetic counseling: a qualitative study of descriptions in textbooks.

In genetic counseling, information must be provided in ways that the client and general public can understand to ensure that decisions are made autonomously. To realize this, we must assess the extent of knowledge held by the general public regarding genetics. To identify the client's original knowledge before genetic counseling, we explored the fundamental knowledge related to genetic counseling that is taught in Japanese compulsory education. A qualitative study was conducted. We selected 50 textbooks for compulsory education (Japanese, social studies, science, health and physical education, technology and home economics, morality, and life) that had been used in more than half of the districts in Japan. The text data were analyzed using qualitative content analysis, and quantitative data were analyzed for methodological triangulation. Codes, subcategories, and categories were generated from the contexts that met the following criteria: the contents included in the official textbook for clinical geneticists, contents derived from such descriptions that were related to genetic counseling, and contents clearly related to genetics. Among the 50 textbooks, 33 textbooks contained fundamental knowledge regarding genetic counseling. A qualitative content analysis identified four major categories: (1) basics of genetics, (2) understanding and control of diseases, (3) efforts and barriers to the realization of a harmonious society, and (4) technology and humans. We found that fundamental knowledge related to genetic counseling is directly or indirectly taught in compulsory education. Our results are an important resource for understanding the client's knowledge baseline and will be helpful for effective genetic counseling.

Challenges of secondary finding disclosure in genomic medicine in rare diseases: A nation-wide survey of Japanese facilities outsourcing comprehensive genetic testing.

Comprehensive genome analysis may reveal secondary findings (SFs) including pathogenic variants of genes other than those originally targeted. Comprehensive genetic analysis of rare diseases is generally performed as research in Japan. Therefore, the status and difficulties in SF disclosure remain unclear. To obtain information for the appropriate disclosure of SFs in rare diseases, we conducted a survey on how SFs are handled in clinical practice by facilities that outsource comprehensive genetic testing to other facilities. The response rate was 66.7% (40/60). Among the responding facilities, 55% had a policy of disclosing SFs with clinical utility and considered targeting actionable SFs with high penetrance. These facilities had difficulties in determining the disclosure targets (51%) and in genetic counseling (38%). Improving genetic literacy, establishment of surveillance systems, and providing insurance coverage for medical care to unaffected carriers were commonly cited as solutions to these difficulties. A comparison of the willingness to disclose SFs between overseas and in Japan showed more reluctance in Japan (86% vs. 65% for actionable SFs and 62% vs. 16% for non-actionable SFs). The group with difficulty in determining disclosure targets was significantly more likely to discuss this at conferences with other facilities and to refer guidelines. This suggests that the group with difficulties was unable to make decisions solely at their own facility and sought collaboration with other facilities. These findings suggest the necessity for a system that allows consultation with experts across facilities and guidelines that set forth policies for determining SFs.

Implementation of Molecular Autopsy for Sudden Cardiac Death in Japan　- Focus Group Study of Stakeholders.

BACKGROUND: We assessed the awareness of multidisciplinary healthcare professionals of the challenges related to implementation of molecular autopsy (MA) for sudden cardiac death (SCD) among children and young adults.Methods and Results: We conducted 11 focus groups with 31 multidisciplinary healthcare professionals, and categorized them into 2 themes: values, and challenges of MA implementation. The participants recognized 2 different values of MA: discovering the unknown cause of SCD, and SCD prevention among family members of victims. The coexistence of these values makes the MA process and role of professionals more complex. Participants were concerned about the psychological burden for bereaved family members and mentioned challenges in each process of the MA delivery system: obtaining consent, cause of death investigation, disclosing results, and preventive intervention. CONCLUSIONS: MA is a valuable procedure both in terms of forensic and preventive medicine. However, the dual meanings and complex characteristics of genetic information is a potential source of concern and confusion among healthcare professionals as well as bereaved family members. Increasing awareness among healthcare professionals of the MA process is essential for connecting all related areas of expertise.

The association of ectopic craniopharyngioma in the fourth ventricle with familial adenomatous polyposis: illustrative case.

BACKGROUND: Craniopharyngioma (CP) often arises in the sellar and suprasellar areas; ectopic CP in the posterior fossa is rare. Familial adenomatous polyposis (FAP) is a genetic disorder involving the formation of numerous adenomatous polyps in the gastrointestinal tract, and it is associated with other extraintestinal manifestations. OBSERVATIONS: The authors reported the case of a 63-year-old woman with FAP who presented with headache and harbored a growing mass in the fourth ventricle. Magnetic resonance imaging (MRI) findings revealed a well-circumscribed mass with high intensity on T1-weighted images and low intensity on T2-weighted images and exhibited no contrast enhancement. Gross total resection was performed and histopathology revealed an adamantinomatous CP (aCP). The authors also reviewed the previous reports of ectopic CP in the posterior fossa and found a high percentage of FAP cases among the ectopic CP group, thus suggesting a possible association between the two diseases. LESSONS: An ectopic CP may be reasonably included in the differential diagnosis in patients with FAP who present with well-circumscribed tumors in the posterior fossa.

Mortality and morbidity of infants with trisomy 21, weighing 1500 grams or less, in Japan.

Although very low birth weight (VLBW) is well studied in neonatology and the perinatal prognosis of VLBW infants has improved over time, little is known about the prognosis of VLBW infants with trisomy 21 (T21). We aimed to investigate the mortality and morbidity of VLBW infants with T21 during NICU admission in Japan, in comparison to those of infants without birth defects (BD-). Maternal and neonatal data of infants weighing 1500 grams or less admitted to the centers of the Neonatal Research Network of Japan from 2003 to 2016 were collected prospectively. Of 60,136 infants, 328 (0.55%) had T21. Although maternal age in the case of T21 infants was higher, maternal complications tended to be less frequent than in those with BD-. Multivariable analysis revealed that morbidities were higher in infants with T21 than in those with BD- but respiratory distress syndrome and retinopathy of prematurity were less frequent in those with T21 (p < 0.001, and p = 0.014, respectively), and no significant difference was observed between the two groups in the proportion of late-onset circulatory collapse of prematurity as well as cystic periventricular leukomalacia (p = 0.739 and p = 0.733, respectively). The survival rate at discharge from the NICU was 77% and 94% for T21 and BD-, respectively. This was the first nationwide survey of VLBW infants with T21 in Japan. Although there were no data regarding the timing of diagnosis, these data will aid prenatal genetic counseling and perinatal management of T21 infants.

Prevalence of pathogenic germline variants in the circulating tumor DNA testing.

BACKGROUND: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs). METHODS: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360®) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings. RESULTS: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms. CONCLUSION: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing.

Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling.

BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice. METHODS: Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan). RESULTS: A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin. CONCLUSION: Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.

Current status and issues related to secondary findings in the first public insurance covered tumor genomic profiling in Japan: multi-site questionnaire survey.

In June 2019, the Japanese National Health Insurance (NHI) system introduced coverage for two types of tumor genomic profiling (TGP): FoundationOneⓇ CDx (F1) and OncoGuide™ NCC OncoPanel System (NCCOP). TGP sometimes reveals germline variants that are potentially pathogenic as secondary findings (SFs). We conducted a questionnaire-based survey to find out the operational statuses of F1 and NCCOP at institutions where TGP was performed to elucidate issues related to SFs. Responses were received from 97 of 112 institutions (86.6%). As of May 31, 2020, 88 (90.7%) and 78 (80.4%) institutions started performing F1 and NCCOP, respectively. Since F1 only examines tumor samples, germline confirmatory testing is necessary to determine whether they are actually germline pathogenic variants (GPVs). When physicians are obtaining informed consent all but 2.3% of the patients requested SF disclosure. Conversely, when presumed germline pathogenic variants (PGPVs) were detected, 46.2% were not willing to receive confirmatory tests as they wanted to prioritize cancer treatment over SFs investigation, while only 23.3% underwent confirmatory tests. Problems in cancer genomic medicine reported by clinical genetics departments included short-staffing (n = 10), insufficient interdepartmental cooperation (n = 9), inconsistent understanding of genetics among healthcare professionals (n = 8), and low utilization rate of SFs due to lack of insurance coverage for confirmatory tests and post-test health checkups (n = 8). Solutions include; determining the appropriate timing to confirm patient intent on SF disclosure, covering confirmatory tests for PGPVs by the NHI, and establishing cooperation between the oncology and clinical genetics departments.

Six years' accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures.

The identification of causative genetic variants for hereditary diseases has revolutionized clinical medicine and an extensive collaborative framework with international cooperation has become a global trend to understand rare disorders. The Initiative on Rare and Undiagnosed Diseases (IRUD) was established in Japan to provide accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases. The fundamental IRUD system consists of three pillars: IRUD diagnostic coordination, analysis centers (IRUD-ACs), and a data center (IRUD-DC). IRUD diagnostic coordination consists of clinical centers (IRUD-CLs) and clinical specialty subgroups (IRUD-CSSs). In addition, the IRUD coordinating center (IRUD-CC) manages the entire IRUD system and temporarily operates the IRUD resource center (IRUD-RC). By the end of March 2021, 6301 pedigrees consisting of 18,136 individuals were registered in the IRUD. The whole-exome sequencing method was completed in 5136 pedigrees, and a final diagnosis was established in 2247 pedigrees (43.8%). The total number of aberrated genes and pathogenic variants was 657 and 1718, among which 1113 (64.8%) were novel. In addition, 39 novel disease entities or phenotypes with 41 aberrated genes were identified. The 6-year endeavor of IRUD has been an overwhelming success, establishing an all-Japan comprehensive diagnostic and research system covering all geographic areas and clinical specialties/subspecialties. IRUD has accurately diagnosed diseases, identified novel aberrated genes or disease entities, discovered many candidate genes, and enriched phenotypic and pathogenic variant databases. Further promotion of the IRUD is essential for determining causes and developing cures for rare and undiagnosed diseases.

[Hereditary Tumor Medical Care in the Age of Cancer Genomic Medicine].

How to efficiently suspect a germline gene variant(presumed germline pathogenic variant: PGPV)in comprehensive tumor-profiling tests using only cancer tissue(cells)as a sample is an important issue. This is because a few percent are derived from germline variants, which leads to the diagnosis of hereditary tumor syndromes and is useful information for the health management of patients and relatives. Clues include allele frequency, gene type, germline founder mutation, age of onset, present illness and past history, cancer type, family history, and tumor cell proportion. More than 97% of patients want to know such secondary findings before the test, but only about 23% of patients undergo confirmation tests even if PGPV is detected, and it is necessary to improve this in the future.

Perception of genetic testing among patients with inherited retinal disease: Benefits and challenges in a Japanese population.

Inherited retinal disease (IRD) is clinically and genetically heterogeneous. Awareness of the importance of genetic testing for IRD in the clinical setting is increasing with the recent development of new therapeutic strategies, such as gene therapy. Here, the perception of genetic testing, including its benefits and potential challenges, among patients with IRD was investigated to establish strategies for IRD genetic testing and counseling practices that can meet the requirements of the patients in Japan. An anonymous self-administered questionnaire was distributed to 275 patients with IRD who underwent genetic testing after clinical consultation and genetic counseling to investigate the motivations for genetic testing, benefits, challenges, status of communication of results to family, and attitude to timing of genetic testing. In total, 228 (82.9%) responses were analyzed. Several major motivations for genetic testing were identified, including gaining information on future treatment options and clarification of the inheritance pattern, among others. No association was found between the sharing of results with family members and the results of genetic testing. Moreover, according to patients who received positive results, the benefits of genetic testing included information on the inheritance pattern, additional information on the diagnosis, and mental preparation for the future. Even patients who received negative or inconclusive (variant of uncertain significance) results reported certain informative and psychological benefits. Altogether, these findings suggest that provisions for genetic testing and genetic counseling are necessary within a certain period after clinical diagnosis and it is necessary to facilitate appropriate family communication about genetic testing results while paying attention to the background of family relationships. Moreover, the benefits of genetic testing can be influenced by the careful interpretation and information provided on the test results during genetic counseling and consultation.

Gender Differences in Smoking Initiation and Cessation Associated with the Intergenerational Transfer of Smoking across Three Generations: The Nagahama Study.

Global tobacco policies lowered overall and male smoking rates, but female smoking rates have remained unchanged. Parent-child studies revealed the effects of parental smoking, but gender differences had mixed results. We investigated the effects of long-term smoking behavior in families over three generations in order to clarify gender differences. A cross-sectional study in a community-based genome cohort was conducted using a self-reported questionnaire. A total of 8652 respondents were stratified by gender regarding smoking initiation. A logistic regression analysis was performed to analyze the family smoking history. A total of 2987 current smokers and ever-smokers were compared regarding smoking cessation. With respect to smoking initiation, women were affected by their smoking mothers (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.8-3.2) and grandmothers (OR, 1.7; CI, 1.1-2.4). Women who continued smoking were affected only by their smoking mothers (OR, 1.6; CI, 1.05-2.49). In conclusion, gender differences in smoking initiation and cessation are possibly associated with family smoking history. Mothers and grandmothers were shown to have a strong influence on women with respect to both smoking initiation and cessation. Future research should focus on providing evidence for effective gender-specific intervention programs to curb long-term smoking in women.

Analysis of triptan use during pregnancy in Japan: A case series.

To evaluate the safety of triptan use during pregnancy in a Japanese population, we descriptively analyzed the data on pregnancy and fetal outcomes from 128 pregnant women using triptans for migraine treatment at two Japanese facilities that provided counseling on drug exposure in pregnancy between 2001 and 2017. The risks of miscarriage, low birth weight, and preterm birth were similar to those reported in the demographic statistics in Japan. The incidence proportion of malformation was also within the baseline risk range. Accumulated data suggest that exposure to triptans during pregnancy does not clearly increase the risk of negative pregnancy and fetal outcomes. This finding can help reduce anxiety in pregnant women with migraines who are taking triptans.

Japanese women's reasons for accompaniment status to hereditary breast and ovarian cancer-focused genetic counseling.

Genetic counselors routinely assess and understand clients' needs at the beginning of a session. Attending a genetic counseling session with or without companions is an objective sign that genetic counselors can easily notice. This study focused on clients' reasons for their accompaniment status for genetic counseling, which we categorize into attending with or without a companion(s). A questionnaire survey and interviews were conducted using snowball sampling, starting with the chief executive officer (CEO) of the Japanese hereditary breast and ovarian cancer (HBOC) support group. Of 32 participants, 19 continued with an in-depth interview after answering the questionnaire. Five themes were identified from the interview: (1) personal confidence, (2) decision-making style, (3) family members' habits and time availability, (4) considerations and conflicts with family members, and (5) healthcare provider's suggestion. Our data suggested that the clients expected their companion(s) to play certain roles. This indicates that the reasons of accompaniment status will be helpful for genetic counselors to understand both clients' and their families' motivations, personalities, habits, and psychosocial backgrounds. In a high-context culture such as that of Japan, accompaniment status may be a helpful sign to understand clients' true worries. In addition, some companions may be future clients in genetic counseling, due to the genetic nature of the disease. In conclusion, our study indicated that it is important for genetic counselors to record accompaniment status before the initial genetic counseling and to pay attention to its reasons at the beginning of the session, which may lead them to understand the client's psychosocial background to facilitate better client-centered genetic counseling.

Physicians' perceptions of the factors influencing disclosure of secondary findings in tumour genomic profiling in Japan: a qualitative study.

Tumour genomic profiling (TGP), conducted in search of therapeutics, sometimes reveals potentially pathogenic germline variants as secondary findings (SFs). Physicians involved in TGP are often specialised in oncology and not in clinical genetics. To better utilise SFs, we explored issues physicians have during disclosure and the potential for collaborations with clinical genetics professionals. Semi-structured interviews were conducted with 14 physicians who had experience in handling outpatient TGP at designated core hospitals for cancer genomic medicine in Japan. The data were analysed thematically. The difficulties physicians experienced during informed consent (IC) included educating patients about SFs, providing detailed information on SFs, and explaining the impact of SFs on patients' family members. When SFs were detected, physicians had reservations regarding the relevance of the disclosure criteria. Confirmatory germline tests were performed using peripheral blood when tumour-only tests detected suspected SFs. Some physicians had reservations about the necessity of confirmatory tests when they did not affect the patients' treatment options. To encourage patients to receive confirmatory tests, improvements are necessary in the healthcare system, such as insurance reimbursements, education for physicians so that they can provide a better explanation to their patients, and genetic literacy of physicians and patients. The physicians offered insights into the challenges they experienced related to IC, disclosure of SFs, and expectations for active collaborations with clinical genetics professionals. Wider healthcare insurance coverage and better genetic literacy of the population may lead to more patients taking confirmatory tests when SFs are suspected.