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[Introduction] Personalized health care is recommended for the prevention and early detection of breast cancer. Advances in technology have made it possible to estimate genetic risk, PGV (pathogenic/likely-pathogenic germline variant) or PRS (polygenic risk score), in practice. However, linkage after risk assessment to personalized health care is still developing. One of the issues is how to tell the result especially in case of newly diagnosed PGV after Genetic Panel Testing or PRS. In this study, we evaluated genetic counseling (GC) using an established patient-reported outcome measure for clinical genetics services scale (Genetic Counseling Outcome Scale24 (GCOS24)) at genetic counseling for disclosure the results of the previous study, and examined the association with management after GC. [Method] We performed targeted sequencing for 11 breast cancer-related genes using peripheral blood DNA from 1995 female breast cancer patients. Of 1995 cases, 101 patients were PGV carriers, who were candidates of this study. Participants were referred to the Clinical Genetics unit, Kyoto University Hospital from 10 institutions (January 2018-March 2022). GCOS24 and relating questionaries were asked before and after GC. GCOS24 is a scale consisting of 24 items that assess five factors: decision control, cognitive control, behavioral control, emotional regulation, and hope. (In light of the current status of hereditary breast cancer care in Japan, 23 items were used.) Each item is rated on a scale of 1-7 points, for a total score of 23-161. In addition, we reviewed medical records to evaluate the post-GC management. [Results] Of the 101 cases, 38 cases were enrolled. The reasons of 63 not-enrolled cases were: 30 cases without follow-up (deaths or transfer to another hospital), 11 cases already diagnosed in clinical practice, 18 cases that did not wish to know their results, and 4 cases whose hospital were developing for hereditary breast cancer care. Median age at the time of genetic GC was 55 (min-max 30-83) years. Details of PGV cases were: BRCA2 23 cases, BRCA1 2, PALB2 4, PTEN 3, TP53 3, ATM 1, CHEK2 1 and NF1 1. GCOS24 after GC were improved than before GC. (Average 99 (min-max 17-124) vs 114 (91-138), Mean difference 23.9, 95% Confidence intervals (CI) 29.6 to 18.3). Thirty patients (79%) had higher increase in scores than 10.3, which was the previously reported Minimum Clinically Important Difference (MCID) of this scale. In all items except 4 items (#6,11,13,21), GCOS24 after GC were significantly improved than before GC. In post-GC management, 8 patients received or planned RRSO (risk reducing salpingo-oophorectomy) among 25 BRCA1/2 cases. There was a case with dysplastic cells detected in the resected ovary. After GC, average of GCOS24 in RRSO cases was 120 (95% CI 110 to 129), while average of GCOS24 of other BRCA1/2 cases was 110 (95% CI 104 to 116). On the other hand, two patients stopped visiting to the hospital because of fear after GC. Average of GCOS24 of 15 junior-high/high school graduate cases were 111 (95% CI 105 to 117), while average of GCOS24 of 23 college graduate cases were 117 (95% CI 111 to 122). [Discussion] In patients diagnosed with hereditary breast cancer by genetic panel testing, GC worked well except for 4 items. These 4 items (#6,11,13,21) were related to emotion. This study revealed there was also a risk to reject surveillance due to fear, suggesting that it is necessary to provide psychological support in some cases. Although the limitation of this study is the small number of cases, GCOS24 were high in RRSO cases, suggesting that GC played an important role when proceeding with intervention. We believe that the findings are helpful for the future implementation of genetic panel testing or PRS testing in healthy subjects for personalized health care. Citation Format: Nobuko Kawaguchi-Sakita, Noriko Senda, Yukiko Inagaki-Kawata, Hiromi Murakami, Sayaka Honda, Takahiro Yamada, Yuki Kataoka, Shoko Takahara, Shigeru Tsuyuki, Kazuhiko Yamagami, Yoshio Moriguchi, Masae Torii, Tatsushi Kato, Hirofumi Suwa, Wakako Tsuji, Eiji Suzuki, Akira Yamauchi, Ryuji Okamura, Shinji Kosugi, Masakazu Toi. Potential Empowerment and risk of Genetic Counseling with Genetic Breast cancer risk assessment in Personalized Health Care: Prospective Cohort Study using Genetic Counseling Outcome Scale (GCOS-24) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-05-02.

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.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.

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-023-00641-3.

With the rapid expansion of genomic medicine, citizens are compelled to think about genetics in daily life. Therefore, this study aims to explore appropriate types of educational media and methods of enlightenment activities for genetics and hereditary cancer. For this purpose, we launched the public awareness project, planned and run by genetic medicine experts. In this study, we presented an 18-minute YouTube video on genetics and hereditary cancer to participants at 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. Among them, only 35 (26.3%) responded to the questionnaire. Most of the respondents understood and appreciated the contents of the video. They identified websites, videos, manga, and books as suitable learning media, irrespective of sex, age, or profession. Moreover, 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.

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.

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 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.

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.

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.

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.Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOneA 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.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.

In June 2019, the Japanese National Health Insurance (NHI) system introduced coverage for two types of tumor genomic profiling (TGP): FoundationOne

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.

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.

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.

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.

Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy. Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.

OBJECTIVE An association between the Moyamoya disease susceptible gene ring finger protein 213 (RNF213) variant and ischemic stroke and coronary artery disease has been suggested in case-control studies. We aimed to investigate the possible association between the RNF213 variant and the incidence of cardiovascular disease in a general population. METHODS The study participants consisted of 9153 Japanese community residents without history of cardiovascular disease. The clinical parameters employed in this analysis were observed at baseline between 2008 and 2010. The RNF213 p.R4859K variant was determined by TaqMan probe assay and then confirmed by Sanger sequencing. RESULTS During 8.52 years follow-up period, we observed 214 incident cases of cardiovascular diseases (99 total stroke cases, 119 major adverse cardiac event cases, including 4 cases of both). The incidence rate was higher for the variant allele carriers (120 cases; incidence rate, 71.0 per 10 000 person-years) than for the homozygotes of the wild-type allele (26.9), and the group differences achieved statistical significance (P = 0.009). Although the RNF213 variant was also associated with systolic blood pressure (dominant model: coefficient of 8.19 mmHg; P

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (