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.

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.

Shared decision making between patients with Fabry disease and physicians in Japan: An online survey.

Background: Fabry disease is a rare, progressive genetic lysosomal disorder that can cause multisystem organ dysfunction. With increasing treatment options for Fabry disease, it is imperative that patients discuss and select treatment plans in conjunction with their physicians. Although shared decision making (SDM) should be recommended for clinical decision making in disease management, evidence is limited as to how patients in Japan are involved in the choice of their Fabry disease treatment and if other gaps exist with physicians in the perception of Fabry disease management. Objective: The main objective of the study was to assess the degree of agreement between patients and treating physicians in the SDM process as assessed by the SDM-Q-9 and SDM-Q-Doc questionnaires. In parallel, this study also investigated other factors that might impact the SDM process. Methods: This was a cross-sectional web-based questionnaire survey of Japanese patients with Fabry disease and their treating physicians conducted from February 2021 to June 2021. Online surveys were developed for patients and physicians, consisting of seven items, including the Japanese version of the 9-item SDM Questionnaire for patients (SDM-Q-9) and physicians (SDM-Q-Doc). Physicians were divided into two cohorts: non-paired and paired with patients. Only the paired cohort physicians answered the SDM questionnaire. Results: A total of 99 physicians and 30 patients answered the respective questionnaires. Among these, 13 physicians were included in a paired SDM analysis with patients. Mean (standard deviation [SD]) patient age at diagnosis of Fabry disease was 47.5 (15.8) years, and 14 (46.7%) were male. Both physicians in the paired cohort and patients considered patient-reported outcomes (both 76.7%) and the findings from laboratory testing as important (90.0% and 60.0% respectively). However, regarding symptoms that affect quality of life of patients, perception gaps were identified in that physicians in the paired cohort placed less importance on patient-reported outcome-related symptoms such as sweating abnormalities and gastrointestinal symptoms than their patients (0% [0/17] and 44.4% [8/18], 11.8% [2/17] and 38.9% [7/18], respectively). In the paired analysis, there was no significant difference in total SDM score between patients and physicians (p = 0.82). However, the largest discordance in perception between patients and physicians was identified for the explanation of the advantages and disadvantages of the treatment options (weighted Kappa coefficient = 0.14). Conclusion: This survey revealed a gap in the perception of disease burden affecting patients' quality of life, and a recognition gap between physicians and patients when they discussed the advantages and disadvantages of treatment options. To improve the SDM process in Fabry disease management and treatment, practical solutions for bridging these gaps should be considered.

Janus Hydrogel Microbeads for Glucose Sensing with pH Calibration.

We present fluorescent Janus hydrogel microbeads for continuous glucose sensing with pH calibration. The Janus hydrogel microbeads, that consist of fluorescent glucose and pH sensors, were fabricated with a UV-assisted centrifugal microfluidic device. The microbead can calibrate the pH values of its surroundings and enables accurate measurements of glucose within various pH conditions. As a proof of concept, we succeeded in obtaining the accurate value of glucose concentration in a body-fluid-like sample solution. We believe that our fluorescent microbeads, with pH calibration capability, could be applied to fully implantable sensors for continuous glucose monitoring.

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan.

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

Eye-recognizable and repeatable biochemical flexible sensors using low angle-dependent photonic colloidal crystal hydrogel microbeads.

This paper presents eye-recognizable and repeatable biochemical flexible sensors using low angle-dependent stimuli-responsive photonic colloidal crystal hydrogel (PCCG) microbeads. Thanks to the stimuli-responsive PCCG microbeads exhibiting structural color, users can obtain sensing information without depending on the viewing angle and the mechanical deformation of the flexible sensor. Temperature-responsive PCCG microbeads and ethanol-responsive PCCG microbeads were fabricated from a pre-gel solution of N-isopropylacrylamide (NIPAM) and N-methylolacrylamide (NMAM) by using a centrifuge-based droplet shooting device (CDSD). As a proof-of-concept of thin and flexible biochemical sensors, temperature- and ethanol-sensing devices were demonstrated. By comparing the structural color of the stimuli-responsive PCCG microbeads and the color chart of the device, sensing information, including skin temperature of the human body and ethanol concentration in alcoholic beverages, was obtained successively. We expect that our device design using low angle-dependent stimuli-responsive PCCG microbeads would contribute to the development of user-friendly biochemical sensor devices for monitoring environmental and healthcare targets.

Influence of MILR1 promoter polymorphism on expression levels and the phenotype of atopy.

The recently identified cell surface immunoreceptor MILR1 (mast cell immunoglobulin-like receptor 1; synonyms, Allergin-1) has been shown to suppress immunoglobulin E (IgE)-mediated, mast cell-dependent responses in both mice and humans. We performed a mutation search of MILR1 together with a genetic association study to determine whether polymorphisms in MILR1 are associated with atopy in human. Mutation screening of MILR1 was performed using DNA from 146 unrelated Japanese. Genotyping of the identified polymorphisms was done with 1505 individuals from the general Japanese adult population. Atopy, as defined by positive responses for specific IgEs against at least one of the 26 common allergens, was evaluated using MAST-26. Five polymorphisms (rs6504230, c.-170_-166delAGGAA, rs8071835, rs143526766 and rs12936887) and two rare missense variants (Val273Ala and Leu311Val) were identified by mutation screening. The C allele of rs6504230 had protective effects against atopy (P=0.002). A luciferase reporter assay using the promoter region of MILR1 revealed that the C allele of rs6504230 was associated with increased expression of MILR1, which was in accordance with the results of expression quantitative trait loci analysis using human leukocytes. Our data indicates that the rs6504230 polymorphism affects MILR1 expression levels in humans, leading to a susceptibility to producing specific IgE antibodies against common allergens.