Identifying Unmet Social Needs in a Patient Living in Isolation: A Case Report.

Loneliness and social isolation are common among older adults. To deliver high-quality care to older patients, healthcare professionals should know the social conditions of their patients. Addressing social determinants of health (SDH) in daily practice is beneficial to both patients and healthcare professionals. We illustrate a patient with congestive heart failure and cognitive decline whose social conditions improved through an SDH assessment. An SDH assessment has some potential advantages, which include facilitating a comprehensive understanding of patients' social conditions, visualizing how patients' social conditions have changed, deepening interprofessional collaboration, and ameliorating unnecessary negative emotions toward patients. This case report conveys two key messages. Firstly, healthcare professionals have the capability to evaluate patients' social backgrounds and enhance their health and social conditions through routine care. Secondly, the utilization of an SDH screening toolkit can support and enhance this initiative.

Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

Impact of medical students' socioeconomic backgrounds on medical school application, admission and migration in Japan: a web-based survey.

OBJECTIVES: The aim of this study was to clarify and compare the socioeconomic backgrounds of medical students with those of other health professions and non-health faculty students in an era of increasing inequity in Japanese society. DESIGN: This was a quantitative nationwide study. Data were collected by a cross-sectional web-based anonymous questionnaire. SETTING: Data from years 3 and 4 medical, health professions and non-health faculty students across Japan were collected in 2021. PARTICIPANTS: Participants were 1991 students from medical schools, 224 from dental, 419 from pharmacy, 326 from nursing, 144 from other health professions and 207 from non-health faculties. RESULTS: The proportion of high-income families (>18 million yen: ca. US$140 000) among medical students was 25.6%, higher than that of pharmacy (8.7%) and nursing students (4.1%) (p<0.01). One-third of medical students had a physician parent, more common than in non-medical students (p<0.01). Students who only applied to public medical schools and a regional quota 'Chiiki-waku' students with scholarship had lower family income and physician parents compared with those who applied to private medical schools (p<0.01), but they still had higher physician parents compared with non-medical students (p<0.01). Logistic regression revealed that having a physician parent (p<0.01), aspiring to the present profession during elementary school (p<0.01) and private upper secondary school graduation (p<0.01) predicted the likelihood of studying medicine. There were regional differences of backgrounds among medical students, and 80% of medical students with urban backgrounds intended to work in urban localities after graduation. CONCLUSIONS: This study provides evidence that medical students in Japan hail from urban and higher income classes and physicians' families. This finding has implications for the health workforce maldistribution in Japan. Widening the diversity of medical students is essential for solving physician workforce issues and meeting broad healthcare needs.

Barriers encountered by nurses in the care of walk-in international patients in an emergency department in Japan.

BACKGROUND: An increasing number of international patients continue to visit emergency departments (EDs) in Japanese hospitals. However, nurses in Japan perceive challenges when caring for patients from other countries. This study explored ED nurses' perceptions of barriers when caring for walk-in international patients. METHODS: Five semi-structured online focus group interviews involving 15 registered nurses with experience in caring for patients in an ED at a university referral hospital located in the center of Tokyo were conducted. Thematic analysis was used to identify patterns from the interviews. RESULTS: The themes that emerged were as follows: (1) hesitation to engage with patients due to ambiguity, (2) loss of harmony in the ED, (3) difficulty with mutual goal settings, and (4) decreased professional self-efficacy. CONCLUSION: The findings provide an understanding of the challenges faced when caring for walk-in international patients. Educational interventions for ED nurses and other strategies, such as the use of interpreters, can enhance nurses' abilities to improve patient safety and maintain equality.

Formation and Growth of Atomic Scale Seeds of Au Nanoparticle in the Nanospace of an Organic Cage Molecule.

Seed-mediated growth has been widely used to synthesize noble metal nanoparticles with controlled size and shape. Although it is becoming possible to directly observe the nucleation process of metal atoms at the single atom level by using transmission electron microscopy (TEM), it is challenging to control the formation and growth of seeds with only a few metal atoms in homogeneous solution systems. This work reports site-selective formation and growth of atomic scale seeds of the Au nanoparticle in a nanospace of an organic cage molecule. We synthesized a cage molecule with amines and phenols, which were found to both capture and reduce Au(III) ions to spontaneously form the atomic scale seeds containing Au(0) in the nanospace. The growth reaction of the atomic scale seeds afforded Au nanoparticles with an average diameter of 2.0±0.2 nm, which is in good agreement with the inner diameter of the cage molecule.

Feasibility and impact of haplogroup matching for mitochondrial replacement treatment.

Mitochondrial replacement technology (MRT) aims to reduce the risk of serious disease in children born to women who carry pathogenic mitochondrial DNA (mtDNA) variants. By transplanting nuclear genomes from eggs of an affected woman to enucleated eggs from an unaffected donor, MRT creates new combinations of nuclear and mtDNA. Based on sets of shared sequence variants, mtDNA is classified into ~30 haplogroups. Haplogroup matching between egg donors and women undergoing MRT has been proposed as a means of reducing mtDNA sequence divergence between them. Here we investigate the potential effect of mtDNA haplogroup matching on clinical delivery of MRT and on mtDNA sequence divergence between donor/recipient pairs. Our findings indicate that haplogroup matching would limit the availability of egg donors such that women belonging to rare haplogroups may have to wait > 4 years for treatment. Moreover, we find that intra-haplogroup sequence variation is frequently within the range observed between randomly matched mtDNA pairs. We conclude that haplogroup matching would restrict the availability of MRT, without necessarily reducing mtDNA sequence divergence between donor/recipient pairs.

The degree of satisfaction and level of learning in male and female surgical residents: a nationwide questionnaire survey of graduating residents in Japan.

PURPOSE: Since 2002, the Japan Surgical Society has established a board certification system for surgeons to be certified for a specialty. Surgery remains a male-dominated field in Japan. This study aimed to clarify if the Japanese surgical residency training system is equally suitable for female and male residents. METHODS: The Japan Surgical Society conducted the first questionnaire survey regarding the system of surgical training for the residents in 2016. The questionnaire included the degree of satisfaction with 7 aspects of the training system, including the number and variety of cases experienced and duration and quality of instruction, and the learning level for 31 procedures. The degree of satisfaction and level of learning were compared between female and male residents. RESULTS: The degree of satisfaction was similar for all items between female and male residents. Female residents chose breast surgery as their subspecialty more frequently than male residents and were more confident in breast surgery procedures than male residents. Conversely, fewer female residents chose gastrointestinal surgery and were less confident in gastrointestinal surgery procedures than male residents. CONCLUSION: Female residents were as satisfied with the current surgical training system as male residents. However, there may be room for improvement in the surgical system, considering that fewer applications for gastrointestinal surgery come from female residents than from males.

A Cross-sectional Study of Regret in Cancer Patients After Sharing Test Results for Pathogenic Germline Variants of Hereditary Cancers With Relatives.

BACKGROUND: Research on whole genome/exome sequencing is increasing worldwide. However, challenges are emerging in relation to receiving germline pathogenic variant results and sharing them with relatives. OBJECTIVE: The aim of this study was to investigate the occurrence of and reasoning related to regret among patients with cancer who shared single-gene testing results and whole exome sequencing with family members. METHODS: This was a single-center, cross-sectional study. The Decision Regret Scale was administered, and descriptive questionnaires were used with 21 patients with cancer. RESULTS: Eight patients were classified as having no regret, 9 patients were classified as having mild regret, and 4 patients were classified as having moderate to strong regret. Reasons patients felt that sharing was the right decision included the following: to allow relatives and children to take preventive measures, the need for both parties to be aware of and ready for the hereditary transmission of cancer, and the need to be able to discuss the situation with others. On the other hand, some patients did not think it was a good decision to share the information because of the associated anxiety. CONCLUSIONS: Regret over sharing test results for pathogenic germline variants of hereditary cancers with relatives tended to be low. The main reason was that patients believed that they were able to benefit others by sharing. IMPLICATIONS FOR PRACTICE: Healthcare professionals need to understand the postsharing perceptions and experiences of patients and support them throughout the sharing process.

Improving the communication skills of medical students --A survey of simulated patient-based learning in Chinese medical universities.

BACKGROUND: It is useful to advance simulated patient (SP) participation in teaching to improve the communication skills of medical students, so this study aims to explore the current state of Chinese mainland SP education. METHODS: A cross sectional survey was designed utilizing well defined quantitative research methods and descriptive statistics. The questionnaire sought information which elucidated the current status of SP-based education, the origin of SP-based learning, SP training, challenges of this learning strategy and future developments. Questionnaires were distributed to 79 medical colleges in mainland China, and 68 were returned. Of these, 64 constituted valid responses (81%). RESULTS: The number of SP-based education activities in medical colleges offering 5-year、7-year and 8-year clinical medicine programs was significantly higher than that in medical colleges which offered only a single 5-year program (p < 0.01). Communication skills training accounted for 73% of the content of SP-based learning activities, and was expected to rise in the future to 90%, in response to a need to improve doctor-patient relationships. Persons recruited as 'simulated patients' included students (21% of the total), residents (49%), medical staff (15%) and teaching staff (14%). Colleges, planning a SP-based education program, preferred teachers (80%) and students (55%) to assume 'simulated patient' roles. In objective structured clinical education (OSCE) scenarios, co-scoring by both SPs and teachers featured more highly in the 'consultation' station and 'doctor-patient communication' station. A number of factors were identified as hindering future development and implementation of SP-based learning including budget restraints, SP selection and training. CONCLUSIONS: SP-based learning programs offer clear benefits for improving the clinical education of medical students and their communication skills. The main obstacles to achieving more widespread and higher quality SP-based education are insufficient funding and the lack of standardized training and performance evaluation processes for simulated patients. Medical colleges should consider reducing the proportion of students and teachers acting as SPs, and attract more citizens to participate in SP-based learning activities. Formalised training and evaluation of SPs performance are necessary to establish a 'standard simulated patient' for a particular medical discipline, thus improving SP-based activities and student learning.

Evaluation of postgraduate rural medical training programs and implications for rural workforce development: a systematic review.

INTRODUCTION: Providing postgraduate rural training programs has been recognised as central for successful recruitment and retention of medical workforce. While there have been many documented cases of rural training program development, documented program outcome evaluations are few. This review investigated how postgraduate training and educational programs for rural and remote medicine are evaluated worldwide. Through the use of a systematic review, the study explored three questions: 'What are the outcomes of postgraduate rural and remote training programs worldwide?', 'How are the program evaluations conducted?' and 'What evaluation models and approaches are used in evaluating the effectiveness of these training programs?' METHODS: A qualitative synthesis was undertaken of evaluations of postgraduate rural training programs published in the English language in medical education journals. The study involved pooling quantitative and mixed-methods research data and findings from qualitative studies, which were aggregated, integrated and interpreted. PubMed, PsycINFO, ERIC and Web of Science databases were searched to identify studies that satisfy the search criteria. RESULTS: Of the 1297 articles identified through the database search, 26 studies were included in the analysis. Most of the evidence from the studies consists of descriptive studies with some longitudinal tracking programs and cohort studies. Nine themes were identified: practice location after training completion; training location and decentralised model; educational aspects; incentives, political contexts and regulations; personal, social and cultural issues; professional development; rural orientation and community engagement; support system; and gender and racial issues. Key outcomes were analysed and cross-validated against the 2020 WHO guideline on health workforce development, attraction, recruitment and retention in rural and remote areas. These studies' most frequent evaluation methods were surveys, followed by interviews, questionnaires and secondary data from existing databases. Methodological characteristics, the relationship between rural background and program outcomes, and implications for decentralised training, telehealth and tele-assessment during the COVID-19 pandemic are discussed. Analysis from the key outcomes suggests evaluation as a strategy to uncover outcomes in postgraduate rural and remote training and medical education. CONCLUSION: Regardless of the similar outcomes, the program evaluations implemented and the robustness of evidence vary across programs and medical schools. The absence of solid evaluation designs and their alignment to the program objectives will lessen the strengths of evidence. Better quality research and evaluation design, objective settings, qualitative inquiry to uncover the contexts, and developing appropriate indicators and benchmarks for monitoring and evaluating strategies must be considered during program development and implementation.

Impact of the Axillary Approach on Epicardial Pacing Lead Durability in Children.

BACKGROUND: To avoid lead failure and pocket infection in neonates and infants requiring pacemakers, we used the axillary approach of placing the generator in the axilla and the leads in the intrathoracic space. We describe the technical details of the axillary approach and evaluate the efficacy of this method. METHODS: We assessed 21 patients (7 male) weighing 8 kg or less who underwent epicardial pacemaker implantation with the axillary approach between 2004 and 2018. The axillary approach entails (1) positioning the pacemaker generator in the axilla to avoid local skin and pocket complications due to tissue compression by the generator, and (2) making a double loop in the pleural space to reduce stress on the pacemaker leads caused by somatic growth. This approach can be combined with median sternotomy for simultaneous intracardiac repair. RESULTS: The patients' median age at pacemaker implantation was 6 months; 16 patients (76%) were aged less than 12 months. The median body weight was 4.5 kg (interquartile range, 3 to 7). In all 5 patients requiring simultaneous cardiac repair, a median sternotomy was performed to access the heart. Sixteen patients required only pacemaker implantation: left thoracotomy was performed in 10 patients, right thoracotomy in 5, and subxiphoid approach in 1. The 5-year and 10-year freedom from pacemaker-related adverse events was 89.4% and 79.5%, respectively. CONCLUSIONS: The axillary approach using intrathoracic double-loop routing of leads to position the generator in the axilla for pacemaker implantation can be a valuable alternative for neonates/infants weighing 8 kg or less with or without complex congenital heart disease.

Sharing genetic test results of germline pathogenic variants of hereditary cancer with relatives: A single-center cross-sectional study.

OBJECTIVE: This study aimed to determine whether Japanese cancer patients share test results of germline pathogenic variants of hereditary cancer with their relatives. METHODS: This single-center cross-sectional study enrolled 21 Japanese patients who received results of germline pathogenic variants of hereditary cancer at least 6 months prior. RESULTS: All patients shared their test results with at least one relative, with the following sharing rates: 85.7% for first-degree relatives, 10% for second-degree relatives and 8.3% for third-degree relatives. Patients most commonly shared the information with their children aged >18 years (86.7%), followed by their siblings (73.6%), spouses (64.7%) and parents (54.5%). Three categories were extracted from qualitative analysis: 'characteristics of my cancer', 'knowledge and caution about inheritability' and 'utilization of medical care.' CONCLUSIONS: The rate of test result sharing with first-degree relatives was comparable with those in Europe and the USA. Patients with germline pathogenic variants also tended to share their test results more with their children and siblings than with their parents. Informing their relatives of the results was suggestive of the motivation to influence their relatives' health outcome and contribute to the well-being of their children and siblings.

Parental genome unification is highly error-prone in mammalian embryos.

Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.

Depression, anxiety and psychological distress in patients with pulmonary hypertension: a mixed-methods study.

INTRODUCTION: Pulmonary hypertension (PH) is a chronic and progressive disease. While prognoses have improved, PH patients still experience side effects and activity restrictions. Accordingly, the key questions asked by this study are 'How many PH patients have depression/anxiety symptoms?' and 'Is there a difference in the symptoms and distress factors between pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) patients, and how are they experiencing distress?' METHODS: A mixed-methods study was conducted to collect and analyse quantitative and qualitative data. We administered questionnaires (Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder-7) and then conducted interviews with participants who reported moderate to severe depressive symptoms (PHQ-9 ≥10). RESULTS: Seventy-four participants were enrolled in the study, 25 with idiopathic PAH and 49 with CTEPH. Their average age was 55.2 years (PAH 42.7 years, CTEPH 61.5 years). Overall, 44.6% of participants had mild or more severe depressive symptoms (PHQ-9 ≥5) and 17.6% had moderate or more severe depressive symptoms (PHQ-9 ≥10). PAH patients had particularly high depressive symptoms (PHQ-9 ≥5: PAH 64.0%, CTEPH 34.7%; PHQ-9 ≥10: PAH 24%, CTEPH 14.3%). We extracted four common themes from the qualitative interview data on participants' experience of psychological distress: 'Loss of myself,' 'Isolation from my surroundings,' 'Hassle associated with oxygen therapy,' and 'Fear of illness progression/deterioration.' One theme- 'Suffering from side effects'-was extracted only for PAH patients, while another-'Rumination on illness due to breathlessness'-was extracted only for CTEPH patients. DISCUSSION AND CONCLUSION: The study found that PH patients are prone to depression. The identification of factors and themes that influence the psychological distress of PH patients is important information that can be used to improve the support for the physical and mental health of these patients. Interventions for these distress may contribute to improving the mental status of PH patients.

"Staying at home" to tackle COVID-19 pandemic: rhetoric or reality? Cross-cutting analysis of nine population groups vulnerable to homelessness in Japan.

Although the "stay-at-home" order is advocated against the coronavirus disease 2019 (COVID-19), the lives of individuals lacking adequate housing are threatened. We developed a framework to assess various populations with unstable housing in terms of socio-economic consequences of COVID-19, risk of COVID-19 infection and progression, existing/urgent measures, and remaining challenges. Within the framework, nine groups vulnerable to homelessness in Japan were classified into (i) "people without accommodation," (ii) "people living in temporary or crisis accommodation," and (iii) populations that include "people living in severely inadequate and insecure accommodation." The assessment revealed that "staying at home" was physically and practically unattainable across groups. The study identified specific institutional, social, and cultural challenges apart from the common economic crisis, whereas the utilization of social welfare was low. Findings suggest that the rapid increase of groups classified as "(i)" and "(ii)" should be addressed by engaging stakeholders to enhance the availability and accessibility of social welfare and rescue measures, and to ensure safe and private accommodations for all groups. It is critical to enhance multi-sectoral collaboration in responding to the common and specific vulnerabilities of these population groups from health, socio-economic, and humanitarian perspectives. Under the pandemic, homelessness should be regarded less as a peculiar problem for specific populations but an extension of daily life. The framework can be a reference when planning the comprehensive yet concise assessment of populations with unstable housing in other countries to inform responses to the pandemic.

Is there disparity between regions and facilities in surgical resident training in Japan? Insights from a national survey.

PURPOSE: This study sought to assess the disparity between regions and facilities in surgical resident training in Japan via a national level needs-assessment. METHODS: A survey was sent to all 909 graduating residents of 2016. Residents trained in the six prefectures with a population of 7 million or more were included in the large prefecture (LP) group. Residents trained in the other 41 prefectures were included in the small prefecture (SP) group. Each group was further divided into a university hospital (UH) group and a non-university hospital (NUH) group. RESULTS: The response rate was 56.3% (n = 512). Excluding nine residents who did not report their prefectures and facilities, surveys from 503 residents were analyzed. The UH group received significantly more years of training. In the SP and UH groups, there were significantly fewer residents who had performed 150 procedures or more under general anesthesia in comparison to the LP and NUH groups, respectively. Self-assessed competencies for several procedures were significantly lower in the SP and UH groups. CONCLUSION: Disparity in surgical resident training was found between regions and facilities in Japan. The surgical residency curriculum in Japan could be improved to address this problem.

A report of the Social Vital Signs Workshop at WONCA Asia Pacific Regional Conference 2019.

We, Team SAIL, held the workshop at WONCA APR Conference 2019 for presenting the concept of Social Vital Signs (SVS) to an international audience.

Rapid two-stage Starnes approach in high-risk neonates with Ebstein anomaly.

OBJECTIVES: The purpose of this study is to review the short- and long-term outcomes of high-risk neonates with Ebstein anomaly treated with a newly developed rapid 2-stage Starnes procedure, which is aimed at reducing the size of the enlarged right side of the heart. METHODS: Fifty-two foetuses with Ebstein anomaly were analysed in this study and divided into 2 groups. The control group comprised 25 foetuses, referred to us before 2008, and the study group was composed of 27 foetuses, referred to us after 2009. The right atrial area index was defined as high risk when it was >1.5. We applied our management approach to 6 high-risk neonates in the study group. This approach consisted of reducing the size of the right side of the heart through a 2-stage process: (i) right atrial plication without the use of a bypass and (ii) a Starnes procedure. Cox proportional hazards models were used to evaluate the effects of our management approach on the survival rates of the neonates. RESULTS: The mean follow-up period was 7.5 ± 3.3 years. All 6 high-risk neonates in the study group survived. The overall hazard ratio was 0.12 (95% confidence interval of 0.03-0.43) in the study group as compared with the control group (P = 0.0007). A Fontan operation was completed in all but 1 case, with the remaining case awaiting a Fontan operation. CONCLUSIONS: We suggest that a rapid 2-stage Starnes approach can be effective in the treatment of high-risk neonates with Ebstein anomaly.

Are graduating residents sufficiently competent? Results of a national gap analysis survey of program directors and graduating residents in Japan.

PURPOSE: To evaluate the self-assessed competency of graduating residents (GRs) in Japan upon completion of their residency and to identify the gap between their competency and the competency expected by their program directors (PDs). METHOD: A list of 31 essential surgical procedures was compiled according to the consensus of surgical educators from around the country. A survey with this list was sent to all 909 GRs and their 611 PDs in 2016. The GRs rated their competency to perform these procedures and the PDs were asked to evaluate the expected competency of their GRs using the Zwisch Scale. RESULT: The response rate was 56.3% for the GRs and 76.8% for the PDs. Fewer than half of the GRs who responded felt confident performing ten (32%) of the surgical procedures evaluated. For most procedures, the GRs' self-reported competency was lower than the expectation reported by their PDs. This gap was more than 10% for 13 of the procedures. CONCLUSION: More than half of the GRs in Japan lacked the confidence in their skill to perform one-third of the surgical procedures selected for evaluation in this study. These findings should be used to update the surgical education curriculum in Japan.

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases.

AIMS: The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. METHODS AND RESULTS: We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as 'pathogenic' by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands. CONCLUSION: Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.