浦川 優作

BACKGROUND: Online genetic care can offer a promising solution to the shortage of qualified medical professionals in genetic medicine, which leads to regional disparities in access. However, despite global adoption, its use in Japan remains limited. METHODS: Two questionnaire surveys were conducted to investigate potential needs and barriers regarding online genetic care: one involving 858 medical professionals (738 physicians and 120 genetic counselors or nurses), and the other involving 443 clients who received in-person genetic counseling. RESULTS: Only 14.0% of the medical professionals had experience with online genetic care, although 85.9% of the professionals engaged in cancer genetics were willing to consider providing it in the future. Notably, a discrepancy was found regarding hospital selection: clients prioritized access to specialized medical care, whereas professionals assumed clients valued accessibility for family members. Professionals expressed greater concerns about adequacy of online communication, client environments and internet security. Among clients, 89.1% estimated they would sufficiently understand and accept total content of counseling session if were conducted online. Older age and infrequent internet use were associated with lower acceptance and higher anxiety regarding online methods. Concerns about ability to use the necessary technology affected clients' willingness to encourage online care for their relatives. CONCLUSION: Online genetic care shows high potential for client acceptance and can effectively address regional disparities in Japan. To bridge the gap between client needs and professional perceptions and to overcome the digital divide, it is necessary to develop secure, accessible systems and provide education for both patients and healthcare providers.

BACKGROUND: Advances in genetics have underscored a strong association between genetic factors and health outcomes, leading to an increased demand for genetic counseling services. However, a shortage of qualified genetic counselors poses a significant challenge. Large language models (LLMs) have emerged as a potential solution for augmenting support in genetic counseling tasks. Despite the potential, Japanese genetic counseling LLMs (JGCLLMs) are underexplored. To advance a JGCLLM-based dialogue system for genetic counseling, effective domain adaptation methods require investigation. OBJECTIVE: This study aims to evaluate the current capabilities and identify challenges in developing a JGCLLM-based dialogue system for genetic counseling. The primary focus is to assess the effectiveness of prompt engineering, retrieval-augmented generation (RAG), and instruction tuning within the context of genetic counseling. Furthermore, we will establish an experts-evaluated dataset of responses generated by LLMs adapted to Japanese genetic counseling for the future development of JGCLLMs. METHODS: Two primary datasets were used in this study: (1) a question-answer (QA) dataset for LLM adaptation and (2) a genetic counseling question dataset for evaluation. The QA dataset included 899 QA pairs covering medical and genetic counseling topics, while the evaluation dataset contained 120 curated questions across 6 genetic counseling categories. Three enhancement techniques of LLMs-instruction tuning, RAG, and prompt engineering-were applied to a lightweight Japanese LLM to enhance its ability for genetic counseling. The performance of the adapted LLM was evaluated on the 120-question dataset by 2 certified genetic counselors and 1 ophthalmologist (SK, YU, and AY). Evaluation focused on four metrics: (1) inappropriateness of information, (2) sufficiency of information, (3) severity of harm, and (4) alignment with medical consensus. RESULTS: The evaluation by certified genetic counselors and an ophthalmologist revealed varied outcomes across different methods. RAG showed potential, particularly in enhancing critical aspects of genetic counseling. In contrast, instruction tuning and prompt engineering produced less favorable outcomes. This evaluation process facilitated the creation an expert-evaluated dataset of responses generated by LLMs adapted with different combinations of these methods. Error analysis identified key ethical concerns, including inappropriate promotion of prenatal testing, criticism of relatives, and inaccurate probability statements. CONCLUSIONS: RAG demonstrated notable improvements across all evaluation metrics, suggesting potential for further enhancement through the expansion of RAG data. The expert-evaluated dataset developed in this study provides valuable insights for future optimization efforts. However, the ethical issues observed in JGCLLM responses underscore the critical need for ongoing refinement and thorough ethical evaluation before these systems can be implemented in health care settings.

Neurofibromatosis type 1 (NF1) presents with a broad spectrum of clinical manifestations, including an increased risk of tumor development and hypertension. Comprehensive data on genotype‒phenotype correlations in patients with NF1 are limited. Therefore, in this study, we aimed to elucidate the detailed genetic and clinical characteristics of NF1 in a hereditary tumor cohort. We performed sequencing and copy number assays in a clinical laboratory and analyzed the clinical data of 44 patients with suspected NF1. Germline pathogenic variants were detected in 36 patients (81.8%), and 20.7% of the variants were novel. Notably, 40.0% of adult patients presented with malignancies; female breast cancer occurred in 20.0% of patients, which was a higher rate than that previously reported. Hypertension was observed in 30.6% of the adult patients, with one patient experiencing sudden death and another developing pheochromocytoma. Three patients with large deletions in NF1 exhibited prominent cutaneous, skeletal, and neurological manifestations. These results highlight the importance of regular surveillance, particularly for patients with malignancies and hypertension. Our findings provide valuable insights for genetic counseling and clinical management, highlighting the multiple health risks associated with NF1 and the need for comprehensive and multidisciplinary care.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy and a major cause of blindness. RP is caused by several variants of multiple genes, and genetic diagnosis by identifying these variants is important for optimizing treatment and estimating patient prognosis. Next-generation sequencing (NGS), which is currently widely used for diagnosis, is considered useful but is known to have limitations in detecting copy number variations (CNVs). In this study, we re-evaluated CNVs in EYS, the main causative gene of RP, identified via NGS using multiplex ligation-dependent probe amplification (MLPA). CNVs were identified in NGS samples of eight patients. To identify potential CNVs, MLPA was also performed on samples from 42 patients who were undiagnosed by NGS but carried one of the five major pathogenic variants reported in Japanese EYS-RP cases. All suspected CNVs based on NGS data in the eight patients were confirmed via MLPA. CNVs were found in 2 of the 42 NGS-undiagnosed RP cases. Furthermore, results showed that 121 of the 661 patients with RP had EYS as the causative gene, and 8.3% (10/121 patients with EYS-RP) had CNVs. Although NGS using the CNV calling criteria utilized in this study failed to identify CNVs in two cases, no false-positive results were detected. Collectively, these findings suggest that NGS is useful for CNV detection during clinical diagnosis of RP.

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.