Large language models (LLMs) are generating interest in medical settings. For example, LLMs can respond coherently to medical queries by providing plausible differential diagnoses based on clinical notes. However, there are many questions to explore, such as evaluating differences between open- and closed-source LLMs as well as LLM performance on queries from both medical and non-medical users. In this study, we assessed multiple LLMs, including Llama-2-chat, Vicuna, Medllama2, Bard/Gemini, Claude, ChatGPT3.5, and ChatGPT-4, as well as non-LLM approaches (Google search and Phenomizer) regarding their ability to identify genetic conditions from textbook-like clinician questions and their corresponding layperson translations related to 63 genetic conditions. For open-source LLMs, larger models were more accurate than smaller LLMs: 7b, 13b, and larger than 33b parameter models obtained accuracy ranges from 21%-49%, 41%-51%, and 54%-68%, respectively. Closed-source LLMs outperformed open-source LLMs, with ChatGPT-4 performing best (89%-90%). Three of 11 LLMs and Google search had significant performance gaps between clinician and layperson prompts. We also evaluated how in-context prompting and keyword removal affected open-source LLM performance. Models were provided with 2 types of in-context prompts: list-type prompts, which improved LLM performance, and definition-type prompts, which did not. We further analyzed removal of rare terms from descriptions, which decreased accuracy for 5 of 7 evaluated LLMs. Finally, we observed much lower performance with real individuals\' descriptions; LLMs answered these questions with a maximum 21% accuracy.

This manuscript reviewed the state of the art about the teaching and training of human resources for genetics and genomics in Brazil. We presented the national scenario of teaching genetics in medical undergraduate and other health courses. We discussed the training of medical geneticists through medical residency and addressed the training in genetics of physicians from specialties other than genetics. We examined the training of health professionals specializing in genetics through lato sensu and stricto sensu postgraduate programs and presented the proposals for multi-professional residency in genetic counseling and genetics and genomics that are currently the subject of discussion in the country. Finally, we highlighted the importance of training primary health care professionals concerning genetics and genomics for the effective establishment of a line of care for individuals with genetic disorders in the Brazilian Unified Health System. Therefore, we provided a thorough overview of how genetics is (or is not) incorporated into professional training in a comprehensive public healthcare system such as the Brazilian.

Children with severe inflammatory diseases are challenging to diagnose and treat, and the etiology of disease often remains unexplained. Here we present DIAPH1 deficiency as an unexpected genetic finding in a child with fatal inflammatory bowel disease who also displayed complex neurological and developmental phenotypes. Bi-allelic mutations of DIAPH1 were first described in patients with a severe neurological phenotype including microcephaly, intellectual disability, seizures, and blindness. Recent findings have expanded the clinical phenotype of DIAPH1 deficiency to include severe susceptibility to infections, placing this monogenic disease amongst the etiologies of inborn errors of immunity. Immune phenotypes in DIAPH1 deficiency are largely driven aberrant lymphocyte activation, particularly the failure to form an effective immune synapse in T cells. We present the case of a child with a novel homozygous deletion in DIAPH1, leading to a premature truncation in the Lasso domain of the protein. Unlike other cases of DIAPH1 deficiency, this patient did not have seizures or lung infections. Her major immune-related clinical symptoms were inflammation and enteropathy, diarrhea and failure to thrive. This patient did not show T or B cell lymphopenia but did have dramatically reduced naïve CD4+ and CD8+ T cells, expanded CD4-CD8- T cells, and elevated IgE. Similar to other cases of DIAPH1 deficiency, this patient had non-hematological phenotypes including microcephaly, developmental delay, and impaired vision. This patient\'s symptSoms of immune dysregulation were not successfully controlled and were ultimately fatal. This case expands the clinical spectrum of DIAPH1 deficiency and reveals that autoimmune or inflammatory enteropathy may be the most prominent immunological manifestation of disease.

BACKGROUND: Understanding genetics is crucial for medical students, particularly in Saudi Arabia, where genetic disorders are prevalent owing to high rates of consanguineous marriages. This knowledge is essential for the early detection, prevention, and management of genetic disorders, and for incorporating medical genetics and genomics into patient care. This study aimed to assess the current state of genetics knowledge among medical students and interns across Saudi Arabia and to identify knowledge gaps in genetics.
METHODS: A cross-sectional study was conducted between August and September 2023 involving 732 medical students from all regions of Saudi Arabia. The participants completed a validated questionnaire assessing their knowledge of basic genetics, genetic inheritance, genetic testing, and clinical genetics.
RESULTS: Over 60% of medical students and interns reported that they considered themselves to have only slight knowledge in all areas of genetics. The results revealed a general lack of medical genetic understanding among students and interns, particularly regarding genetic inheritance and testing. For genetic inheritance, slight knowledge was found in 65.2% of pre-clinical, 60.1% of clinical, and 53.2% of interns, with significant differences between groups (p < 0.001). In genetic testing, 75.4% of pre-clinical, 83.9% of clinical, and 90.6% of interns showed slight knowledge, with significant differences across stages (p = 0.021). This study also found that lectures, genetics laboratories, and problem-solving sessions were the preferred resources for learning genetics.
CONCLUSIONS: The current study revealed a notable deficiency in the understanding of medical genetics among medical students and interns in Saudi Arabia, particularly regarding genetic inheritance and testing. This is consistent with previous research highlighting the widespread lack of genetics knowledge among medical students. Integrating more comprehensive genetics education, especially during the clinical years, could improve students\' preparedness and confidence in managing genetic disorders. These findings highlight the critical need for curriculum development to equip future physicians with the essential skills for managing genetic disorders.

BACKGROUND: Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.
METHODS: Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father\'s unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.
RESULTS: The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.
CONCLUSIONS: This is the first report linking UXS1 to short-limbed short stature in humans.

Between 2016 and 2018, interviews with 33 persons were conducted about the history of human genetics in Germany between 1970 and the 2000s. 29 interviewees gave consent to have the interviews used for historical research. These interviews are currently being analysed with the methods of qualitative content analysis and grounded theory. The focus of this article lies on the critical examination of the method of oral history and its application to human genetics. The oral history project focuses on questions regarding (1) biographical data and careers of interviewees, (2) development and application of diagnostic and therapeutic techniques, (3) establishment and growth of institutions of human genetics and (4) social debates regarding the discipline.

Historians have repeatedly pointed to personal and institutional continuities between eugenics in Germany before 1945 and the developing human genetics in post-war Germany. But how was this external perception discussed among German human geneticists and did it play a role in the discipline\'s self-image? On the basis of printed sources and biographical interviews, the historical consciousness and the assumption of historical responsibility among German human geneticists active in the field between the 1970s and the 2010s were investigated. In the memories of the contemporary witnesses, historical awareness played a role for their discipline even before the 1980s, and since the founding of the Deutsche Gesellschaft für Humangenetik in 1987, the question of the form of showing historical responsibility has been discussed repeatedly. It has been expressed, for example, in discussions with the public and renaming of prizes.

Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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With the rapid development of multimedia technology, the student centered flipped classroom model (FCM) and massive open online courses (MOOCs) have been increasingly introduced and implemented in higher medical education. However, comparative analyses of the offline face-to-face FCM and completely online FCM have been rarely reported. In this study, we focused specifically on a set of flipped classrooms in which prerecorded videos were provided before class. Using the Zhihuishu platform as the major online course platform, our team built a MOOC and evaluated the teaching effectiveness of the FCM in both the offline face-to-face class and the online electronic live class for medical genetics education. Questionnaires, paper-based and oral exams were used to collect data on the teaching effects of the different teaching methods. We found that student satisfaction and overall student performance in the offline FCM group was significantly higher than that in the completely online teaching group. Although online FCM allowed students to play back and review anywhere and anytime after class, students taught in offline FCM had a significantly higher degree of knowledge mastery, had a deeper understanding of theoretical knowledge, and were better at knowledge comprehensive application. The effects of their training on genetic disease clinical diagnosis and treatment skills were significantly better, and their capacity for scientific research was also significantly improved. Our research discussed the advantages of the online courses and the problems brought about by using these technologies, and it provided insight into online teaching practices in the era of internet-based medical education.