European Journal of Human Genetics最新文献

Black women in the UK experience disproportionately poor maternal outcomes yet remain underrepresented in research on prenatal screening and diagnostic genetic testing (prenatal testing). We therefore know little about how Black parents feel and what they understand about these tests. Using a cross-sectional online survey, we assessed attitudes towards prenatal tests, knowledge of genetic terms and prenatal tests, and mistrust amongst Black and mixed Black heritage parents in the UK who had been pregnant in the last five years. 110 parents completed the survey (95% female). Screening was valued by most (89%), although only half (50%) reported willingness to undergo invasive diagnostic testing. Preparing for a child with a genetic condition or disability were key motivators for testing, whilst opposition to termination and concerns about miscarriage risk drove refusal. Healthcare professionals (HCPs) were the main source of information when discussing prenatal testing, though mistrust in healthcare systems was high and associated with lower reported uptake of both screening and diagnostic tests. Nearly three-quarters valued speaking to an HCP who shared their ethnic background. Misconceptions about sickle cell were common, with 40% believing it affects only African and Caribbean populations. While most parents recognised the term 'DNA', only 28% understood the term 'genome'. Our findings highlight support for prenatal testing but reveal knowledge gaps and high mistrust that may undermine informed choice. Addressing misconceptions - particularly around sickle cell and available prenatal tests - alongside culturally responsive counselling and community-based education is essential to achieving equitable prenatal care for Black parents.

Newborn screening (NBS) is an effective measure of secondary prevention. The application of genomic sequencing in population-based screening would enable further expansions of the NBS disease panel and a genomic NBS (gNBS). The selection of NBS target diseases is still based on the Wilson and Jungner screening principles from 1968, which are considered incomplete, particularly for an extension towards gNBS. The present work aims to establish a multi-dimensional framework for future gNBS programs. An interdisciplinary expert panel comprising researchers from pediatric and adolescent medicine, human genetics, ethics, medical psychology, law, and patient representatives used a nominal group technique-like multi-stage consensus process to define criteria for gNBS, considering ethical, legal, and social implications, medical aspects, and patient perspectives. Overall, 18 criteria were developed, clustered into four subcategories: I. Clinical criteria (characteristics of the target disease); II. Diagnostic criteria (requirements of the test); III. Therapeutic-interventional criteria (prerequisites of the intervention); IV. Program management criteria (requirements of the program). Subcategories I-III define selection criteria for target diseases, subcategory IV defines criteria for how to establish and manage the program. In conclusion, this multi-dimensional framework serves as a well-balanced basis for developing thoroughly revised and internationally accepted consensus screening criteria.

Genetic practices are increasingly recognised as essential components of modern healthcare. Allied health professionals and nurses are ideally placed to initiate discussions about genetic investigations with patients and families. However, there are known barriers such as a lack of confidence and knowledge. A key step to addressing these barriers is identifying implementation strategies that support the integration of genetics across healthcare disciplines. We conducted a systematic review to identify empirical and conceptual implementation strategies to support genetic practices among allied health professionals and nurses. We searched CINAHL, Embase, Emcare, Medline, Scopus, and Web of Science for articles published from 2020. Twenty-eight full-text articles were included in the review. Identified implementation strategies were mapped to the Theoretical Domains Framework (TDF) to identify key areas for behaviour change. Empirical strategies, including workshops, online learning, case-based education, and leadership development, demonstrated positive effects on supporting genetic integration into clinical practice. Conceptual strategies identified included: (1) education/learning, (2) professional development, (3) policy, (4) evaluation tools, and (5) educational resources. The TDF domains of Knowledge, Social Influences, and Social/Professional Role and Identity were commonly found, while the TDF domains of Intentions, Reinforcement, Optimism, Emotion and Goals were underrepresented. Findings demonstrate that empirical and conceptual implementation strategies lack evaluation and tend to focus solely on commonly targeted domains. Future research is needed to investigate the feasibility and effectiveness of implementation strategies, explore the underrepresented domains, and support efforts to increase genetic literacy and practices among allied health professionals and nurses.

Germline variants in CTNNA1, encoding αE-catenin, have been implicated in hereditary diffuse gastric cancer (HDGC) and macular dystrophy patterned-2 (MDPT2). However, the functional mechanisms associated specifically with each molecular variant type underlying these distinct clinical outcomes remain poorly understood. Here, we established a humanized Drosophila melanogaster model conditionally targeting two distinct Drosophila tissues: the eye and the wing. We assessed the functional impact of eight CTNNA1 variants identified in 50 carrier families. We used tissue-specific RNAi and CRISPR/Cas9 to deplete endogenous Drosophila α-catenin (Dα-cat) and expressed either human wild-type (WT) or mutant αE-catenin (Hα-cat). We demonstrate that WT Hα-cat rescued Dα-cat loss, supporting conserved functionality across species. Hα-cat truncating variants failed to rescue epithelial architecture or viability and were associated with increased apoptosis, although one nonsense variant located in the CTNNA1 last exon exhibited milder phenotypes. Interestingly, while most missense variants behaved similarly to WT, p. Asn853Ser, in CTNNA1 last exon, exhibited partial functional loss and did not fully rescue apoptosis caused by Dcat expression loss. These results highlight variant-type and tissue-type specificities. This work provides a humanized Drosophila model for the CTNNA1 gene, which reveals variant-type and locus-specific impacts of CTNNA1 alterations, occurring either in HDGC or MDPT2 families. Our study highlights the value of in vivo functional modeling for clinical variant interpretation and supports improved classification and management strategies for CTNNA1 variant carriers.

Genomic sequencing has transformed the diagnostic approach for mitochondrial disease, yet integration into standard clinical practice is limited by access and funding. We conducted a post-implementation evaluation of genome sequencing (GS) for mitochondrial disease in Australia, which became publicly funded through the Medicare Benefits Scheme (MBS) in November 2023, to allow for broader access to testing. Test request data, including demographics, phenotypic information, and the diagnostic outcomes, were collected from November 2023 to May 2025 from the Victorian Clinical Genetics Services, the current laboratory provider of the MBS-funded service. Test uptake was 26% of predicted, with lower test rates in regional and remote areas. Over the first 19 months, 300 individuals suspected of mitochondrial disease underwent GS with a median turnaround time of 84 days (8 days-218 days). The diagnostic yield was 20%, with 56% of diagnoses in known mitochondrial disease genes. Of these, 70% (24 of 34) were in mitochondrial DNA. Seventeen diagnoses were in individuals who had prior non-diagnostic testing (exome sequencing or gene panel). We demonstrate that publicly-funded GS can deliver meaningful diagnostic outcomes for mitochondrial disease on a national scale. To maximise its impact, attention must now shift towards ensuring equitable access, particularly for regional and remote areas, and embedding sustainable mainstreaming models that support both genetic and non-genetic clinicians.

Genomic information collected in research settings is a valuable resource that can be shared for future (secondary) research with the consent of the individual. Whether individuals participating in genomic research are comfortable with broad consent and all research sharing scenarios is largely unknown. The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission) investigated the feasibility and acceptability of population reproductive carrier screening for severe recessive genetic conditions occurring in childhood. Enrolment and consent for participation was completed digitally using an online Portal or REDCap. Consent included an option to complete ten specific questions about preferences for future research use of samples and data. Preferences for future research were completed by 23.5% (4288) of individuals. The remaining 76.5% gave broad consent to data sharing. Those who chose to complete the questions shared similar demographics to the rest of the cohort. Individuals were most permissive of sharing with not-for-profit (78.0%) and university (78.2%) research organisations, for general (79.8%) and health / medical / biomedical research (82.2%). People were less likely to consent for use by governments (59.2%) and commercial organisations (33.7%). Nearly 60% of people want to be notified every time their data is shared. Updates to consent preferences were made 1785 times, by 282 people. This study supports the need for research programmes to facilitate flexible models of consent, including specific and dynamic consent. It also demonstrates a scalable model in which participant-led choices contribute to reduced ambiguity about data sharing permissions.

Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identical twin brothers presenting with spontaneous pneumothoraces in adulthood, leading to a diagnosis of Tatton-Brown-Rahman syndrome (TBRS), a DNMT3A-related overgrowth disorder not previously associated with pneumothorax. Both individuals exhibited tall stature, mild intellectual disability, hypermobility, and cardiac abnormalities. Whole genome sequencing identified a rare de novo DNMT3A missense variant (c.1585 G > A, p.D529N) absent from population databases and predicted to be damaging. Methylation profiling confirmed genome-wide hypomethylation consistent with impaired DNMT3A function, supporting pathogenicity. No variants were found in known familial pneumothorax genes. Apical blebs observed at surgery and connective tissue features suggest a mechanistic link between TBRS and pneumothorax, analogous to other monogenic connective tissue disorders. This case expands the phenotypic spectrum of TBRS and highlights the importance of genetic evaluation in familial pneumothorax. Diagnosis enables personalised care, including surveillance for extrapulmonary complications such as aortic root dilatation and haematological malignancy. Our findings suggest that TBRS should be considered in patients presenting with pneumothorax, tall stature, and neurodevelopmental features. Further cases are needed to confirm this association and refine clinical management strategies.

Large language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses, and their accuracy compared to existing diagnostic tools is not well characterized. To assess the current capabilities of LLMs to diagnose genetic diseases, we benchmarked these models on 5213 previously published case reports using the Phenopacket Schema, the Human Phenotype Ontology and Mondo disease ontology. Prompts generated from each phenopacket were sent to seven LLMs, including four generalist models and three LLMs specialized for medical applications. The same phenopackets were used as input to a widely used diagnostic tool, Exomiser, in phenotype-only mode. The best LLM ranked the correct diagnosis first in 23.6% of cases, whereas Exomiser did so in 35.5% of cases. While the performance of LLMs for supporting differential diagnosis has been improving, it has not reached the level of commonly used traditional bioinformatics tools. Future research is needed to determine the best approach to incorporate LLMs into diagnostic pipelines.

Genomic newborn screening (gNBS) provides the potential to offer significant health benefits. However, more evidence, including psychosocial impacts on parents, is needed before gNBS is ready for population-level implementation. The aim of this qualitative study was to explore parental experiences of receiving gNBS results from a prospective study, BabyScreen+. BabyScreen+ screened 1000 newborns for >600 genetic conditions that were early-onset, severe, and had management options available (prevention, surveillance or treatment). We interviewed parents three months after receiving their result. Interviews were analysed using reflexive thematic analysis, guided by Interpretive Description. Twenty-seven parents were interviewed, including nine who received a 'high chance' result for their newborn. Waiting for gNBS results was not unduly anxiety provoking. Low chance results provided psychosocial benefits including peace-of-mind and empowerment. Receiving a high chance result was unexpected and shocking, especially if the result was for a condition with significant treatment recommendations (e.g., transplantation). Psychosocial adaption to the subsequent diagnosis was an evolving process; access to genetic counselling, high-quality information and prompt referrals to specialists increased confidence in managing the condition and facilitated adaptation. All parents valued the high chance gNBS result given its clinical utility. The study provides support for gNBS by highlighting that it can provide valuable health information with minimal harms. Findings can be used to inform the implementation of population-scale gNBS.

Whole genome sequencing (WGS) has generated interest as a potential way to enhance and expand the scope of newborn screening (NBS) programs. The effective implementation of WGS in NBS programs relies on several factors, including parental perceptions. Young adults are potential future parents when WGS is expected to be fully implemented in NBS programs. Therefore, it is essential to understand their perspectives regarding the integration of WGS into NBS programs. Given that there is a dearth of studies in this topic, we explored the perceptions of young adults about the integration of WGS into NBS programs. We conducted semi-structured qualitative interviews with 58 young adults and used the content analysis to analyze the qualitative data. Our findings provide evidence that the majority of our study participants would choose to have their future newborns undergo WGS in NBS programs. The primary motivation for wanting to do so was that WGS would help them to seek out and take measures to prevent diseases for their children. However, some participants expressed concerns about receiving non-medically actionable WGS results. Our findings highlight the need for policymakers, healthcare providers, and researchers to carefully evaluate the type of WGS results returned to parents before integrating WGS into NBS programs.