European Journal of Human Genetics最新文献

Europe's Beating Cancer Plan is a substantial European Union (EU) investment into cancer prevention and treatment. Integration of genetic services towards personalised cancer prevention and care is a flagship of this plan. Genetic counselling is critical to this integration, facilitating informed patient decision making and improved clinical management. However, growing demands for genetic testing and concurrently increasing workforce shortages necessitate new strategies to equitably ensure sustainable access to counselling across the EU. This project aimed to inform future European activities by identifying priority European strategies for addressing common European genetic literacy, workforce, and reimbursement barriers to genetic counselling in cancer noted in prior work. A Delphi survey was conducted, with genetics, oncology, and patient stakeholders invited from all EU Member States. The response rate was 62% (124 total invitations). Over three phases, 77 participants - 28 geneticists; 14 oncologists; 18 genetic counsellors; 16 patient representatives; 1 otherwise qualified expert - rated 19 strategies according to their Importance, Urgency, and Feasibility and selected their top three priority strategies. Five strategies met pre-defined consensus thresholds and received a clear plurality of priority ratings: (1) EU-wide genetic counsellor recognition; (2) Including genetics expertise in oncology guideline creation; (3) Shared EU genetic counsellor registration/education with legal weight; (4) Mandatory counselling reimbursement when clinical guidelines are met; (5) Mandatory inclusion of genetics in oncology fellowship/continuing education. Results provide a roadmap of European actions which promise to sustainably improve access to genetic counselling in cancer care. Upcoming and ongoing EU projects promise to advance their implementation.

Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the RNF213 gene has been implicated as a susceptibility factor for MMD, the precise genetic basis of the disease remains elusive. This study aimed to investigate other genetic factors contributing to differences in disease manifestation and vascular phenotypes. We conducted whole-exome sequencing of patients with RNF213-related vasculopathy and healthy controls. In total, 122 patients (comprising 69 with bilateral MMD, 13 with unilateral MMD, and 40 with intracranial artery stenosis [ICAS]) and 458 controls were enrolled. Following appropriate quality control measures, case-control analysis and in-case analysis (bilateral MMD vs. unilateral MMD and ICAS) were conducted using single-variant association testing and gene-based aggregation testing. Although no significant locus or gene was found in the case-control analysis, the PKHD1 gene emerged as a top candidate associated with bilateral MMD in the in-case analysis. Two rare damaging variants, p.Ile2364Asn and p.Ser3210Cys, were significantly more prevalent in the bilateral MMD group and were further validated in an independent cohort of 216 individuals. Publicly available single-cell transcriptome data of mouse cerebrovascular and perivascular cells revealed that Pkhd1 expression was significantly higher in specific endothelial-cell clusters. Despite some limitations, our study provides new insights into the potential role of the PKHD1 gene in bilateral MMD, highlighting the need for further investigation of endothelial gene expression in patients with RNF213 and PKHD1 mutations.

Newborn screening (NBS) aims to identify rare but treatable conditions in newborns to offer early interventions. The possibilities of genomic sequencing are being researched to further strengthen NBS. This scoping review explores public and parent perspectives on genomic sequencing in NBS. We performed a literature search in Embase and Psych-abs databases to find relevant articles from 2005 until August 2024. Twenty-seven articles describing 20 studies from 7 countries were included, mostly describing survey studies. The public and parents reported a positive interest in genomic sequencing in NBS, but were overall more willing to participate in standard NBS compared to genomic NBS. Respondents' perceived benefits of genomic NBS included increased health gain for newborns, preparedness for parents and their child, enabling family planning, and benefits for other family members and population health. Most perceived concerns related to the storage and privacy of genomic sequencing data, fear of insurance discrimination, and psychological worries as a result of genomic sequencing test results. Articles reported limited public concerns regarding test accuracy or the possibility of receiving uncertain results. Preferences on how genomic sequencing should be offered were mentioned regarding decision-making and informed consent, result delivery, data storage, and program offer and costs. In conclusion, the public and parents seem generally supportive of genomic sequencing in NBS. However, to uphold support and participation comparable with current NBS programs, arguments and beliefs of the public and parents should be further explored if genomic sequencing is to be successfully implemented into or alongside NBS programs.

The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognized ClinPGx website. Nevertheless, except for a few indications, the implementation of PGx in clinical practice currently remains limited in most countries. At the same time, whole genome sequencing (WGS) is increasingly applied in clinical diagnostics, particularly for rare and oncological diseases. These data could also be used for simultaneous PGx analysis. In a retrospective study, we analysed short-read WGS data from 1,000 individuals, including index patients with suspected rare disorders and their relatives. For a subset of 359 individuals, medical reports were reviewed to document drug prescriptions. Guidelines published by PGx consortia on ClinPGx were used for phenotype assignment and interpretation. Clinically relevant PGx variants were detected in 97% (n = 970) of the cohort. Among patients with drug prescriptions (n = 359), 30% (n = 111) had been prescribed at least one medication for which their PGx profile would recommend therapy adjustment. Additionally, CNVs and rare variants were detected, which in 28% (n = 8) resulted in modified therapeutic recommendations. While the most (cost)-efficient strategy for broad PGx implementation remains subject of future research, our findings demonstrate that existing WGS data, such as those generated in the context of rare disease patients, could provide substantial benefits for PGx diagnostics with minimal additional effort.

Insights into the perspectives, decision-making and experiences of non-US consumers regarding health-related direct-to-consumer genetic testing (DTC-GT) are currently lacking. These insights are essential to allow the implementation of consumer-tailored approaches that facilitate responsible use of DTC-GT. To fill this knowledge gap, the present study employed interviews to examine the consumer journeys of twenty Dutch health-related DTC-GT consumers. Overall, participants appeared quite satisfied with their DTC-GT consumer journeys. Participants' initial contacts with DTC-GT, as well as their pre-test information acquisition, occurred via a diversity of sources. Participants' pre-test expectations revealed considerable presumed clinical utility of DTC-GT. Feeling unheard within the regular healthcare system supported multiple participants' decisions to undergo health-related DTC-GT. Participants mentioned a modifying effect of price on their decision-making, and several participants stated not having considered potential negative consequences of DTC-GT prior to DTC-GT usage. Several potentially adverse consequences of undergoing DTC-GT were identified that could affect individual consumers, the regular healthcare system, and society as a whole. Three considerations to potentially stimulate responsible use of DTC-GT aligning with participants' needs and preferences were derived, namely improving pre-test information provision, implementing adequate post-test support systems for consumers, and development, implementation and enforcement of cross-border regulation and legislation. Based on these findings, we advocate for stakeholder discussions to further explore the feasibility and desirability of translating these considerations into deliverables. Ultimately, these deliverables could aid in empowering (potential) consumers for responsible use of health-related DTC-GT.

Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32. So far, CFNDS has only been described in four living individuals and one terminated fetus from four families, and the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies. We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause. Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of CCDC32. This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq. Furthermore, we review the clinical phenotype of this rare disorder and its potential disease mechanisms.

Observational epidemiology suggests a link between the dermatological disorder acne vulgaris and several psychiatric disorders. However, the biological mechanisms that underlie the relationship between acne and mental health are poorly characterised. Here, we employed a genetic approach using large-scale genome-wide association studies of acne and ten psychiatric disorders to both estimate causal effects and uncover potential shared genetic risk factors. Multiple psychiatric disorders displayed evidence of small-to-moderate genetic correlations with acne. However, only genetic liability to schizophrenia displayed some evidence of a causal effect on the risk of acne, though horizontal pleiotropy cannot be fully excluded. Using a Gaussian mixture-model based approach, we then identified a cluster of schizophrenia-associated variants with distinct effects on acne liability, refining the molecular mechanisms that may link schizophrenia and acne. Shared genetic risk architecture between schizophrenia and acne was also investigated using Bayesian approaches. This revealed a subset of genetic loci associated with both acne and schizophrenia via shared or different causal variants, implicating biological processes including glutamatergic signalling. Finally, we found that genetic risk for schizophrenia was also associated with increased acne severity using a population-based cohort. In summary, we revealed genetic support for a biological relationship between acne and schizophrenia that may at least partially drive the elevated rates of acne amongst people living with schizophrenia.

Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with intensive surveillance to facilitate early cancer detection. However, participating in diagnostic imaging and endoscopy surveillance programs is often time-consuming, overwhelming, inconvenient, and anxiety-inducing. To improve this, multi-cancer early detection tests are being developed using cell-free DNA (cfDNA) sequencing analysis to detect cancers with more sensitivity than conventional screening methods. Our community (the CHARM consortium: Cell-free DNA in Hereditary And high-Risk Malignancies) has been exploring the use of cfDNA sequencing in hereditary cancer, and has launched the CHARM2 prospective randomized controlled trial, which is enrolling 1000 participants with Hereditary Breast and Ovarian Cancer, Lynch syndrome, Li-Fraumeni syndrome, Neurofibromatosis type 1 and Hereditary Diffuse Gastric Cancer to improve equitable access, early detection and surveillance for high-risk individuals. All participants will have screening as per conventional syndrome-specific surveillance recommendations. Half the participants (experimental cohort) will also have cfDNA analysis at least three times a year, with abnormal results triggering dedicated clinical imaging and diagnostic evaluation, and heightened surveillance. Vetted by our patient advisors, validated patient-reported outcome and experience measures assessing participant psychosocial outcomes, engagement, and test preferences will be administered to both arms. Our goal is to inform if and how cfDNA analysis could be implemented into routine clinical care and offer a path to equitable and more convenient cancer screening for all high-risk Canadians.

Pancreatic ductal adenocarcinoma occur in the context of a suspected or proven genetic predisposition in 5-10% of cases. While universal germline multigene panel testing is currently recommended by NCCN and ASCO, this approach was previously limited to patients with personal and/or family criteria suggestive of hereditary predisposition. We report the results of this « selective » approach applied in our institution from January 2018 to June 2023. Germline testing of a panel of 13 « clinically actionable » genes (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D, STK11) was performed in 496 patients with pancreatic ductal adenocarcinoma and suspected genetic predisposition based on the validation of prespecified clinical criteria. A germline pathogenic/likely pathogenic variant of one of these genes was identified in 49 patients corresponding to 9.9% of the study population. ATM and BRCA2 were the two most frequently implicated genes (18 and 16 cases, respectively) and the prevalence of pathogenic/likely pathogenic variants of these genes was significantly higher than in gnomAD controls. The overall contribution of core and non-core genes of the Homologous Recombination DNA repair system was 83.7% while the contribution of the Mismatch Repair system was 10.2%. An exploratory approach consisting of unmasking the results of the NGS analysis of 123 « research » genes involved in the carcinogenesis was applied to the 447 patients tested negative for the different genes of our diagnostic panel. This approach failed to identify other susceptibility genes to pancreatic adenocarcinoma.