Human Genetics最新文献

{"title":"High frequency of mosaic NF2-related schwannomatosis diagnosed after somatic analysis of multi-nodular schwannomas in schwannomatosis patients.","authors":"Matthieu Peyre, Cécile Barbance, Suzanne Tran, Laurence Pacot, Benoît Terris, Michel Kalamarides, Béatrice Parfait","doi":"10.1007/s00439-026-02825-6","DOIUrl":"10.1007/s00439-026-02825-6","url":null,"abstract":"<p><p>Following the recent introduction of molecular diagnosis criteria for schwannomatosis, we decided to study the results of somatic molecular testing in patients with a tumor burden suggestive of non-NF2-related Schwannomatosis, with a particular focus on patients harboring multi-nodular schwannomas. We selected 22 patients harboring multiple peripheral nerve schwannomas, with or without associated lumbar schwannomas after a brain and spine MRI workup ruling out cranial nerve schwannomas, meningiomas and ependymomas. For each patient, at least 2 separate anatomically distinct tumor nodules were available for analysis. We distinguished mono-nodular from multi-nodular tumors and performed targeted sequencing of the NF2, SMARCB1 and LZTR1 genes for all tumors and germline DNA when available. We analyzed 69 tumor nodules in 22 patients, 19 of whom had a non-familial disease. Most patients (54%) had a diffuse schwannomatosis. Following germline and somatic genetic analysis, 11 patients were diagnosed with LZTR1-related schwannomatosis (50%), 3 patients with possible LZTR1- or SMARCB1-related Schwannomatosis (14%), 7 patients with mosaic NF2-related Schwannomatosis (32%), and 1 patient with 22q-related schwannomatosis (4%). Patients with multi-nodular schwannomas (n = 9), all with a non-familial disease, harbored a mosaic NF2-related Schwannomatosis in a majority of cases (5/9; 55%; p = 0.02), while patients with mononodular schwannomas harbored more frequently a LZTR1-related Schwannomatosis (9/13; 69%; p = 0.03). This study illustrates the underestimated high frequency of mosaic NF2-related schwannomatosis in patients harboring multi-nodular peripheral nerve schwannomas. As multi-nodular schwannomas are associated with higher surgical morbidity, the pivotal role of the NF2 gene in their tumorigenesis opens perspectives for Schwannomatosis research.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147456811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics workforce views on automating genomic reanalysis: trust, equity and governance.","authors":"Emily A King, Fiona Lynch, Zornitza Stark, Danya F Vears","doi":"10.1007/s00439-026-02824-7","DOIUrl":"10.1007/s00439-026-02824-7","url":null,"abstract":"<p><p>Automation of genomic data reanalysis can increase diagnostic rates in a timely and cost-effective manner. However, implementing automated reanalysis brings with it both ethical and practical challenges. We sought to explore how clinical and laboratory staff view these challenges as part of a broader study piloting automated genomic reanalysis. Focus groups were conducted with 21 genetics health professionals recruited from a previous survey and purposively sampled from clinical genetics diagnostics services and laboratories. Participants were supportive of automating reanalysis but discussed trust and accuracy, and emphasized the need for transparency, updated phenotypic information and human checking in an automated model. Legal versus moral obligation to return results when patients are unable to be recontacted was extensively discussed. Participants held concerns about a potential legal obligation to return results arising as reanalysis becomes routine and potential for impacts on workflow. A centralized system with national governance was proposed to ensure development and implementation of an equitable service and facilitate communication between patients and genetics services. However, this may be limited by existing infrastructure and the public’s perception of government services. In conclusion, participants in this study supported automated reanalysis, however issues regarding transparency, trust and accuracy will need to be systematically addressed to support implementation.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147354824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the public's intention to adopt CRISPR-Cas9: the effect of beliefs, knowledge, and innovativeness.","authors":"Jasmine Melamed, Sivia Barnoy","doi":"10.1007/s00439-026-02822-9","DOIUrl":"10.1007/s00439-026-02822-9","url":null,"abstract":"<p><p>CRISPR-Cas9 is a gene editing technology with wide-ranging medical potential and significant ethical implications. This study examined how personality traits, familiarity with CRISPR, knowledge about CRISPR, and beliefs concerning its applications are connected to the public’s willingness to adopt this technology, drawing on Rogers’ Diffusion of Innovations framework. A sample of 500 young adults aged 20–45 completed questionnaires assessing innovativeness as well as familiarity, knowledge, beliefs, and willingness to adopt CRISPR-Cas9 for therapeutic and non-therapeutic purposes. Results showed that only 24% of participants were familiar with CRISPR and that knowledge levels were generally low. Based on Rogers’ typology, 18.8% were identified as innovators, and 26.8% as early adopters, and only 3.2% as laggards. Beliefs were strongly associated with willingness to adopt CRISPR-Cas9 (r = .63, p < .001), moderating the weak associations of personality traits with adoption intentions. These findings suggest that beliefs are an important factor in CRISPR-Cas9 adoption and they appear to have more influence on willingness to adopt CRISPR-Cas9 than knowledge and innovativeness in this sample. Efforts to promote informed public discussion on CRISPR should be made, with an emphasis on ethical aspects alongside scientific information. This is critical for the responsible adoption of this technology.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher mitochondrial DNA methylation is associated with increased risk of stroke: a nested case-control study.","authors":"Xueru Fu, Yuewan Fang, Yujie Zhao, Bin Yang, Yaqin Su, Li Yang, Weifeng Huo, Liuding Wen, Yuying Wu, Yang Zhao, Fulan Hu, Ming Zhang, Hongwei Wen, Lei Yin, Dongsheng Hu, Chuande Chen","doi":"10.1007/s00439-026-02823-8","DOIUrl":"10.1007/s00439-026-02823-8","url":null,"abstract":"<p><p>Aberrant mitochondrial DNA (mtDNA) methylation has been implicated in stroke-related mechanisms such as oxidative stress and inflammation, but its association with risk of stroke remains unclear. This nested case-control study aimed to prospectively investigate the impact of mtDNA methylation on risk of stroke. A total of 343 stroke patients and 343 sex- and age-matched controls were included. Targeted bisulfite sequencing assessed methylation at 45 CpG sites in the COX1, COX2, COX3, and ATP6 regions. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between mtDNA methylation and risk of stroke. Wilcoxon rank-sum test was conducted to initially explore the possible factor influencing mtDNA methylation levels in the controls. After Bonferroni correction, methylation levels at 17 CpG sites within the COX1, COX2, COX3, and ATP6 regions were shown to be significantly higher in stroke patients than in controls, with ORs ranging approximately from 1.05 to 2.31. Higher average methylation levels in the COX1, COX2, COX3, and ATP6 regions were significantly associated with increased risk of stroke, with corresponding ORs (95% CIs) of 1.27 (1.04–1.55), 1.75 (1.18–2.59), 1.64 (1.34–2.00), and 1.22 (1.04–1.43). Sex-stratified analyses revealed that these associations were predominantly present in women, with sex acting as a significant effect modifier of the relationship between mtDNA methylation and stroke risk across multiple CpG sites (P interaction < 0.05). In addition, higher methylation levels were observed in men, individuals aged ≥ 65, smokers, non-hypertensive cases, and those with low physical activity. Overall, our findings suggest that higher methylation levels in COX1, COX2, COX3, and ATP6 were associated with an increased risk of stroke, particularly among women, suggesting that mtDNA methylation may serve as the potential biomarker for stroke risk stratification and prevention.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A homozygous synonymous variant in SMG5, encoding a nonsense-mediated mRNA decay factor, causes developmental delay with growth retardation and relative macrocephaly.","authors":"Debora Tibbe, Tess Holling, Michael Spohn, Malik Alawi, Sheela Nampoothiri, Kerstin Kutsche","doi":"10.1007/s00439-025-02813-2","DOIUrl":"10.1007/s00439-025-02813-2","url":null,"abstract":"<p><p>The nonsense-mediated mRNA decay (NMD) pathway is a translation-dependent mechanism that maintains cellular RNA homeostasis by eliminating mRNAs containing a premature termination codon (PTC). NMD also targets ~ 15% of all physiological coding and non-coding spliced transcripts, thereby playing a significant role in shaping the cellular transcriptome. SMG5 is one of several NMD effector proteins required for the cleavage of mRNAs. In a female patient with craniofacial dysmorphism, developmental delay, severe growth retardation, and relative macrocephaly, we identified the homozygous synonymous variant c.2967G > A; p.Gln989 = in SMG5, affecting the last base of the penultimate exon. In patient fibroblasts, most of the SMG5 pre-mRNAs were aberrantly spliced, while a small proportion of canonically spliced SMG5 transcripts was found. Levels of SMG5 were reduced to ~ 25%. We identified a significant increase in the total protein amount and the size of the cell, Golgi apparatus, and nucleus in patient-derived fibroblasts. Cell proliferation was compromised, and the cell cycle was delayed. Patient fibroblasts showed global transcriptional dysregulation, with genes involved in nucleosome assembly and organization being upregulated and downregulated genes associated with differentiation, development, and morphogenesis. We found a global upregulation of NMD-sensitive transcripts, including a significant and experimentally validated increase in the relative abundance of naturally occurring PTC-containing transcripts of the splicing factor genes SRSF2, SRSF4, SRSF6, and SF3B3 in the patient’s fibroblasts. Together, our findings indicate that the homozygous synonymous SMG5 variant c.2967G > A acts as a hypomorphic allele, associated with mild inhibition of the NMD pathway and underlying the patient’s phenotype.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147305221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical characteristics and genetic variant spectrum of 27 patients with coagulation factor XI deficiency.","authors":"Juan Ren, Yalin Yu, Duanyang Wang, Shuai Fang, Xiuhua Chen, Lixia Hao, Jiaoyu Zhao, Lei Wang, Linhua Yang, Gang Wang","doi":"10.1007/s00439-026-02819-4","DOIUrl":"10.1007/s00439-026-02819-4","url":null,"abstract":"<p><p>Hereditary factor XI (FXI) deficiency is a rare bleeding disorder characterized by diminished plasma FXI activity (FXI: C) due to F11 gene mutations. Clinical manifestations are often asymptomatic or involve mild-to-moderate bleeding, typically occurring after trauma or surgery involving tissue with high fibrinolytic activity. The molecular basis of FXI deficiency is widely heterogeneous across different populations. This study aimed to characterize the spectrum of clinical features and the underlying genetic landscape of this disorder in a cohort of Han Chinese individuals from Shanxi province. We investigated the clinical characteristics and underlying molecular variants in 27 unrelated patients with FXI deficiency, who exhibited significantly low FXI: C levels (median, 4 [< 2–31.6]%), with 21 having severe deficiency (FXI: C, < 2–13.5%) and 6 having partial deficiency (FXI: C, 20.9–31.6%). Most patients presented for coagulation abnormalities found during laboratory testing. Twenty patients were asymptomatic, and seven exhibited minor bleeding manifestations. Genetic variants were identified by direct sequencing. Genetic analysis revealed 19 cases with compound heterozygous variants, one with a homozygous variant, and seven with heterozygous variants. A total of 23 different variants were detected, including six novel variants (three missense variants, two deletion variants and one nonsense variant). Bioinformatic analysis predicted that these novel variants could impair the function and structure of the FXI protein. To investigate the pathogenic mechanisms of the three novel missense variants, we performed in vitro cellular experiments, which demonstrated that these variants resulted in reduced FXI: C. In conclusion, coagulation factor XI deficiency exhibits high heterogeneity in clinical presentation and genetic variation.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in NR6A1 as a cause for congenital renal, vertebral and uterine anomalies.","authors":"Adeline Jacquinet, Lydie Flasse, Manon Dohet, Romane Vanhaeren, Hélène Pendeville, Carol Saunders, Anna Lehman, Catherine Pienkowski, Karine Morcel, Daniel Guerrier, Vincent Bours, Bernard Peers","doi":"10.1007/s00439-025-02806-1","DOIUrl":"10.1007/s00439-025-02806-1","url":null,"abstract":"<p><p>The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants in NR6A1. The variant spectrum includes two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis. In vitro studies demonstrated partial loss-of-function for both missense variants. To investigate the role of NR6A1 in development, CRISPR-Cas9 zebrafish mutants for the orthologs nr6a1a and nr6a1b were generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior hox genes. This study provides strong evidence linking NR6A1 heterozygous deleterious variants to renal, uterine and costovertebral defects in humans.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Horizon: CNV interpretation through rapid automated ACMG-aligned pathogenicity analysis.","authors":"Mariam Eldesouky, Suhana Shiyas, Amirul Islam, Md Nahid Hasan, Md Tanvir Hossain, Hosneara Akter, Md Saiful, Bakhrom K Berdiev, Wolfgang M Kuebler, Proton Rahman, Marc Woodbury-Smith, Syed M Hasan, Mohammed Uddin, Nasna Nassir","doi":"10.1007/s00439-026-02821-w","DOIUrl":"10.1007/s00439-026-02821-w","url":null,"abstract":"<p><p>Our study assesses the Horizon model, a novel CNV classification tool developed in line with American College of Medical Genetics (ACMG) guidelines, to enhance the classification of pathogenicity in CNVs. Horizon utilizes a ranking-based algorithm, incorporating multiple proprietary databases and variant inheritance models as per ACMG standards. The model’s effectiveness was verified through Area Under the Curve (AUC) analyses on three datasets comprising 635 pathogenic inherited or de novo variants, as classified by clinical geneticists and several established tools. Horizon achieved an AUC of 0.96 (accuracy: 0.9611) in the discovery cohort, demonstrating high accuracy in CNV interpretation and proficiency in predicting pathogenicity. We observed an AUC of 0.96 (accuracy: 0.8776) in the de novo variant cohort and an overall AUC of 0.93 across all cohorts, surpassing tools like ClassifyCNV (AUC: 0.81),AnnotSV (AUC: 0.85), and ISV-CNV (AUC: 0.84). It showed particular effectiveness in interpreting duplication CNVs and the highest performance for CNVs sized 3–5 Mb. The Horizon model offers robust and accurate CNV interpretation, outperforming existing tools and aligning closely with clinical evaluations. Its comprehensive approach, integrating a range of genomic features and following ACMG guidelines, makes it a crucial tool in the genomic interpretation landscape, facilitating the rapid and accurate diagnosis of genetic disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"23"},"PeriodicalIF":3.4,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiscore, a gene ranker powered by artificial intelligence and real-world clinical data, shows high sensitivity for the molecular diagnosis of Mendelian disorders in nearly 10,000 exomes and genomes.","authors":"Vincent D Ustach, Maria J Guillen Sacoto, Stephen McGee, Vladimir G Gainullin, Kevin Arvai, Amber Begtrup, Flavia M Facio, Matthew Greenberg, Hákon Guðbjartsson, Kirsty McWalter, Francisca Millán, Kristin Monaghan, Kyle Retterer, Gabriele Richard, Nadav Topaz, Rebecca Torene, Britt Johnson, Timothy Laurent","doi":"10.1007/s00439-025-02797-z","DOIUrl":"10.1007/s00439-025-02797-z","url":null,"abstract":"<p><p>A challenge for clinical exome and genome sequencing (ES/GS) analysis is correlating the clinical presentation of the cases being tested with known gene-phenotype associations (GPAs). We developed Multiscore, a gene prioritization tool, to facilitate gene-level predictions of phenotypic fit. Multiscore combines data inputs and algorithms to generate similarity subscores that feed a random forest (RF) classifier trained to predict the probability of association between the patient’s clinical features and the gene. The reference GPAs are extracted from: (1) OMIM, (2) patient descriptions in the literature, and (3) GeneDx (GDx) clinical data. We used 9,989 ES/GS cases to assess performance of the tool in combination with genotype filtering. Genotype filters rendered an average of 173 genes with variants requiring clinical review. Multiscore prioritized the reported positive gene with a median rank of 3 and mean rank of 6.35. The average recall (sensitivity) of Multiscore was 33% in the top 1, 69% in the top 5, 83% in the top 10, and 93% in the top 20 ranked genes. Multiscore was able to handle non-exact HPO term matches allowing the use of real-world clinical data. 74 genes lacking OMIM entries were prioritized using only the GDx and literature datasets. Multiscore allows the phenotype review to prioritize the most relevant genes, increasing case throughput and broadening access to diagnoses for patients.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"22"},"PeriodicalIF":3.4,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12909342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reasons for and against presymptomatic genetic testing in frontotemporal dementia: a qualitative study.","authors":"Charlotte H Graafland, Harro Seelaar, Jessica L Panman, John C van Swieten, Eline M Bunnik, Laura Donker Kaat","doi":"10.1007/s00439-025-02795-1","DOIUrl":"10.1007/s00439-025-02795-1","url":null,"abstract":"<p><p>The majority of individuals at 50% risk of carrying a pathogenic variant causing frontotemporal dementia (FTD) chooses not to undergo presymptomatic genetic testing. To explore reasons of individuals at risk of genetic FTD for and against genetic testing, we conducted a secondary analysis of semi-structured interviews with 28 Dutch individuals at risk of genetic FTD: 11 carriers, three non-carriers and 14 individuals at 50% risk. We analyzed the data using inductive thematic analysis. Reasons in favor of presymptomatic genetic testing included wanting to know and relieving uncertainty, hoping to test negative, relevance for life planning, reproductive decision-making, explaining future symptoms, and contributing to the common good. Reasons against presymptomatic genetic testing were fearing psychological impact, fearing effects on employment, insurability or mortgage, maintaining hope, and no immediate relevance for life planning, partly due to uncertainty surrounding age of onset. Reasons were similar in all groups, but were weighed differently. Decision-making processes were influenced by (expectations of) psychological burden before and after testing, personal experiences with FTD in the family, and whether genetic status was perceived as actionable. Perceived relevance was partly influenced by age (in relation to age of onset), life circumstances and research participation. When supporting individuals at risk of FTD in decision-making regarding genetic testing, genetic counselors should be aware of and tailor counseling to the individual’s age and lived experience with being at risk, experiences with FTD and related disorders in the family, and factors influencing the perceived relevance of genetic status for reproductive or life decision-making.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"21"},"PeriodicalIF":3.4,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12909385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}