European Journal of Human Genetics最新文献_第6页

Clinical implementation of polygenic risk scores—updates on ancestry-adjusted PRS and their use in practice 多基因风险评分的临床应用——更新经血统调整的PRS及其在实践中的应用。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-31 DOI: 10.1038/s41431-026-02202-x

Eleanor Roberts, Nicola Flaum, D. Gareth Evans

引用次数: 0

Re: Clinical implementation of polygenic risk scores — equity metrics are needed before clinical translation 多基因风险评分的临床实施-临床转化前需要公平指标。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-31 DOI: 10.1038/s41431-026-02203-w

Laura Piñero-Roig

引用次数: 0

To screen or not to screen G6PD deficiency in gNBS: insights from the BabyDetect pilot and current evidence. 筛查或不筛查gNBS中G6PD缺乏症：来自BabyDetect试点和当前证据的见解

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-31 DOI: 10.1038/s41431-026-02204-9

Valerie Jacquemin, Kristine Hovhannesyan, Benoit Florkin, Tamara Dangouloff, François Boemer, Laurent Servais

{"title":"To screen or not to screen G6PD deficiency in gNBS: insights from the BabyDetect pilot and current evidence.","authors":"Valerie Jacquemin, Kristine Hovhannesyan, Benoit Florkin, Tamara Dangouloff, François Boemer, Laurent Servais","doi":"10.1038/s41431-026-02204-9","DOIUrl":"https://doi.org/10.1038/s41431-026-02204-9","url":null,"abstract":"As genomic newborn screening (gNBS) progresses toward broader implementation, questions arise regarding conditions to include on first-tier sequencing panels. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common monogenic disorder worldwide, is inconsistently screened in Europe despite its established role in neonatal hyperbilirubinemia and hemolytic crises. Using data from the Belgian BabyDetect pilot, one of the first European programs to include the evaluation of genomic and biochemical newborn screening in the same cohort, together with international evidence, we assessed the readiness of G6PD deficiency for inclusion in gNBS. In BabyDetect, genomic screening identified 94 newborns carrying pathogenic or likely pathogenic G6PD variants, including 17 neonates not detected by routine biochemical screening, demonstrating the complementary value of sequencing. However, identifying additional moderately deficient infants introduces uncertainty regarding penetrance, follow-up burden, healthcare impact and cost-effectiveness. Screening readiness was evaluated using an adapted NEXUS 2015 semi-quantitative framework, where G6PD deficiency scored 17/21, reflecting strong clinical benefit, high feasibility and ethical favorability, with moderate analytic validity, population impact, and evidence strength. Published economic modeling suggests the principal value of screening derives from reducing severe hyperbilirubinemia complications and later hemolytic crises, with additional benefits from improved pharmacovigilance and risk mitigation for subsequent siblings within affected families. Given the minimal marginal cost of adding G6PD to existing gNBS workflows, available evidence indicates that G6PD deficiency is well-suited for inclusion in gNBS when paired with confirmatory testing and proportionate, pediatric-led follow-up.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648468","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}

引用次数: 0

The co-design, development, and preliminary evaluation of a comprehensive breast cancer risk report incorporating polygenic risk information. 结合多基因风险信息的综合乳腺癌风险报告的共同设计、开发和初步评估。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-31 DOI: 10.1038/s41431-026-02180-0

Mia N Hanley, Rebecca Purvis, Sharne Limb, Sibel Saya, Adrian Bickerstaffe, Jack Wheeler, Yuhan Shen, Matilda Hilton, Minchen Dai, Edbert Liu, Rowan Forbes Shepherd, Paul A James, Laura E Forrest

{"title":"The co-design, development, and preliminary evaluation of a comprehensive breast cancer risk report incorporating polygenic risk information.","authors":"Mia N Hanley, Rebecca Purvis, Sharne Limb, Sibel Saya, Adrian Bickerstaffe, Jack Wheeler, Yuhan Shen, Matilda Hilton, Minchen Dai, Edbert Liu, Rowan Forbes Shepherd, Paul A James, Laura E Forrest","doi":"10.1038/s41431-026-02180-0","DOIUrl":"https://doi.org/10.1038/s41431-026-02180-0","url":null,"abstract":"The clinical implementation of polygenic risk scores (PGS) in comprehensive cancer risk assessments is imminent. The successful implementation relies on clear communication to consumers to facilitate understanding of personalised risk information and motivate cancer prevention behaviours. Development of provider- and consumer-friendly resources to aid communication and understanding of PGS results is a critical implementation task. This study aimed to produce an acceptable report for delivering comprehensive, PGS-informed breast cancer risk assessments in research and clinical settings. A two-phase, multi-methods research program was conducted, focusing on co-design with a broad group of interest holders to gather preferences and feedback on the content, layout and visual tools of a risk report. Phase 1 involved a literature review, a quantitative survey with consumers and qualitative interviews with consumers and medical practitioners to generate an initial prototype report. Phase 2 involved qualitative interviews with genetic counsellors to seek feedback about the prototype and refine it into a final version. The report was operationalised as a web-based application that generates personalised versions in PDF. The evidence-based, interest-holder-informed comprehensive breast cancer risk report produced is highly usable, able to support ongoing clinical implementation research on PGS across cancer use-cases and contexts. Future work should explore consumer evaluation of the report and the feasibility of interactive and digital delivery mechanisms.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648506","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}

引用次数: 0

BRCA1 and BRCA2 population screening in Latvia: feasibility, engagement, and early lessons from a pilot study. 拉脱维亚BRCA1和BRCA2人群筛查：可行性、参与和试点研究的早期经验教训

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-30 DOI: 10.1038/s41431-026-02191-x

Arvids Irmejs, Zanda Daneberga, Kristine Kiploka, Marta Augucevica, Anneta Cerneikina, Linda Gailite, Agate Kalcenaua, Ilva Kononova, Emil Syundyukov, Edvins Miklasevics, Cathrine Bjorvatn, Hildegunn Høberg Vetti, Janis Gardovskis

{"title":"BRCA1 and BRCA2 population screening in Latvia: feasibility, engagement, and early lessons from a pilot study.","authors":"Arvids Irmejs, Zanda Daneberga, Kristine Kiploka, Marta Augucevica, Anneta Cerneikina, Linda Gailite, Agate Kalcenaua, Ilva Kononova, Emil Syundyukov, Edvins Miklasevics, Cathrine Bjorvatn, Hildegunn Høberg Vetti, Janis Gardovskis","doi":"10.1038/s41431-026-02191-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02191-x","url":null,"abstract":"Pathogenic variants in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancer (HBOC) cases, and are associated with substantial morbidity, mortality, and economic burden. Population screening for BRCA1 and BRCA2 pathogenic variants (PVs) may enable cancer prevention and reduce downstream costs and mortality. The feasibility pilot of BRCA1 and BRCA2 PV population screening in Latvia was conducted among cancer-free females aged 25-59 years, using digital recruitment tools and saliva-based BRCA1 and BRCA2 gene NGS with CNV analysis. Psychological impact was assessed using PHQ-9 and GAD-7. After 3,438 email invitations and media campaigns, 536 participants provided samples. Eight PVs were identified, and all carriers reported at least one affected first-degree relative. PHQ-9 and GAD-7 scores showed no significant pre- and post-testing differences. Saliva-based population screening for BRCA1 and BRCA2 pathogenic variants is feasible in Latvia showing considerable (1.5%) frequency of PVs, acceptable psychological outcomes, but requires improved engagement strategies and equitable access pathways.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629858","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}

引用次数: 0

Beyond the sequence 超出序列

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-30 DOI: 10.1038/s41431-026-02194-8

Seda S. Zonuzi

引用次数: 0

PALM3 and hearing loss: a potential dual diagnosis interfering with novel gene discovery PALM3和听力损失：干扰新基因发现的潜在双重诊断。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-29 DOI: 10.1038/s41431-026-02206-7

Paria Najarzadeh Torbati, Lukas Hallbrucker, Michaela A. H. Hofrichter, Daniel Owrang, Jonas Setzke, Manfred W. Kilimann, Anahid Hemmatpour, Mohsen Rajati, Ehsan Ghayoor Karimiani, Thomas Haaf, Christian Vogl, Barbara Vona

{"title":"PALM3 and hearing loss: a potential dual diagnosis interfering with novel gene discovery","authors":"Paria Najarzadeh Torbati, Lukas Hallbrucker, Michaela A. H. Hofrichter, Daniel Owrang, Jonas Setzke, Manfred W. Kilimann, Anahid Hemmatpour, Mohsen Rajati, Ehsan Ghayoor Karimiani, Thomas Haaf, Christian Vogl, Barbara Vona","doi":"10.1038/s41431-026-02206-7","DOIUrl":"10.1038/s41431-026-02206-7","url":null,"abstract":"Hereditary hearing loss is highly genetically heterogeneous, with emerging overlap between genes implicated in early-onset and age-related hearing loss. We report a consanguineous family with autosomal recessive, non-syndromic hearing loss in which the proband harbors a homozygous splice-site variant in PALM3 NM_001145028.2:c.314+1G>A and a homozygous missense variant in OTOA NM_144672.4:c.1939G>C p.(Gly647Arg). A minigene assay for the PALM3 variant demonstrated aberrant splicing with exon skipping, resulting in either a frameshift or a large in-frame deletion, both consistent with loss of function and impacting all known transcripts. While the organ of Corti from 12-month-old heterozygous Palm3 mice showed preserved overall architecture, a study describing Palm3 knockout mice exhibit auditory dysfunction, supporting a possible auditory phenotype with loss of function. Although a dual molecular diagnosis cannot be excluded, the combined genetic, functional, and comparative data support PALM3 as a candidate gene potentially contributing to autosomal recessive hearing loss.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1585-1589"},"PeriodicalIF":4.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02206-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618987","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}

引用次数: 0

Lived experiences in rare genetic diseases: a narrative synthesis of 317 qualitative studies (2004-2024). 罕见遗传疾病的生活经历：317项定性研究的叙事综合（2004-2024）。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-29 DOI: 10.1038/s41431-026-02201-y

Marianne Gush, Shahida Moosa

{"title":"Lived experiences in rare genetic diseases: a narrative synthesis of 317 qualitative studies (2004-2024).","authors":"Marianne Gush, Shahida Moosa","doi":"10.1038/s41431-026-02201-y","DOIUrl":"https://doi.org/10.1038/s41431-026-02201-y","url":null,"abstract":"Rare genetic diseases (RDs), though individually uncommon, collectively impose a substantial global burden with significant social, emotional and economic implications. Understanding the lived experiences of RD patients, caregivers and service providers is essential to fully address the challenges they face. This study presents a narrative synthesis of original qualitative research on RDs published between 2004 and 2024, identifying 317 studies across multiple databases. Reflexive thematic analysis was used to synthesise and interpret the findings, allowing for an integrative understanding of both commonalities and disparities in experiences and research focus globally. While studies from Europe (45%) and North America (32%) dominated the field, markedly fewer included participants from Africa (3%), Asia (11%) and South America (2%), particularly from low- to middle-income countries. Across studies, recurring themes included navigating emotional resilience; the redefinition of identity in the face of RD; the social experience of illness; healthcare experiences, including access to and quality of healthcare services; the financial and logistical burden of care; the experience of research and new technologies; and the influence of society, culture and power structures. The pronounced underrepresentation of LMIC settings, persisting despite targeted search efforts, is itself a substantive finding, raising critical questions about where rare disease knowledge is produced and whose experiences are considered worthy of formal documentation. The synthesis underscores the urgent need for geographically inclusive, methodologically diverse and community-engaged approaches to qualitative RD research.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600725","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}

引用次数: 0

Characterizing ARID1B-related disorders and variants of uncertain significance using DNA methylation. 利用DNA甲基化表征arid1b相关疾病和不确定意义的变异。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-29 DOI: 10.1038/s41431-026-02199-3

Anthony Chen, Manav Jain, Danielle Baribeau, William T Gibson, Matthew A Deardorff, Fowzan S Alkuraya, Juan Dario Ortigoza-Escobar, Graeme Nimmo, Stephen W Scherer, Sanaa Choufani, Sarah J Goodman, Rosanna Weksberg

{"title":"Characterizing ARID1B-related disorders and variants of uncertain significance using DNA methylation.","authors":"Anthony Chen, Manav Jain, Danielle Baribeau, William T Gibson, Matthew A Deardorff, Fowzan S Alkuraya, Juan Dario Ortigoza-Escobar, Graeme Nimmo, Stephen W Scherer, Sanaa Choufani, Sarah J Goodman, Rosanna Weksberg","doi":"10.1038/s41431-026-02199-3","DOIUrl":"https://doi.org/10.1038/s41431-026-02199-3","url":null,"abstract":"Sequence variants in ARID1B, a subunit of the BRG1 (BRM)-associated factors (BAF) complex, are often challenging to classify clinically due to the broad phenotypic spectrum of ARID1B-related disorders (ARID1B-RD). Our previous work has shown that pathogenic variants in epigenetic regulatory genes are associated with DNA methylation (DNAm) signatures, which have proven diagnostic utility for variant classification. Given the role of ARID1B in chromatin remodeling, we profiled whole-blood DNAm for 22 individuals with ARID1B variants and 240 typically developing individuals using Illumina's Infinium EPIC array. We identified a unique DNAm signature for ARID1B-RD of 160 CpG sites (FDR < 0.05; Δβ > 5%) in six individuals with ARID1B-RD, validating this signature in two more individuals with ARID1B-RD and demonstrating its diagnostic utility by classifying 14 additional individuals with ARID1B variants. Collectively, our findings support the use of DNAm to clarify the interpretation of ARID1B variants, particularly missense and in-frame variants that are rarely reported and challenging to classify, as well as truncating variants in exons 1 and 3 that have been previously reported in unaffected individuals. Comparing the DNAm profiles of individuals with ARID1B-RD to individuals with other disorders of the BAF complex, we saw a spectrum of shared DNAm changes. The ARID1B-RD DNAm signature was able to distinguish the DNAm profiles of individuals with pathogenic variants in ARID1B from those with pathogenic variants in SMARCA2, ARID1A, and ATRX. However, it was not able to distinguish between individuals with pathogenic variants in ARID1B and SMARCB1.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148619043","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}

引用次数: 0

Bridging the gap: integrating hereditary cancer into precision oncology 弥合差距：将遗传性癌症纳入精准肿瘤学。

IF 4.6 2区生物学

European Journal of Human Genetics Pub Date : 2026-07-28 DOI: 10.1038/s41431-026-02196-6

Alejandra Rezqallah, Mara Cruellas, Judith Balmaña

{"title":"Bridging the gap: integrating hereditary cancer into precision oncology","authors":"Alejandra Rezqallah, Mara Cruellas, Judith Balmaña","doi":"10.1038/s41431-026-02196-6","DOIUrl":"10.1038/s41431-026-02196-6","url":null,"abstract":"Advances in next-generation sequencing have expanded the identification of hereditary cancer patients, which account for approximately 10% of all cancer diagnoses. Precision medicine has profoundly reshaped the landscape of oncology, particularly in the management of hereditary cancer syndromes, through the convergence of germline genetics and targeted therapeutics. Disruption of homologous recombination repair genes such as BRCA1/2 and PALB2 confers synthetic lethal sensitivity to Poly ADP-ribose polymerase inhibitors and combination strategies targeting replication stress or cell-cycle checkpoints. Mismatch repair deficiency results in microsatellite instability and an increased neoantigen load, enabling durable responses to immune checkpoint blockade and supporting organ-preserving approaches in selected localized settings. Germline VHL inactivation induces a constitutive pseudohypoxic state that can be therapeutically exploited with HIF2α inhibitors in von Hippel–Lindau–associated neoplasms, illustrating interception of a lineage-agnostic metabolic axis. Activating germline RET pathogenic variants in hereditary medullary thyroid carcinoma demonstrate how highly selective kinase inhibitors can achieve superior efficacy–toxicity profiles compared with earlier multikinase agents. In patients with neurofibromatosis type 1, dysfunction of the neurofibromin GTPase-activating protein leads to RAS pathway hyperactivation, defining a rational therapeutic target. This evolving paradigm underscores the expanding role of germline testing beyond individuals with strong personal or family histories of cancer. Timely and equitable access to genetic results is essential to ensure that patients benefit from precision therapies without unnecessary delays. This review provides an integrative framework for bridging hereditary cancer and precision oncology.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 9","pages":"1210-1224"},"PeriodicalIF":4.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600746","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}

引用次数: 0