European Journal of Human Genetics最新文献

{"title":"Novel start codon variant in the 5'UTR of LDLR associated with familial hypercholesterolaemia.","authors":"Martin Bird, Chris Jyun-Peng Tung, Alan M Pittman, Elijah R Behr, Axel Nohturfft, Marta Futema","doi":"10.1038/s41431-025-01893-y","DOIUrl":"https://doi.org/10.1038/s41431-025-01893-y","url":null,"abstract":"<p><p>Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706870","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":"Reassessment of variants of uncertain significance in tumor suppressor genes using new ClinGen PP1/PP4 criteria guidance.","authors":"Young-Gon Kim, Changhee Ha, Ja-Hyun Jang, Mi-Ae Jang, Jong-Won Kim","doi":"10.1038/s41431-025-01911-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01911-z","url":null,"abstract":"<p><p>Recently, new clinical genome resource (ClinGen) guidance focusing on cosegregation (PP1) and phenotype-specificity criteria (PP4) were introduced, based on the observation that the phenotype specificity could provide greater level of pathogenicity evidence. This study aimed to reassess variants of uncertain significance (VUS) found in tumor suppressor genes with specific phenotypes using these new recommendations. We retrieved VUS from an in-house database of all germline variants detected using sequencing since 2008. Patients carrying VUS from seven target tumor suppressor genes, NF1, TSC1, TSC2, RB1, PTCH1, STK11, and FH, were selected and the pathogenicity of each variant was reassessed using the new ClinGen PP1/PP4 criteria. In total, 128 unique VUS from 145 carriers were evaluated. Initial classification using the classic PP1/PP4 criteria from ACMG/AMP and point-based classification resulted in 21 variants being reclassified (2 pathogenic variants, 3 likely pathogenic variants [LPVs], 15 likely benign variants, and 1 benign variant), leaving 101 VUS. Applying the new ClinGen PP1/PP4 criteria, 32 (31.4%) remaining VUS were reclassified as LPVs. The reclassification rate was highest in STK11 (88.9%). Representative cases highlighted successful reclassification owing to highly specific phenotypes aligned with the new criteria. The new ClinGen PP1/PP4 criteria significantly improved the reclassification of VUS in tumor suppressor genes associated with specific phenotypes. The new criteria could substantially enhance the accuracy of variant classification.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697924","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 new multisystem ERCC1-hepatorenal syndrome: insights from a clinical cohort, molecular pathogenesis, and management guidelines.","authors":"Susan M White, Annelotte P Wondergem, Isa Breet, Maren Dittmaier, Katrina Bell, Christopher M Richmond, Winita Hardikar, Kanika Bhatia, Catherine Quinlan, David Orchard, Areetha D'Souza, Walter J Chazin, Christopher Smith, Rebecca Sparkes, Simon Lam, Alexandra Carter, Robert J Hopkin, Leticia Khendek, Bonnie R Sullivan, Naja Becher, Anne Katrine W Simonsen, Helene Kvistgaard, Katherine Dempsey, Alexander G Miethke, Pernille Axél Gregersen, Eliza Phillips, Martijn S Luijsterburg","doi":"10.1038/s41431-025-01910-0","DOIUrl":"https://doi.org/10.1038/s41431-025-01910-0","url":null,"abstract":"<p><p>DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667477","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":"Comment on \"Determining a role for Patient and Public Involvement and Engagement (PPIE) in genomic data governance for cancer care.\"","authors":"Clara Fabian-Therond","doi":"10.1038/s41431-025-01908-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01908-8","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667478","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":"Uncovering genetic diversity and admixture of British Africans with HLA alleles inferred from whole genome sequencing.","authors":"Yunjia Liu, Ze Meng, Indra Adrianto, Albert M Levin, Qing-Sheng Mi, Qiang Wang, Hongsheng Gui","doi":"10.1038/s41431-025-01888-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01888-9","url":null,"abstract":"<p><p>The human leukocyte antigen (HLA) region is highly diverse and plays a crucial role in immune regulation and antigen presentation. Accurate HLA typing is essential for understanding disease susceptibility, transplantation compatibility, and pharmacogenetics. However, its application in African descent populations is challenging due to complex linkage disequilibrium patterns and the lack of ancestry-matched populations in HLA reference panels. Here, we leveraged the latest whole-genome sequencing (WGS) data from UK Biobank African individuals to perform better HLA genotyping, and further utilized allelic and haplotypic data to explore population genetics patterns of this region. With WGS-inferred HLA alleles, we identified specific admixture patterns (predominant West and East African and minor European ancestries) within British African population, revealing their complex evolutionary history. Not only did we reveal the genetic diversity within this population, but also highlighted its differences from African Americans, ancestral Africans, and other global populations. We further identified regional ancestry differences in the HLA genomic region, highlighting discordance between global and local admixture estimates. British Africans also presented unique HLA frequency distributions for both typical and disease-associated alleles or haplotypes. These findings emphasize the need for expanding African-specific HLA reference panel and prove better HLA typing can be achieved by coupling sequencing technologies with computational approaches. The HLA genetic characteristics observed in British Africans provide valuable insights into population-specific immune responses and susceptibility. Overall, this study advances our understanding of HLA diversity and genetic admixture in British African population, with important implications for both disease mechanism and clinical utility.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648896","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":"Implications of monogenic bicuspid aortic valve (BAV) forms among sporadic BAV patients.","authors":"Christopher M H Bruenger, Frank Oeffner, Laura L Koebbe, Sebastian Zimmer, Verena Veulemans, Matti Adam, Jessica Bigge, Stefanie Heilmann-Heimbach, Malte Kelm, Stephan Baldus, Markus M Nöthen, Georg Nickenig, Carlo Maj, Baravan Al-Kassou, Johannes Schumacher","doi":"10.1038/s41431-025-01909-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01909-7","url":null,"abstract":"<p><p>Bicuspid aortic valve (BAV) represents the most common congenital heart defect and is genetically heterogeneous. While the majority of cases results from common risk variants that confer disease cumulatively, a small proportion of BAV cases has a monogenic etiology where penetrant rare variants (RVs) in single genes are disease causing. We assessed the proportion of monogenic BAV cases in 740 non-syndromic and non-familial BAV patients that should be representative for cardiovascular centers of maximum care. We used next generation sequencing- (NGS-) based single-molecule molecular inversion probes (smMIPs) and analyzed all monogenic BAV genes that have been identified so far (NOTCH1, SMAD6, ROBO4, GATA4, GATA6, and ADAMTS19). In these genes, we identified potential damaging RVs in 2% of our patients, which were not significantly enriched compared to 726 population-based controls. We conclude that the contribution of monogenic BAV forms is only small among non-syndromic and sporadic BAV patients.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616904","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":"Revising the reproductive story: psychosocial and reproductive impacts 12 months after reproductive genetic carrier screening.","authors":"Erin Tutty, Belinda J McClaren, Sharon Lewis, Kristine Barlow-Stewart, Tiffany Boughtwood, Jade Caruana, Jane L Halliday, Edwin P Kirk, Nigel G Laing, John Massie, Martin B Delatycki, Alison D Archibald","doi":"10.1038/s41431-025-01903-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01903-z","url":null,"abstract":"<p><p>The responsible implementation of reproductive genetic carrier screening (RGCS) involves understanding the long-term psychosocial and reproductive impacts of results. This mixed-methods study examined these impacts within 'Mackenzie's Mission', an Australia-wide study that offered couple-based RGCS for >1280 genes to 10,000 reproductive couples. Data from participant surveys completed at enrolment and 12 months post-result were analysed. Participants with an increased chance result were interviewed. Reflexive thematic analysis, guided by Interpretive Description was used. 4948 participants (27% response) completed the 12 month post-result survey. Most had minimal decision regret (median ≤5, 0 = no regret, 100 = high regret) and high reproductive confidence. Participants found to have an increased chance result had elevated anxiety (n = 116, median = 39 out of 80, clinically meaningful is ≥40). Interviewees (N = 19, from 16 couples) felt their increased chance result \"change[d] everything\" about their reproductive plans. Although revising their reproductive plan was an emotionally complex \"journey\", participants were \"grateful\" for the information. The concept of the 'Reproductive Story', was used to interpret the results. A reproductive story refers to a person's expected narrative about parenthood that, if altered, can cause psychosocial distress. Receiving an increased chance result disrupts the reproductive story. By 12 months post-result, most people with an increased chance result felt empowered to revise their reproductive story, but anxiety was elevated. Findings suggest a need for longitudinal models of post-RGCS psychosocial support.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599839","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":"Vertical inheritance and unique differential phenotypes of reciprocal recombinant chromosome 18 within a multi-generation family.","authors":"Ting Wen, Gulsen Akay, Janice Palumbos, Betsy Ostrander, Denise I Quigley, Allen N Lamb, Erica F Andersen, Bo Hong, David Viskochil","doi":"10.1038/s41431-025-01878-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01878-x","url":null,"abstract":"<p><p>Carriers of balanced pericentric inversions are at risk for producing unbalanced gametes because of meiotic recombination resulting in de novo deletion and duplication of distal chromosome ends. Recombinant chromosomes generally lead to significant imbalances resulting in anomalous clinical phenotypes in offspring, hence they are typically not inherited. Therefore, the vertical transmission of recombinant chromosomes is a clinically rare event. Using genomic microarray and karyotyping, we describe inheritance of recombinant chromosomes in a three-generation family with the grandmother carrying a mosaic pericentric inversion of chromosome 18. Three children inherited the balanced inversion and one child with a mild phenotype inherited a de novo recombinant chromosome 18. In the third generation, a newborn with a variant of holoprosencephaly inherited an unmodified recombinant chromosome from her mother. Despite having the same karyotype predicting loss of the TGIF1 gene from the 18p terminus, the mother exhibits a relatively unaffected phenotype. The cousin of the child with holoprosencephaly carries the reciprocal recombinant chromosome 18 with a much milder phenotype. We verified the cytogenetic mechanism and corresponding clinical phenotypes in affected individuals and illustrated possible recombinant chromosome consequences of the inversion of chromosome 18 in this three-generation family.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590795","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":"Interrupted CTG repeats in the 37-43 units size range in the 3'UTR of DMPK are common alleles.","authors":"Hilde Swinkels, Maike Leferink, Maartje Pennings, Bart van der Sanden, Christian Gilissen, Jordi Corominas Galbany, Erik-Jan Kamsteeg","doi":"10.1038/s41431-025-01907-9","DOIUrl":"10.1038/s41431-025-01907-9","url":null,"abstract":"<p><p>The size of non-pathogenic CTG repeats in the 3'UTR of the DMPK gene varies from 5-35, whereas repeats over 50 units are pathogenic. The Intermediate repeats of 36-50 are considered 'premutation', as they are present in individuals unaffected by myotonic dystrophy, but are prone to further enlargement into the pathogenic range upon transmission to offspring. In this study, we showed that CCGCTG interrupted intermediate repeats, in the repeat size of 37-43 units, have been detected in multiple families with a history of myotonic dystrophy. However, segregation and microsatellite marker analysis of these interrupted intermediate alleles revealed that these alleles are not the same alleles (haplotypes) that were found expanded in affected family members. In contrast to the pure intermediate alleles, the CCGCTG intermediate repeats within families did not show intergenerational variability in size. Furthermore, we showed that the CCGCTG interrupted intermediate alleles have an allele frequency of approximately 0.35% in the general population, while CCGCTG interruptions were not detected in pathogenic repeat expansions over 50 repeat units in our control cohort. We postulate that intermediate repeats of size 37-43 having CCGCTG interruptions are not prone to further expansion, and therefore not act as premutations, which has great relevance for individuals with these alleles and has implications for genetic counseling and testing.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583464","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":"Estimating the use of biological samples in Finnish biobanks and hospital collections.","authors":"Aaro Tupasela, Tom Southerington, Johanna Mäkelä, Lila Kallio, Merja Perälä, Veli-Matti Kosma, Arto Mannermaa, Tiina Jokela, Kimmo Pitkänen, Mika Kontro, Tiina Vesterinen, Eero Punkka, Theresa Knopp, Minna Ruddock, Raisa Serpi, Anne-Mari Moilanen, Leena Viiri, Sanna Siltanen, Enni Makkonen, Päivi Ingalsuo","doi":"10.1038/s41431-025-01906-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01906-w","url":null,"abstract":"<p><p>Finland has steadily developed its biobanking infrastructures since the early 2010s. This article presents a systematic overview of the number of biological samples that have been provided for research since 2013 when the Finnish Biobank Act came into force. Using data from individual biobanks and from permits issued by Fimea (formerly Valvira), we present the most up-to-date and complete account of sample use at a national level. Between 2014 and 2023 a total of 1,474,881 samples were provided through 998 sample requests. A better understanding of the use of biological samples at the national level can help highlight the important impact biobanking has as an infrastructure for supporting research. We argue that developing standards can help in developing national biobanking strategies and identify areas where biobanking can be further developed. We also conclude that the ability to combine tissue samples and health data flexibly and efficiently is essential and needs to be secured also within the context of the European Health Data Space (EHDS).</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567302","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}