European Journal of Human Genetics最新文献

{"title":"Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers.","authors":"Marie-Charlotte Villy, Youenn Drouet, Lise Larcher, Yoann Vial, Benjamin Dauriat, Léa Veyrune, Laurène Fenwarth, Marie-Mathilde Auboiroux, Lucie Freiman, Sophie Nambot, Léa Patay, Marjolaine Willems, Emma Lachaier, Bénédicte Bonte, Delphine Lebon, Mathis Lepage, Olivier Ingster, Nathalie Gachard, Thomas Cluzeau, Michael Loschi, Jean Soulier, Pascale Flandrin-Gresta, Pascal Turlure, Nicolas Duployez, Emmanuelle Clappier, Dominique Stoppa-Lyonnet, Christine Lasset, Chrystelle Colas, Marie Sebert","doi":"10.1038/s41431-025-01952-4","DOIUrl":"https://doi.org/10.1038/s41431-025-01952-4","url":null,"abstract":"<p><p>Monoallelic germline DDX41 pathogenic variants (PV) are responsible for the most frequent monogenic predisposition to myeloid neoplasms (MN), i.e., to myelodysplastic syndrome and acute myeloid leukemia. MN are rare clonal diseases affecting hematopoietic tissues, and curative approaches frequently implicate hematopoietic stem cell transplantation, requesting testing for relatives of DDX41-mutated MN patients. Establishing the penetrance of germline DDX41 PV is crucial to determine how to monitor the unaffected relatives who carry the familial DDX41 PV. Our study aims to assess the risk of MN in relatives of affected DDX41 carriers using the Genotype-Restricted-Likelihood (GRL) approach. We identified 63 families with probands carrying a germline DDX41 PV (ACMG class 4 or class 5 variant) affected with MN, from 11 French centers. One hundred and sixty relatives, including 73 males (46%), were genotyped at the median age of 51 [range: 15-84] years, 80 of them (50%) being carriers of the familial DDX41 PV. The cumulative risk of MN at 70 years for DDX41 PV carriers was estimated at 19.5% [95% CI: 5.8%-62.5%], corresponding to a relative risk compared to the general population of 55 [95% CI: 16.4-176.5]. This risk appeared higher in males, although the difference did not reach statistical significance. Based on these findings, we suggest yearly complete blood count from the age of 50 for DDX41 PV carriers. Of note, we observed cases before the age of 50 in females, which could suggest sex-differentiated monitoring.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225164","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":"Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders.","authors":"Tinatin Tkemladze, Christopher Campbell, Kakha Bregvadze, Eka Kvaratskhelia, Elene Abzianidze, Leigh Demain, Sarah Jenkinson, Sarah Hilton, Michael Levy, Jennifer Kerkhof, David Gokhale, Bekim Sadikovic, Siddharth Banka","doi":"10.1038/s41431-025-01939-1","DOIUrl":"https://doi.org/10.1038/s41431-025-01939-1","url":null,"abstract":"<p><p>DNA methylation (DNAm) episignature analysis is an emerging tool for diagnosing individuals with neurodevelopmental disorders, congenital anomalies, and growth disorders. We evaluated its clinical utility as a first-tier test in 62 individuals without prior molecular testing. DNAm arrays identified a diagnosis in 30.6% (19/62) of cases. The positivity rate was highest for Fragile X syndrome (100%, 5/5), followed by syndromic disorders (44%, 8/18) and imprinting disorders (25%, 6/24), including Silver-Russell, Beckwith-Wiedemann, and Prader-Willi syndromes. No diagnoses were made in 15 individuals with non-syndromic neurodevelopmental disorders. Alternative diagnoses were identified in 4.8% (3/62) of cases. These findings suggest that DNAm arrays can serve as an effective first-tier diagnostic tool, particularly for syndromic and imprinting disorders, with potential to improve diagnostic efficiency and reduce reliance on sequential genetic testing. While these findings support the use of DNAm arrays as an effective first-tier tool in selected populations, larger, unselected cohort studies are needed to validate its generalizability.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225082","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":"DNA methylation episignature for Smith-Magenis and Potocki-Lupski syndromes: a mirror perspective.","authors":"Liselot van der Laan, Karim Karimi, Kathleen Rooney, Mariëlle Alders, Alfredo Brusco, Amaia Lasa-Aranzasti, Nicola Brunetti-Pierri, Anna M Cueto-Gonzalez, Barbara R DuPont, Gerarda Cappuccio, Christele Dubourg, David Everman, Vincent Gatinois, Benjamin Ganne, David Genevieve, Giovanni Battista Ferrero, Marlies Kempers, Michael A Levy, Marcello Niceta, Antonio Novelli, Valeria Orlando, Sylvie Odent, Wesley G Patterson, Abeltje M Polstra, Tony Roscioli, Nathalie Ruiz-Pallares, Quentin Sabbagh, Slavica Trajkova, Marco Tartaglia, Matthew A Tedder, Annick Toutain, Udo Koehler, Irena Valenzuela, Johanna M van Hagen, Anne-Marie van der Kevie-Kersemaekers, Peter Henneman, Marcel M A M Mannens, Bekim Sadikovic, Mieke M van Haelst","doi":"10.1038/s41431-025-01956-0","DOIUrl":"https://doi.org/10.1038/s41431-025-01956-0","url":null,"abstract":"<p><p>Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal genomic disorders caused by deletions and duplications of the 17p11.2 chromosomal region, respectively. This study aimed to identify and validate DNA methylation episignatures specific to SMS and PTLS, and to investigate their reciprocal relationship and shared molecular features with other neurodevelopmental disorders. Genome-wide DNA methylation was analyzed in individuals with an SMS (n = 26) or PTLS (n = 27) phenotype associated with copy number variation, and SMS patients with RAI1 sequence variants using the Infinium EPIC array. Differentially methylated CpG sites were identified and used to develop support vector machine (SVM)-based classifiers, which demonstrated high sensitivity and specificity for both syndromes. The analysis revealed a mirror-like episignature, with SMS showing predominant hypomethylation and PTLS displaying hypermethylation at shared loci. Functional correlation with other neurodevelopmental disorders highlighted significant overlap with known episignatures, including those associated with MEF2C-related disorders. Notably, individuals with RAI1 sequence variants did not exhibit the same DNA methylation patterns, suggesting that the epigenetic alterations are primarily driven by copy number changes. These findings establish SMS and PTLS as distinct yet interconnected epigenetic entities, offering valuable diagnostic biomarkers and insights into the molecular pathophysiology of 17p11.2-associated neurodevelopmental disorders.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198821","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 implementation of polygenic risk scores.","authors":"E Roberts, N Flaum, D G Evans","doi":"10.1038/s41431-025-01931-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01931-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190955","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":"Uncertainty, ethics, and progress in genomic medicine","authors":"Seda Sinem Zonuzi","doi":"10.1038/s41431-025-01955-1","DOIUrl":"10.1038/s41431-025-01955-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1217-1218"},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01955-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181679","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":"N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder.","authors":"Asier Iturrate, Nurit Assia Batzir, Ranit Jaron, David Garcia-Valentin, Julian Nevado, Jair Tenorio-Castano, Pablo Lapunzina, Kamila Lee, Rotem Greenberg, Dvora Sassi, Sharon Aharoni, Alla Kuzminsky, Lina Basel-Salmon, Naama Orenstein, Yakov Fellig, Shay Ben-Shachar, Dina Marek-Yagel, Victor L Ruiz-Perez","doi":"10.1038/s41431-025-01944-4","DOIUrl":"https://doi.org/10.1038/s41431-025-01944-4","url":null,"abstract":"<p><p>Excitation-contraction (EC) coupling is an essential process for skeletal muscle function. Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of CACNB1 in the affected individuals from each family. CACNB1 encodes the β1 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca²⁺ channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all CACNB1 transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified CACNB1 variants was further validated by replicating one of them (c.85-1G>A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of β1 subunits, these cells displayed severely reduced protein levels of α1S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in CACNB1 cause a new congenital muscular disorder.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190927","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":"The importance of accurate phenotyping in large-scale analyses of common disorders such as hearing loss.","authors":"Morag A Lewis, Bradley A Schulte, Judy R Dubno, Karen P Steel","doi":"10.1038/s41431-025-01957-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01957-z","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) is a common, complex disease with high heritability, but its underlying genetic landscape remains unclear. Studying such a condition requires large cohorts, detailed genotyping, and deep phenotyping. However, while large cohorts with next-generation sequence data are becoming increasingly common, the challenge of administering audiometric tests at scale has meant that in-depth auditory phenotyping is rarely included. Here we present our analyses of three cohorts with different forms of phenotype data, which reveal the differences made by even small changes in phenotyping. Detailed audiometry enables interrogation of genetic data by auditory phenotypes, but if these data are not available, self-reports of hearing difficulty may also serve. However, relying on medical records alone is ineffective for classifying biobank participants for a common condition like ARHL, and is likely to result in many people being wrongly classified in the control group.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181762","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":"From screening to strategy: Clinical implications of COL4A3/COL4A4 variants found in reproductive genetic testing.","authors":"Gráinne Butler, David J Amor, Catherine Quinlan","doi":"10.1038/s41431-025-01953-3","DOIUrl":"https://doi.org/10.1038/s41431-025-01953-3","url":null,"abstract":"<p><p>Reproductive genetic carrier screening (RGCS) is expanding in both public and private healthcare. The primary aim is to identify carrier status for genetic disorders, inform reproductive decision making and promote reproductive autonomy. As screening panels have increased, the potential for findings with personal health implications rises. We report the prevalence of COL4A3/COL4A4 heterozygous variants within a population undergoing RGCS in a private setting and propose a comprehensive management plan for the ongoing care of this patient cohort. Acknowledging that comprehensive guidelines exist for genetic testing and management of Alport syndrome as a broad patient group, this communication seeks to highlight the increasingly common finding of autosomal dominant Alport syndrome and proposes accessible and practical strategies for the clinicians encountering these patients.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181918","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":"PKD1 5'UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development.","authors":"Laura Wedd, Yvonne Hort, Chirag Patel, John A Sayer, Rocio Rius, Andrew J Mallett, Denny L Cottle, Ian M Smyth, Timothy Furlong, John Shine, Amali Mallawaarachchi","doi":"10.1038/s41431-025-01949-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01949-z","url":null,"abstract":"<p><p>Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5'untranslated region (UTR). We then designed a PKD1 5'UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.-69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5'UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5'UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5'-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5'UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174183","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 heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy.","authors":"Liedewei Van de Vondel, Jonathan De Winter, Alice Monticelli, Natacha Camacho, Tine Deconinck, Katrien Janssens, Goedele Malfroid, Alicia Alonso-Jiménez, German Demidov, Steven Laurie, Willem De Ridder, Biljana Ermanoska, Vincent Timmerman, Jonathan Baets","doi":"10.1038/s41431-025-01938-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01938-2","url":null,"abstract":"<p><p>We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The deletion was detected through exome-sequencing based copy number variant (CNV) detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin. SPTAN1 loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role of SPTAN1 haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148261","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}