European Journal of Human Genetics最新文献

{"title":"EMD missense variant causes X-linked isolated dilated cardiomyopathy with myocardial emerin deficiency.","authors":"Linda Bulmer, Charlotta Ljungman, Johan Hallin, Pia Dahlberg, Christian L Polte, Carola Hedberg-Oldfors, Anders Oldfors, Anders Gummesson","doi":"10.1038/s41431-025-01827-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01827-8","url":null,"abstract":"<p><p>Pathogenic variants in the EMD gene cause X-linked Emery-Dreifuss muscular dystrophy type 1 (EDMD1), typically presenting with joint contractures and skeletal muscle atrophy, followed by atrial arrhythmias, cardiac conduction defects, and atrial dilatation. Although an association with isolated dilated cardiomyopathy (DCM) has been suggested, evidence is currently insufficient to verify the gene-disease association. We investigated the causality of a missense variant, c.23C>G, p.Ser8Trp, in EMD in a large family with a history of DCM and suspected sudden cardiac death (SCD) in males. DCM was diagnosed in six hemizygous males aged 36-50 and detailed phenotyping identified end-stage heart failure, cardiac conduction defects, and ventricular arrhythmias as prominent features. Cardiac magnetic resonance imaging showed late gadolinium enhancement with mixed ischemic and non-ischemic patterns. Muscular dystrophy was absent in all six males, of whom five underwent neuromuscular examination including serum-creatine kinase measurement. Immunohistochemical analysis showed greatly reduced levels of emerin in both cardiac and skeletal muscle samples. The EMD variant c.23C>G co-segregated with DCM, with an estimated LOD score of 3.9 and full-likelihood Bayes factor of >2500:1 in favor of causality. Among the 17 heterozygous females, ages 20-87, one developed DCM at age 72. We concluded that the EMD c.23C>G missense variant is associated with DCM in the absence of muscular dystrophy, thereby providing new evidence of isolated DCM as a distinct cardiac EMD-phenotype, separate from EDMD1. The phenotypic similarities with LMNA-DCM, with a high risk of cardiac conduction defects and ventricular arrhythmias, might warrant early interventions to prevent SCD.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596605","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":"Assessing the prevalence of unmet need for genetic counseling in Canada and exploring associations with sociodemographic factors.","authors":"Kennedy Borle, Jehannine Austin, Larry D Lynd","doi":"10.1038/s41431-025-01812-1","DOIUrl":"https://doi.org/10.1038/s41431-025-01812-1","url":null,"abstract":"<p><p>Understanding the prevalence and distribution of unmet need for genetic counseling (GC) can help inform health human resource planning. It is known that not all patients who could benefit from GC are currently accessing it, however, the prevalence of unmet need in Canada is unknown. Using a cross-sectional design, we surveyed 1160 Canadians to estimate the prevalence and distribution of unmet need for GC. The survey included measures of unmet need (NSGC Pathways Tool), personal utility (PrU), capability (ICECAP-A), distrust in healthcare (Revised Health Care System Distrust Scale) and demographic variables. A market research company (Leger Opinion Panel) was used for recruitment. We used descriptive statistics to estimate prevalence and multivariable regression to explore factors associated with unmet need. We found that 39% of respondents (457/1160) had unmet need for GC and 68% of this unmet need was unperceived. In the multivariable regression analysis, unmet need for GC was more likely in individuals who: had a mental health condition, were younger ( <math><mo>≤</mo></math> 45 yo), reported higher personal utility, and lower levels of capability (all p < 0.05 in multivariable analysis). There is a high prevalence of unmet need for GC in Canada and individuals experiencing other challenges to accessing healthcare may also be more likely to have unmet need for GC.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596540","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":"Spring in EJHG","authors":"Alisdair McNeill","doi":"10.1038/s41431-025-01828-7","DOIUrl":"10.1038/s41431-025-01828-7","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"259-260"},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01828-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583674","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":"Correction: Profound hypotonia in an infant with δ-aminolevulinic acid dehydratase deficient porphyria.","authors":"Alexis N Roach, Hannah Barkley, Carissa Rodriquez, T Andrew Burrow, Karl E Anderson, Ankita Shukla","doi":"10.1038/s41431-025-01804-1","DOIUrl":"10.1038/s41431-025-01804-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596595","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":"Building a hereditary cancer program in Colombia: analysis of germline pathogenic and likely pathogenic variants spectrum in a high-risk cohort.","authors":"María Carolina Sanabria-Salas, Ana Lucía Rivera-Herrera, María Carolina Manotas, Gonzalo Guevara, Ana Milena Gómez, Vilma Medina, Sandra Tapiero, Antonio Huertas, Marcela Nuñez, Miguel Zamir Torres, Julián Riaño-Moreno, Rafael Parra-Medina, Juan Carlos Mejía, Luis G Carvajal-Carmona","doi":"10.1038/s41431-025-01807-y","DOIUrl":"https://doi.org/10.1038/s41431-025-01807-y","url":null,"abstract":"<p><p>Genetic studies in Latin America have expanded, but further efforts are needed to understand cancer susceptibility genes beyond BRCA1 and BRCA2, especially by characterizing the prevalence and spectrum of pathogenic or likely pathogenic variants (PVs) in the region. This study aimed to determine the frequency of hereditary cancer syndromes (HCS) in Colombians with solid tumors and to characterize the spectrum of PVs. Using data from the Colombia's largest Institutional Hereditary Cancer Program, we included patients aged ≥18 years with solid tumors who met HCS criteria and were offered genetic testing with a 105-cancer gene panel. We calculated the prevalence of PVs and HCS by cancer type (beyond breast) and gene. For patients with breast cancer, we examined genotype-phenotype correlations with molecular subtypes and stratified positivity rates by different genetic testing criteria. Among 769 patients, we identified 216 PVs in 43 genes in 197 patients (26%). Thirty-three PVs were recurrent. Autosomal HCS was found in 21% (160/769) of patients (159 dominant, one recessive), while 5% (37/769) were heterozygous carriers of PVs in autosomal recessive genes. In 42% (321/769) of the cases, only one or more variants of uncertain significance (VUS) were identified, whereas 33% (251/769) had neither PVs nor VUS detected (negative results). HCS prevalence varied by cancer type (11-26%). The triple-negative subtype and bilateral presentation were strong predictors of inherited breast cancer. Our study reveals a significant presence of PVs among high-risk Colombian patients with solid tumors, underscoring the importance of genetic counseling and testing in the region.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596585","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":"Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis.","authors":"Diana M Cornejo-Sanchez, Thashi Bharadwaj, Rui Dong, Gao T Wang, Isabelle Schrauwen, Andrew T DeWan, Suzanne M Leal","doi":"10.1038/s41431-025-01789-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01789-x","url":null,"abstract":"<p><p>Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585068","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":"ARID2-related disorder: further delineation of the clinical phenotype of 27 novel individuals and description of an epigenetic signature.","authors":"Clara Houdayer, Kathleen Rooney, Liselot van der Laan, Céline Bris, Mariëlle Alders, Angela Bahr, Giulia Barcia, Clarisse Battault, Anais Begemann, Dominique Bonneau, Antoine Bonnevalle, Aicha Boughalem, Alice Bourges, Marie Bournez, Ange-Line Bruel, Daniela Buhas, Floriane Carallis, Benjamin Cogné, Valérie Cormier-Daire, Julian Delanne, Tanguy Demaret, Anne-Sophie Denommé-Pichon, Julie Désir, Christèle Dubourg, Mélanie Fradin, David Geneviève, Himanshu Goel, Alice Goldenberg, Karen W Gripp, Agnès Guichet, Anne Guimier, Adeline Jacquinet, Boris Keren, Louis Legoff, Michael A Levy, Haley McConkey, Bryce A Mendelsohn, Cyril Mignot, Vincent Milon, Mathilde Nizon, Beatrice Oneda, Laurent Pasquier, Olivier Patat, Christophe Philippe, Vincent Procaccio, Rebecca Procopio, Clément Prouteau, Thomas Rambaud, Anita Rauch, Raissa Relator, Sophie Rondeau, Gijs W E Santen, Jennifer Schleit, Arthur Sorlin, Katharina Steindl, Matt Tedder, Marine Tessarech, Frédéric Tran Mau-Them, Detlef Trost, Pleuntje J Van der Sluijs, Marie Vincent, Sandra Whalen, Christel Thauvin-Robinet, Bertrand Isidor, Bekim Sadikovic, Antonio Vitobello, Estelle Colin","doi":"10.1038/s41431-025-01798-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01798-w","url":null,"abstract":"<p><p>Rare genetic variants in ARID2 are responsible for a recently described neurodevelopmental condition called ARID2-related disorder (ARID2-RD). ARID2 belongs to PBAF, a unit of the SWI/SNF complex, which is a chromatin remodeling complex. This work aims to further delineate the phenotypic spectrum of ARID2-RD, providing clinicians with additional data for better care and aid in the future diagnosis of this condition. We obtained the genotypes and phenotypes of 27 previously unreported individuals with ARID2-RD and compared this series with findings in the literature. We also assessed peripheral blood DNA methylation profiles in individuals with ARID2-RD compared to episignatures of controls, unresolved cases, and other neurodevelopmental disorders. The main clinical features of ARID2-RD are developmental delay, speech disorders, intellectual disability (ID), behavior problems, short stature, and various dysmorphic and ectodermal features. Genome-wide differential methylation analysis revealed a global hypermethylated profile in ARID2-RD that could aid in reclassifying variants of uncertain significance. Our study doubles the number of reported individuals with ARID2 pathogenic variants to 53. It confirms loss-of-function as a pathomechanism and shows the absence of a clear genotype-phenotype correlation. We provide evidence for a unique DNA methylation episignature for ARID2-RD and further delineate the ARID2-associated phenotype.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566446","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":"Novel MYH10 heterozygous variants associated to a syndrome combining mainly ptosis and ocular coloboma expand the MYH10 related phenotypes.","authors":"Sophie Scheidecker, Séverine Bär, Ariane Kröll-Hermi, Clarisse Delvallée, Bruno Rinaldi, Anita Korpioja, Véronique Geoffroy, Elise Schaefer, Samira Secula, Catherine Jaeger, Corinne Stoetzel, Olivier Kassel, Uwe Straehle, Aida Bertoli-Avella, Emir Zonic, Jean-Baptiste Lamouche, Xavier Zanlonghi, Christelle Etard, Jean Muller, Elisa Rahikkala, Sylvie Friant, Hélène Dollfus","doi":"10.1038/s41431-025-01803-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01803-2","url":null,"abstract":"<p><p>Syndromes associating both eyeball and periocular developmental anomalies, combining iris chorioretinal (ocular) coloboma and ptosis, are described in very rare clinical entities such as Baraitser-Winter cerebrofrontofacial syndrome (BWCFF). We report on six individuals from 3 unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features suggesting BWCFF. However, no neurodevelopmental disorders (NDD) as usually observed in this syndrome were detected. Exome sequencing (ES) or genome sequencing (GS) was performed and allowed the identification of 3 novel heterozygous variants in the MYH10 gene, encoding the non-muscle myosin heavy chain II B. These 3 likely causative variants occur in the MYH10 tail domain required for myosin filament assembly. The MYH10 protein is mislocalized leading to abnormal actin networks in the patients' fibroblasts compared to controls. MYH10 dysfunction leads to delayed development of the eye, as well as a muscular phenotype in the zebrafish model. Heterozygous variants in MYH10 have been recently reported to be associated with an autosomal dominant NDD with other congenital anomalies, but no patients were reported with the association of ocular coloboma and ptosis as main features. Herein, we report other MYH10 variants which cause mainly an ophthalmic phenotype without NDD expanding the phenotype associated with MYH10 and representing a differential diagnosis with BWCFF. The reason for the genotype-phenotype variability with either prominent NDD or prominent ocular features will require further investigations.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566447","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":"BCL11B-related disease: a single phenotypic entity?","authors":"J. Heather Vedovato-dos-Santos,&nbsp;Rebecca S. Tooze,&nbsp;Sivagamy Sithambaram,&nbsp;Emma McCann,&nbsp;Yasemin Alanay,&nbsp;Ozlem A. Dogan,&nbsp;Meltem Kilercik,&nbsp;Aysen Bingol,&nbsp;Memet M. Ozek,&nbsp;David Johnson,&nbsp;Christoffer Nellaker,&nbsp;Andrew O. M. Wilkie,&nbsp;Stephen R. F. Twigg","doi":"10.1038/s41431-025-01824-x","DOIUrl":"10.1038/s41431-025-01824-x","url":null,"abstract":"Craniosynostosis (CRS), the premature fusion of sutures between the skull bones, is characterised by a long “tail” of rare genetic diagnoses. This means that pathogenic variants in many genes are responsible for a minority of cases, and identifying these disease genes and delineating the associated phenotype is extremely important for patient diagnosis and for genetic counselling of families. One such gene is BCL11B. Heterozygous pathogenic variants in BCL11B have been described as causative for two Mendelian phenotypes, but until recently the gene remained only marginally associated with CRS. We have carried out a systematic review of literature, providing evidence that BCL11B-related disease (BRD) should be regarded as a single phenotypic entity. Furthermore, we describe four new patients, all of whom presented with CRS, thus expanding the phenotype of BRD and highlighting CRS as an important diagnostic clue.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"451-460"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01824-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540065","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":"Consent for genomic sequencing: a conversation, not just a form","authors":"Danya F. Vears","doi":"10.1038/s41431-025-01805-0","DOIUrl":"10.1038/s41431-025-01805-0","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"397-398"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01805-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540625","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}