European journal of medical genetics最新文献

{"title":"RHOA-associated disorder can be non-mosaic","authors":"Daisuke Nakato ,&nbsp;Naoya Morisada ,&nbsp;Sota Iwatani ,&nbsp;Chikako Nishida ,&nbsp;Daisuke Watanabe ,&nbsp;Mamiko Yamada ,&nbsp;Hisato Suzuki ,&nbsp;Fuyuki Miya ,&nbsp;Kenjiro Kosaki ,&nbsp;Toshiki Takenouchi","doi":"10.1016/j.ejmg.2025.105019","DOIUrl":"10.1016/j.ejmg.2025.105019","url":null,"abstract":"<div><div>Recurrent somatic mosaic pathogenic variants of <em>RHOA</em> have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for <em>RHOA</em> variants. Conversely, no patients with non-mosaic germline variants of <em>RHOA</em> have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all <em>RHOA</em> variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2–3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic <em>de novo</em> germline variant <em>RHOA</em>:c.202C&gt;A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of <em>RHOA</em> negates the previous notion that patients with <em>RHOA</em> variants are not viable. The differential diagnosis of a “non-mosaic” RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105019"},"PeriodicalIF":1.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of a case of melorheostosis deformity and pain with intramedullary nailing","authors":"Laura Ruzzini ,&nbsp;Michaela V. Gonfiantini ,&nbsp;Emanuela Asunis ,&nbsp;Grazia M. Ubertini ,&nbsp;Andrea Bartuli ,&nbsp;Pierfrancesco Costici","doi":"10.1016/j.ejmg.2025.105018","DOIUrl":"10.1016/j.ejmg.2025.105018","url":null,"abstract":"<div><div>Melorheostosis is a rare sclerosing bone dysplasia characterized by the thickening and irregular ossification of the affected bones. This disease can affect any bone in the skeletal system, with the long bones of the lower extremities being more frequently involved. Symptoms include pain, oedema, joint stiffness, muscle atrophy and bone deformity.</div><div>Management of this disease is challenging and not standardized. It depends on the symptoms, and it varies from physical therapy to pharmacological approach or surgery to correct limb deformities, muscle and tendon contractures and joint stiffness.</div><div>This case report presents the clinical management and treatment of a patient with lower limb deformities due to melorheostosis using retrograde intramedullary nailing of the femurs.</div><div>The procedure provided stability to the affected bones, resulting in correction of deformities and alleviation of lower limb pain, improving her quality of life.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105018"},"PeriodicalIF":1.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rare triplication of 16p11.2: Unravelling the genomic complexity and review of the literature","authors":"Liselot van der Laan ,&nbsp;Lotte Kleinendorst ,&nbsp;Martin A. Haagmans ,&nbsp;Laura Roquas ,&nbsp;Jasper J. van der Smagt ,&nbsp;Klaas Koop ,&nbsp;Peter Henneman ,&nbsp;Mieke M. van Haelst","doi":"10.1016/j.ejmg.2025.105013","DOIUrl":"10.1016/j.ejmg.2025.105013","url":null,"abstract":"<div><div>16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.2 triplication, whose healthy father has a smaller 16p11.2 duplication that partially overlaps with that of the daughter. She has a global developmental delay, autism spectrum disorder, anxiety, and sensory processing issues, alongside dysmorphic features. Genetic analysis revealed triplication within the 16p11.2 duplication region. We used different technical approaches to pinpoint the exact genetic architecture of the triplication and to gain further functional insights. Using array-CGH and Fluorescence In Situ Hybridization (FISH), we detected the location of the triplication. We later sought to confirm this with Oxford Nanopore Technologies (ONT); however, detecting duplications and triplications proved to be challenging. Finally, RNA sequencing showed overexpression of genes within the triplication region, including <em>INO80E, PAGR1, SPN, KIF22, HIRIP3, TAOK2, and TMEM219</em>, some of which had been associated with neurodevelopmental disorders and/or increased body mass index by GWAS (1). Our findings contribute to the understanding of the phenotypic spectrum and molecular mechanisms of 16p11.2 triplication. Moreover, the challenges in detecting triplications using current sequencing methods highlight the need for improved diagnostic techniques.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105013"},"PeriodicalIF":1.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early onset basal cell carcinoma: Consider Bazex-Dupré-Christol syndrome","authors":"Aislinn Cragg ,&nbsp;David Hunt ,&nbsp;Hywel Cooper ,&nbsp;Schaida Schirwani","doi":"10.1016/j.ejmg.2025.105004","DOIUrl":"10.1016/j.ejmg.2025.105004","url":null,"abstract":"<div><div>Bazex–Dupré–Christol syndrome is a rare genetic condition characterised by basal cell carcinomas, follicular atrophoderma and hypotrichosis. Until recently, the molecular basis of the condition was largely unknown. A recent study has identified a section of duplicated DNA on the X chromosome of those with the condition which appears to be the underlying cause of the syndrome. This case study looks at a family with five affected members over three generations. They had been diagnosed with the syndrome in early life and had previously undergone genetic testing with no cause being found. The index patient within this family has now been identified as having the same duplication as those tested in the initial study.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105004"},"PeriodicalIF":1.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel KDM5C variant corrects a previously erroneous diagnosis","authors":"Julia Chapin ,&nbsp;Bekim Sadikovic ,&nbsp;Jennifer Kerkhof ,&nbsp;Charles E. Schwartz ,&nbsp;Roger E. Stevenson ,&nbsp;Cindy Skinner ,&nbsp;Melanie May ,&nbsp;Michael Friez ,&nbsp;Robert Roger Lebel","doi":"10.1016/j.ejmg.2025.104997","DOIUrl":"10.1016/j.ejmg.2025.104997","url":null,"abstract":"<div><div>Over two decades ago, a primigravid female presented with concern for recurrence of an adverse phenotype affecting her three brothers. The three brothers presented with intellectual disability, developmental delay, behavior problems and dysmorphic features. The screening tools available at the time revealed an <em>FGD1</em> variant present in all three brothers, their mother being a carrier, absent in their unaffected uncle, and absent in the proband herself. This variant was hypothesized to be explanatory, but years later more advanced genetic screening showed that it was benign. Episign analysis revealed the true cause, a novel pathogenic <em>KDM5C</em> variant. This case study provides further insight into the <em>KDM5C</em> phenotype and demonstrates the importance of amending past errors as science evolves.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 104997"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxford Nanopore long-read sequencing with CRISPR/Cas9-mediated target selection for accurate characterization of copy number variants in the LDLR gene","authors":"Robin A. Pilz ,&nbsp;Dariush Skowronek ,&nbsp;Loisa D. Bonde ,&nbsp;Tadeusz Kałużewski ,&nbsp;Ole J. Schamuhn ,&nbsp;Raila Busch ,&nbsp;Agnieszka Gach ,&nbsp;Matthias Rath ,&nbsp;Elisabeth Steinhagen-Thiessen ,&nbsp;Ute Felbor","doi":"10.1016/j.ejmg.2025.105003","DOIUrl":"10.1016/j.ejmg.2025.105003","url":null,"abstract":"<div><h3>Introduction</h3><div>Familial hypercholesterolemia (FH) affects around 1 in 250 people. Most FH cases are caused by pathogenic <em>LDLR</em> variants, with copy number variations (CNVs) accounting for about 10 %. However, short-read gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) are limited in the specification of CNV breakpoints and the identification of complex structural variants (SVs).</div></div><div><h3>Materials and methods</h3><div>We designed crRNAs for Cas9-mediated target selection of <em>LDLR</em> and performed long-read sequencing (LRS) on an Oxford Nanopore MinION device using high-molecular-weight (HMW) DNA or DNA from standard purification. After establishing the LRS approach, we characterized two known <em>LDLR</em> CNVs and tested two individuals with strong clinical evidence of FH but no pathogenic variant in short-read gene panel sequencing.</div></div><div><h3>Results</h3><div>Complete coverage of <em>LDLR</em> was achieved for both HMW DNA and DNA from standard purification. LRS allowed us to specify CNV breakpoints and showed that the known <em>LDLR</em> deletion is 19.2 kb in size encompassing exons 1–2 and the 5′-untranslated and promoter regions. Furthermore, LRS verified the <em>in tandem</em> localization of a large <em>LDLR</em> duplication covering exons 4–8. Both CNVs were classified as loss-of-function. Moreover, breakpoint information enabled confirmatory analysis by PCR and Sanger sequencing for both CNVs. No SVs were detected in two apparently mutation-negative FH probands using our approach.</div></div><div><h3>Conclusions</h3><div>Nanopore LRS with CRISPR/Cas9-mediated target selection allows for accurate characterization of CNVs and can therefore serve as a complementary method to short-read sequencing-based FH diagnostics by facilitating variant interpretation and enabling cost-effective PCR-based variant confirmation in subsequent familial analyses.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 105003"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Public attitudes towards disclosure of genetic risk in the family: A survey in a sample of the Portuguese general population","authors":"Iara Ribeiro ,&nbsp;João Tavares ,&nbsp;Liliana Sousa ,&nbsp;Álvaro Mendes","doi":"10.1016/j.ejmg.2025.105007","DOIUrl":"10.1016/j.ejmg.2025.105007","url":null,"abstract":"<div><div>Genetic and genomic testing often have implications not only for the individual tested but also for their genetic relatives. This study aims to characterize public attitudes toward the familial disclosure of genetic risks. An online survey was completed by a sample of the Portuguese general population (n = 1034), assessing preferences for genetic testing, the receipt of genetic risk information, and the sharing of such information with family members. Results reveal a strong preference among respondents for receiving information on genetic risks and undergoing genetic testing. There was also ample agreement that family members should be informed about the risk of developing an inherited condition and undergo genetic testing. Additionally, participants expressed a preference for healthcare professionals to inform both themselves and their family members of genetic risks. Our findings suggest broad acceptance of the possibility for healthcare-mediated disclosure of genetic risks to family members. However, this approach to disclosure warrants further investigation, as direct contact with patients' relatives remains a contentious issue. A broad discussion is needed on how to best cascade relevant genetic information to patients' family members, taking into account the perspectives of all key stakeholders.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 105007"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare care – Cross-sector care coordination","authors":"Gareth Baynam ,&nbsp;Joanne Siffleet ,&nbsp;Theresa Abbott ,&nbsp;Sue Baker ,&nbsp;Daniella Dye ,&nbsp;Amanda Newell ,&nbsp;Stephanie Broley ,&nbsp;Kaila Stevens","doi":"10.1016/j.ejmg.2025.104995","DOIUrl":"10.1016/j.ejmg.2025.104995","url":null,"abstract":"<div><div>Rare and undiagnosed diseases collectively represent a global health priority, presenting distinct challenges for healthcare systems due to their low prevalence, cumulative frequency, and complex care requirements. The impact of rare and undiagnosed diseases on children and their families extends beyond physical and mental health, affecting every aspect of their lives. This paper outlines the development of an innovative Model of Care that emphasises cross-sector care coordination as an approach to enhance the health and wellbeing of Western Australian children living with rare and undiagnosed diseases. Detailing insights gained will support and guide healthcare professionals to create services that improve outcomes for people living with rare diseases and undiagnosed diseases and their families.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 104995"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seven loci associated with schizophrenia and bipolar I disorder in selected southern African population groups","authors":"Sue-Rica Schneider ,&nbsp;Johannes Jacobus Spies ,&nbsp;Paul Janus Pretorius ,&nbsp;Renate Rebello ,&nbsp;Errol Duncan Cason","doi":"10.1016/j.ejmg.2025.105005","DOIUrl":"10.1016/j.ejmg.2025.105005","url":null,"abstract":"<div><div>Two major psychiatric disorders, schizophrenia and bipolar I disorder, are regarded as distinct disorder entities; however, they share intricate connections through characteristic overlap and underlying genetic aetiology, challenging the traditional dichotomy. This convergence emerged as an essential area of investigation in understanding the genetic determinants of schizophrenia and bipolar I disorder. Moreover, psychiatric genetic research has revealed demographic disparities, with South African population groups notably underrepresented. Therefore, this preliminary targeted candidate gene association study of 20 single nucleotide polymorphisms implicated in schizophrenia and bipolar I disorder aimed to investigate association and overlap. Candidate loci for schizophrenia and bipolar I disorder were selected through an exploratory Illumina® Infinium PsychArray-24 analysis combined with literature and database searches. Genotyping of the selected loci was performed with the Agena Bioscience MassARRAY® platform on 96 cases (58 schizophrenia and 38 bipolar I disorder patients) and 44 controls of Afrikaner, Sotho, and Tswana descent. Association analysis was performed by comparing and combining population and phenotype groups. Significant (p &lt; 0.05) loci in the <em>ADAMTSL1</em>, <em>CACNA1B</em>, <em>CACNA1C</em>, <em>CDH13</em>, <em>CTNNA2</em>, <em>RBFOX1</em>, and <em>TRIO</em> genes were identified as possible susceptibility factors, and differences were observed with the association between population and phenotype groups. Through further pathway analysis, the calcium and cadherin-catenin pathways were identified as possible role players in the aetiology of schizophrenia and bipolar I disorder. The study represented an essential step towards understanding the genetic contribution towards schizophrenia and bipolar I disorder in distinct population groups and has the potential to contribute towards the knowledge base and inform future research efforts.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 105005"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiogenetics and uncertainty: Evaluation of professional vulnerability in France","authors":"Lea Gaudillat ,&nbsp;Lea Patay ,&nbsp;Caroline Sawka ,&nbsp;Amandine Baurand ,&nbsp;Sophie Nambot ,&nbsp;Camille Level ,&nbsp;Gabriel Laurent ,&nbsp;Jean-Christophe Eicher ,&nbsp;Geraldine Bertaux ,&nbsp;Sylvie Falcon Eicher ,&nbsp;Charlotte Denis ,&nbsp;Sarah Carvallo ,&nbsp;Cécile Cazeneuve ,&nbsp;Alexandre Janin ,&nbsp;Gilles Millat ,&nbsp;Christine Peyron ,&nbsp;Christel Thauvin-Robinet ,&nbsp;Philippe Charron ,&nbsp;Laurence Faivre","doi":"10.1016/j.ejmg.2025.104999","DOIUrl":"10.1016/j.ejmg.2025.104999","url":null,"abstract":"<div><div>Scientific advances in genomics are transforming healthcare and prevention. However, they also increase situations of uncertainty, which in turn increase vulnerability not only for patients and their families but also for professionals. Cardiogenetics plays a crucial role in preventing sudden death in young individuals, but it can pose complex challenges for healthcare teams. To study professionals' perspectives and experiences regarding cardiogenetics-related vulnerability, a national online survey was conducted in France to gather insight from professionals involved in the care pathway of individuals with cardiogenetic conditions. The survey targeted clinical geneticists, genetic counselors, cardiologists, nurses, and psychologists, in collaboration with the CARDIOGEN network.</div><div>Out of 86 respondents, the majority (64%) reported experiencing vulnerability, which was not correlated with their profession, experience, or the organization of their clinics. Acknowledged vulnerabilities were mainly related to uncertainties regarding incomplete penetrance, variable expression, and genotype-phenotype disparities in cardiogenetics, exacerbated by the evolving interpretation of genetic data, due to the increased access to genomics. Additionally, the implications of these issues, particularly in cases of unexplained sudden deaths that necessitated genetic investigations and family follow up recommendations, raised further concerns. The reported vulnerabilities encompassed both the need for specialized knowledge and the structural complexities of teams combining skills in genetics and cardiology. In addition, the professionals’ capacity to empathize can add a degree of vulnerability. Finally, it seems important to focus on how cardiogenetics teams are organized, particularly through close collaboration among genetics and cardiology units, which could help reduce this feeling of vulnerability.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"74 ","pages":"Article 104999"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}