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

Beyond genomics: using RNA-seq from dried blood spots to unlock the clinical relevance of splicing variation in a diagnostic setting.

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-28 DOI: 10.1038/s41431-025-01792-2

Aida M Bertoli-Avella, Mandy Radefeldt, Ruslan Al-Ali, Luba M Pardo, Sabrina Lemke, Anika Leubauer, Daniel L Polla, Rebecca Hörnicke, Ligia S Almeida, Krishna Kumar Kandaswamy, Christian Beetz, Jorge Pinto Basto, Peter Bauer

{"title":"Beyond genomics: using RNA-seq from dried blood spots to unlock the clinical relevance of splicing variation in a diagnostic setting.","authors":"Aida M Bertoli-Avella, Mandy Radefeldt, Ruslan Al-Ali, Luba M Pardo, Sabrina Lemke, Anika Leubauer, Daniel L Polla, Rebecca Hörnicke, Ligia S Almeida, Krishna Kumar Kandaswamy, Christian Beetz, Jorge Pinto Basto, Peter Bauer","doi":"10.1038/s41431-025-01792-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01792-2","url":null,"abstract":"We aimed to assess the impact of splicing variants reported in our laboratory to gain insight into their clinical relevance. A total of 108 consecutive individuals, for whom 113 splicing variants had been reported, were selected for RNA-sequencing (RNA-seq), considering the gene expression in blood. A protocol was developed to perform RNA extraction and sequencing using the same sample (dried blood spots, DBS) provided for the DNA analysis, including library preparation and bioinformatic pipeline analysis. Splicing in genes of interest was inspected using IGV, with at least three unaffected individuals as controls. From the 113 variants, we confirmed an abnormal splicing in 64 variants (57%). In 15 variants (13%), we did not observe a splicing alteration. In the remaining 34 variants, no decision could be made on the splicing effect due to insufficient sample quality (21%) or a low number of reads (9%). The most common event leading to aberrant splicing was exon skipping, identified in 31 variants (48%). Other events included cryptic donor/acceptor site usage (n = 25; 39%), intron retention (n = 4; 6%), and other complex events (n = 4; 6%). In three patients, pathologically reduced enzymatic activity (measured using the same DBS) served as additional confirmation of the abnormal splicing caused by variants in HEXA, GAA, and GLA. We implemented an RNA-seq pipeline using the same sample provided for genomic testing. This multiomic approach, as implemented in our routine diagnostic processes, clarifies the clinical relevance of most of the analyzed variants and delivers more comprehensive genetic testing.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052090","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

RNA-sequencing unveils FLT4 splice site variants in variable congenital heart disease.

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-27 DOI: 10.1038/s41431-025-01788-y

Maxim Verlee, Erika D'haenens, Laurenz De Cock, Laura Muiño Mosquera, Katya De Groote, Kristof Vandekerckhove, Joseph Panzer, Ellen Roets, Björn Menten, Sofie Symoens, Paul Coucke, Tim Van Damme, Sarah Vergult, Bert Callewaert

引用次数: 0

Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-23 DOI: 10.1038/s41431-025-01785-1

Jeanette Yuen, Siqin Zhou, Rebecca Caeser, Mallika Venkatramani, Diana Nur Bte Ishak, Shao-Tzu Li, Zewen Zhang, Jianbang Chiang, Sock Hoai Chan, Joanne Ngeow

{"title":"Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice","authors":"Jeanette Yuen, Siqin Zhou, Rebecca Caeser, Mallika Venkatramani, Diana Nur Bte Ishak, Shao-Tzu Li, Zewen Zhang, Jianbang Chiang, Sock Hoai Chan, Joanne Ngeow","doi":"10.1038/s41431-025-01785-1","DOIUrl":"10.1038/s41431-025-01785-1","url":null,"abstract":"The popularity of multi-gene testing has identified more families with two or more pathogenic variants (PV) in cancer predisposition genes, also known as ‘MINAS’ (multilocus inherited neoplasia alleles syndromes). They are at risk of suboptimal treatment and management as little on this topic is known. We conducted a systematic review of published MINAS cases within cancer predisposition genes to understand their association with more severe presentations. We analysed 413 MINAS carriers, which included 33 novel cases from the Cancer Genetics Service, National Cancer Centre Singapore. Statistical tests were conducted to assess association between carrier characteristics and the number PV identified. Results suggest that MINAS carriers have more malignancies (31.7% vs 21.5% vs 10.3% %; p < 0.001), a younger median age of first cancer diagnosis (40.0 vs. 44.0 vs. 49.0 years; p < 0.001) and an early onset of cancer (defined as <5% PV-associated cancer risk at age of diagnosis) (24.9% vs 7.7% vs 4.7%; p < 0.001) compared to monoallelic and non-carriers. We also studied the association of clinical characteristics by the dominant or recessive nature of PV harboured, where more dominant-dominant (D-D) carriers reported multiple malignancies (34.0%), compared to dominant-recessive (D-R) (23.9%) and recessive-recessive (R-R) carriers (20%;) (p = 0.051). Our findings suggest that MINAS carriers are prone to more and younger malignancies and the dominant or recessive nature of PV within double carriers can affect clinical presentation. We suggest a framework to guide management based on the dominant or recessive nature of PV within double PV carriers.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"289-296"},"PeriodicalIF":3.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01785-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022533","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

Polycomb-associated and Trithorax-associated developmental conditions-phenotypic convergence and heterogeneity.

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-22 DOI: 10.1038/s41431-025-01784-2

Alice Smail, Reem Al-Jawahiri, Kate Baker

{"title":"Polycomb-associated and Trithorax-associated developmental conditions-phenotypic convergence and heterogeneity.","authors":"Alice Smail, Reem Al-Jawahiri, Kate Baker","doi":"10.1038/s41431-025-01784-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01784-2","url":null,"abstract":"Polycomb group (PcG) and Trithorax group (TrxG) complexes represent two major components of the epigenetic machinery. This study aimed to delineate phenotypic similarities and differences across developmental conditions arising from rare variants in PcG and TrxG genes, using data-driven approaches. 462 patients with a PcG or TrxG-associated condition were identified in the DECIPHER dataset. We analysed Human Phenotype Ontology (HPO) data to identify phenotypes enriched in this group, in comparison to other monogenic conditions within DECIPHER. We then assessed phenotypic relationships between single gene diagnoses within the PcG and TrxG group, by applying semantic similarity analysis and hierarchical clustering. Finally, we analysed patient-level phenotypic heterogeneity in this group, irrespective of specific genetic diagnosis, by applying the same clustering approach. Collectively, PcG/TrxG diagnoses were associated with increased reporting of HPO terms relating to integument, growth, head and neck, limb and digestive abnormalities. Gene group analysis identified three multi-gene clusters differentiated by microcephaly, limb/digit dysmorphologies, growth abnormalities and atypical behavioural phenotypes. Patient-level analysis identified two large clusters differentiated by neurodevelopmental abnormalities and facial dysmorphologies respectively, as well as smaller clusters associated with more specific phenotypes including behavioural characteristics, eye abnormalities, growth abnormalities and skull dysmorphologies. Importantly, patient-level phenotypic clusters did not align with genetic diagnoses. Data-driven approaches can highlight pathway-level and gene-level phenotypic convergences, and individual-level phenotypic heterogeneities. Future studies are needed to understand the multi-level mechanisms contributing to both convergence and variability within this population, and to extend data collection and analyses to later-emerging health characteristics.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022500","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

GestaltGAN: synthetic photorealistic portraits of individuals with rare genetic disorders 格式塔根：合成具有罕见遗传疾病个体的逼真肖像。

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-15 DOI: 10.1038/s41431-025-01787-z

Aron Kirchhoff, Alexander Hustinx, Behnam Javanmardi, Tzung-Chien Hsieh, Fabian Brand, Fabio Hellmann, Silvan Mertes, Elisabeth André, Shahida Moosa, Thomas Schultz, Benjamin D. Solomon, Peter Krawitz

{"title":"GestaltGAN: synthetic photorealistic portraits of individuals with rare genetic disorders","authors":"Aron Kirchhoff, Alexander Hustinx, Behnam Javanmardi, Tzung-Chien Hsieh, Fabian Brand, Fabio Hellmann, Silvan Mertes, Elisabeth André, Shahida Moosa, Thomas Schultz, Benjamin D. Solomon, Peter Krawitz","doi":"10.1038/s41431-025-01787-z","DOIUrl":"10.1038/s41431-025-01787-z","url":null,"abstract":"The facial gestalt (overall facial morphology) is a characteristic clinical feature in many genetic disorders that is often essential for suspecting and establishing a specific diagnosis. Therefore, publishing images of individuals affected by pathogenic variants in disease-associated genes has been an important part of scientific communication. Furthermore, medical imaging data is also crucial for teaching and training deep-learning models such as GestaltMatcher. However, medical data is often sparsely available, and sharing patient images involves risks related to privacy and re-identification. Therefore, we explored whether generative neural networks can be used to synthesize accurate portraits for rare disorders. We modified a StyleGAN architecture and trained it to produce artificial condition-specific portraits for multiple disorders. In addition, we present a technique that generates a sharp and detailed average patient portrait for a given disorder. We trained our GestaltGAN on the 20 most frequent disorders from the GestaltMatcher database. We used REAL-ESRGAN to increase the resolution of portraits from the training data with low-quality and colorized black-and-white images. To augment the model’s understanding of human facial features, an unaffected class was introduced to the training data. We tested the validity of our generated portraits with 63 human experts. Our findings demonstrate the model’s proficiency in generating photorealistic portraits that capture the characteristic features of a disorder while preserving patient privacy. Overall, the output from our approach holds promise for various applications, including visualizations for publications and educational materials and augmenting training data for deep learning.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"377-382"},"PeriodicalIF":3.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01787-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001735","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

A patient with TPCN2-related hypopigmentation and ocular phenotype tpcn2相关性色素沉着与眼部表型1例。

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-14 DOI: 10.1038/s41431-024-01779-5

Cécile Courdier, Vincent Michaud, Modibo Diallo, Claudio Plaisant, Eulalie Lasseaux, Isabelle Helot, Elodie Philippe, Els Vrielynck, Marjolaine Willems, Benoit Arveiler

{"title":"A patient with TPCN2-related hypopigmentation and ocular phenotype","authors":"Cécile Courdier, Vincent Michaud, Modibo Diallo, Claudio Plaisant, Eulalie Lasseaux, Isabelle Helot, Elodie Philippe, Els Vrielynck, Marjolaine Willems, Benoit Arveiler","doi":"10.1038/s41431-024-01779-5","DOIUrl":"10.1038/s41431-024-01779-5","url":null,"abstract":"Pigmentation is orchestrated by hundreds of genes involved in cellular functions going from early developmental fate of pigment cells to melanin synthesis. The Two Pore Channel 2 (TPC2) a Ca2+ and Na+ channel acidifies melanosomal pH and thus inhibits pigmentation. A young patient was recently reported with generalized hypopigmentation but uneventful ocular examination, caused by the de novo heterozygous TPCN2 variant c.628C>T;p.Arg210Cys that constitutively activates TPC2. Here we report a young patient with the same de novo variant presenting with generalized hypopigmentation, and ophthalmologic features including low grade retinal hypopigmentation and foveal hypoplasia, photophobia, mild hypermetropia, and astigmatism, which are features of albinism. Skin fragility and episodes of fever with diarrhea and fatigue were also observed. This extends the phenotype of patients with TPCN2 variants, warranting further investigations in patients with alterations of this gene, and raises the question whether TPCN2 might be considered as an albinism gene.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"383-386"},"PeriodicalIF":3.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-024-01779-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982933","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

Artificial intelligence in clinical genetics 临床遗传学中的人工智能。

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-13 DOI: 10.1038/s41431-024-01782-w

Dat Duong, Benjamin D. Solomon

{"title":"Artificial intelligence in clinical genetics","authors":"Dat Duong, Benjamin D. Solomon","doi":"10.1038/s41431-024-01782-w","DOIUrl":"10.1038/s41431-024-01782-w","url":null,"abstract":"Artificial intelligence (AI) has been growing more powerful and accessible, and will increasingly impact many areas, including virtually all aspects of medicine and biomedical research. This review focuses on previous, current, and especially emerging applications of AI in clinical genetics. Topics covered include a brief explanation of different general categories of AI, including machine learning, deep learning, and generative AI. After introductory explanations and examples, the review discusses AI in clinical genetics in three main categories: clinical diagnostics; management and therapeutics; clinical support. The review concludes with short, medium, and long-term predictions about the ways that AI may affect the field of clinical genetics. Overall, while the precise speed at which AI will continue to change clinical genetics is unclear, as are the overall ramifications for patients, families, clinicians, researchers, and others, it is likely that AI will result in dramatic evolution in clinical genetics. It will be important for all those involved in clinical genetics to prepare accordingly in order to minimize the risks and maximize benefits related to the use of AI in the field.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"281-288"},"PeriodicalIF":3.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-024-01782-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978055","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

Welcome to 2025 from EJHG 欢迎来到EJHG的2025年

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-08 DOI: 10.1038/s41431-024-01777-7

Alisdair McNeill

引用次数: 0

Predicting the phenotype of Pompe Disease from features of GAA variants. 从GAA变异的特征预测庞贝病的表型。

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-07 DOI: 10.1038/s41431-024-01771-z

Geetanjali Rajamani, Nishitha R Pillai, Seth A Stafki, Peter I Karachunski, Peter B Kang

引用次数: 0

Double trouble: a comprehensive study into unrelated genetic comorbidities in adult patients with Facioscapulohumeral Muscular Dystrophy Type I. 双重麻烦：一项关于I型面肩肱肌营养不良症成人患者不相关遗传合并症的综合研究。

IF 3.7 2区生物学

European Journal of Human Genetics Pub Date : 2025-01-07 DOI: 10.1038/s41431-024-01770-0

Angela Puma, Giulia Tammam, Andra Ezaru, Abderhmane Slioui, Eleonora Torchia, Giorgio Tasca, Luisa Villa, Michele Cavalli, Leonardo Salviati, Patrick J van der Vliet, Richard Jlf Lemmers, Jonathan Pini, Silvère M van der Maarel, Sabrina Sacconi

{"title":"Double trouble: a comprehensive study into unrelated genetic comorbidities in adult patients with Facioscapulohumeral Muscular Dystrophy Type I.","authors":"Angela Puma, Giulia Tammam, Andra Ezaru, Abderhmane Slioui, Eleonora Torchia, Giorgio Tasca, Luisa Villa, Michele Cavalli, Leonardo Salviati, Patrick J van der Vliet, Richard Jlf Lemmers, Jonathan Pini, Silvère M van der Maarel, Sabrina Sacconi","doi":"10.1038/s41431-024-01770-0","DOIUrl":"https://doi.org/10.1038/s41431-024-01770-0","url":null,"abstract":"Facioscapulohumeral dystrophy type 1 (FSHD1) displays prominent intra- and interfamilial variability, which complicates the phenotype-genotype correlation. In this retrospective study, we investigated FSHD1 patients classified as category D according to the Comprehensive Clinical Evaluation Form (CCEF), a category defined by FSHD patients showing uncommon clinical features, to identify genetic causes explaining these uncommon phenotypes. Demographics, clinical data and clinical scales of FSHD1 patients were retrospectively evaluated. Patients were divided into four CCEF categories, and comparisons between groups were performed. In category D, when uncommon features suggested the presence of an unrelated genetic disease, a more extensive collection of data was performed. 157 FSHD1 patients were included in the study (82 males, 75 females) with mean age of 52.1 ± 13.5 years at the time of the study. D4Z4 repeat sizes ranged between 2 and 10 RU. According to the CCEF, 114 patients were classified into category A, 8 into category B and C each, and 27 into category D. In category D, 9 patients presented uncommon features related to commonly acquired comorbidities, whereas in the remaining 18 patients, all but two with upper-sized FSHD1 D4Z4 repeats (7-10 RU), we suspected an unrelated genetic neurological disease based on clinical phenotype. In 14/18 patients, we identified FSHD-unrelated genetic causes, most often unrelated repeat expansion disorders. This emphasizes the need of careful clinical and genetic work-up to avoid confusion between FSHD-intrinsic clinical variability and clinical features unrelated to the disease.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947033","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