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Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs). 两名双原发性胃肠道间质瘤(GIST)患者的共同种系基因组变异。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-24 DOI: 10.1136/jmg-2024-110109
David S Moura, Daniel López López, Davide di Lernia, Marta Martin-Ruiz, Maria Lopez-Alvarez, Rafael Ramos, Jose Merino, Joaquin Dopazo, Jose Lopez-Guerrero, Jose L Mondaza-Hernandez, Pablo Romero, Nadia Hindi, Jesus Garcia-Foncillas, Javier Martin-Broto

Background: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.

Methods: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.

Results: Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected.

Conclusion: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

背景:胃肠道间质瘤(GIST)是胃肠道常见的间质瘤,通常表现为 KIT 和 PDGFRA 基因的结构变异。虽然体细胞肿瘤的突变图谱已被充分描述,但 GIST 易感性背后的基因尚未被完全发现。本研究探讨了两个原发性 GIST 病例的基因组图谱,旨在确定共同的种系致病变异,并揭示肿瘤发生过程中潜在的关键角色:方法:两名基因型和表型不同的 GIST 患者接受了种系全基因组测序。方法:对两名基因型和表型不同的 GIST 患者进行了种系全基因组测序,并进行了 CNV 和单核苷酸变异 (SNV) 分析:结果:两名携带不同基因突变(PDGFRA和KIT)的低风险GIST患者的CFHR1和CFHR3基因都存在同源的种系致病性缺失。CNV 分析显示,其他基因(如 SLC25A24)也存在共同的致病性缺失。结论:我们的研究为我们了解种系遗传病提供了新的视角:我们的研究为了解与 GIST 发病相关的种系变异(即 CFHR1 和 CFHR3 深度缺失)提供了新的视角。我们有必要进一步进行功能验证,以阐明已发现的种系突变在 GIST 发病中的确切作用。
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引用次数: 0
Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients. 在 24 名法国患者中扩大塔顿-布朗-拉赫曼综合征的遗传和临床范围。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-110031
Hortense Thomas, Tom Alix, Émeline Renard, Mathilde Renaud, Justine Wourms, Stéphane Zuily, Bruno Leheup, David Geneviève, Natacha Dreumont, Emmanuelle Schmitt, Myriam Bronner, Marc Muller, Marion Divoux, Marion Wandzel, Jean-Marie Ravel, Mylène Dexheimer, Aurélie Becker, Virginie Roth, Marjolaine Willems, Christine Coubes, Gaëlle Vieville, Françoise Devillard, Élise Schaefer, Sarah Baer, Amélie Piton, Bénédicte Gérard, Marie Vincent, Mathilde Nizon, Benjamin Cogné, Lyse Ruaud, Nathalie Couque, Audrey Putoux, Patrick Edery, Gaëtan Lesca, Nicolas Chatron, Marianne Till, Laurence Faivre, Frédéric Tran-Mau-Them, Jean-Luc Alessandri, Marine Lebrun, Chloé Quélin, Sylvie Odent, Christèle Dubourg, Véronique David, Marie Faoucher, Cyril Mignot, Boris Keren, Élise Pisan, Alexandra Afenjar, Sophie Julia, Éric Bieth, Guillaume Banneau, Alice Goldenberg, Thomas Husson, Dominique Campion, François Lecoquierre, Gaël Nicolas, Camille Charbonnier, Anne De Saint Martin, Sophie Naudion, Manon Degoutin, Sophie Rondeau, Caroline Michot, Valérie Cormier-Daire, Abderrahim Oussalah, Carine Pourié, Laëtitia Lambert, Céline Bonnet

Background: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.

Methods: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.

Results: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.

Conclusion: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.

背景:塔顿-布朗-拉赫曼综合征(Tatton-Brown-Rahman Syndrome,TBRS;OMIM 615879)又称DNA甲基转移酶3α(DNMT3A)-生长过度综合征(DOS),由塔顿-布朗于2014年首次描述。这种综合征的特征是生长过快、智力障碍和独特的面部特征,是DNMT3A种系功能缺失变异的结果,DNMT3A编码一种参与表观遗传调控的DNA甲基转移酶。在包括急性髓性白血病(AML)在内的血液恶性肿瘤中,经常可以观察到 DNMT3A 的体细胞变异。迄今为止,已有 100 例 TBRS 患者出现了新的种系变异。我们的目的是在全国范围内对 24 名法国患者进行临床和分子水平的进一步研究,并调查智力障碍的严重程度与变异类型之间的相关性:方法:我们通过法国国家 AnDDI-Rares 网络发布的调查问卷收集了 24 名 TBRS 患者的遗传和医疗信息:在此,我们描述了法国首个全国性队列,该队列包含 24 名 DNMT3A 基因可能致病/致病变异的患者,其中包括 17 个新型变异。我们证实,主要的表型特征是智力残疾(100%)、独特的面部特征(96%)和过度生长(87%)。我们强调了新的临床特征,如多毛症,并进一步描述了神经系统特征和脑电图结果:这项针对全国范围内 TBRS 患者的研究证实了之前发表的数据,并提供了更多信息,明确了临床特征,有助于诊断和改善护理。这项研究为不断增长的 TBRS 知识库增添了新的价值,并拓宽了其临床和分子谱。
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引用次数: 0
Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome. 动脉瘤和夹层:Tatton-Brown-Rahman 综合征表型的演变。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-109861
Vicken Totten, Gisela Teixido-Tura, Fermina Lopez-Grondona, Paula Fernandez-Alvarez, Amaia Lasa-Aranzasti, Patricia Muñoz-Cabello, Rika Kosaki, Eduardo F Tizzano, Wendy Dewals, Emma Borràs, Elena Gonzalez Cañas, Berta Almoguera, Bart Loeys, Irene Valenzuena

Background: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described.

Methods: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition.

Results: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery.

Conclusions: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.

背景:塔顿-布朗-拉赫曼综合征(TBRS)是一种罕见疾病,由 DNMT3A 杂合致病变异引起,于 2014 年首次被描述。塔顿-布朗-拉赫曼综合征的特征是发育过度、智力障碍、面部畸形、肌张力低下、肌肉骨骼特征以及神经和精神特征。心脏表现也有报道,主要是先天性畸形,如房间隔缺损、室间隔缺损和心脏瓣膜病。方法:在此,我们对以前未报道过的 8 例 TBRS 和动脉扩张和/或夹层(主要是胸主动脉瘤 (TAA))患者进行了详细的临床和分子描述。我们还回顾了之前发表的七例患有 TBRS 的 TAA 病例,试图更好地描述血管表型,并确定该病症的具体后续治疗方案:我们纳入了八名新的 TBRS 患者,他们主要表现为涉及主动脉的动脉瘤。其中三名患者出现夹层,需要进行重症手术:结论:动脉瘤和动脉夹层是一种潜在的致命疾病,与年龄有关。主动脉疾病在 TBRS 患者中的发病率远高于普通人群。这组病例以及之前发表的病例说明,考虑主动脉扩张/横断的重要性,主要是主动脉扩张/横断,但也包括其他动脉扩张/横断。因此,动脉血管衰弱也可能是 TBRS 的一个主要特征,建议进行血管监测。
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引用次数: 0
Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation. Charcot-Marie-Tooth 的下一代测序:关于改进 ACMG 变异评估指南的建议。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-110019
Alessandro Geroldi, Alessia Mammi, Andrea Gaudio, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Sara Massucco, Lucio Marinelli, Marina Grandis, Angelo Schenone, Paola Mandich, Emilia Bellone, Fabio Gotta

Background: The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.

Methods: We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.

Results: Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.

Conclusions: The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.

背景:大规模并行测序技术在 Charcot-Marie-Tooth (CMT) 分子分析中的应用,能够快速、经济地鉴定出大量潜在的重要变异,用于诊断目的。我们的目标是减少变异体的数量,只关注那些具有致病意义的变异体。2015 年美国医学遗传学和基因组学学院(ACMG)指南有助于实现这一目标,但现在显而易见的是,对这些规则进行病理学或基因特异性审查至关重要,以避免盲目应用标准可能导致的误读。本研究展示了修订后的 ACMG 标准如何与 CMT 特异性文献数据和专业知识相结合,从而改变变异体的最终分类:方法:我们根据目前对 CMT 的了解对 ACMG 标准进行了回顾,并提出了根据 CMT 的特殊性对其进行调整的建议:结果:在分析的 226 例指数患者中,诊断率为 20%。值得注意的是,有 9% 的病例在应用修订后的标准后最终诊断发生了改变,这往往导致变异型病原体分类的缺失:结论:高通量测序技术的普及使没有特定疾病专业知识的实验室也能进行基因检测。针对特定疾病的 ACMG 标准是防止意义不确定的变异体扩散和误读变异体的重要工具。
{"title":"Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation.","authors":"Alessandro Geroldi, Alessia Mammi, Andrea Gaudio, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Sara Massucco, Lucio Marinelli, Marina Grandis, Angelo Schenone, Paola Mandich, Emilia Bellone, Fabio Gotta","doi":"10.1136/jmg-2024-110019","DOIUrl":"10.1136/jmg-2024-110019","url":null,"abstract":"<p><strong>Background: </strong>The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.</p><p><strong>Methods: </strong>We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.</p><p><strong>Results: </strong>Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.</p><p><strong>Conclusions: </strong>The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"847-852"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China. 在中国,各种基因突变的肌萎缩侧索硬化症患者表现出不同的运动表型和存活率。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-109909
Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.

Methods: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.

Results: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).

Conclusion: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.

背景:肌萎缩性脊髓侧索硬化症(ALS)是一种以运动神经元进行性变性为特征的破坏性神经退行性疾病。遗传因素对 ALS 有重大影响。因此,本研究旨在探讨 ALS 基因型(SOD1、TARDBP、FUS、C9orf72)与表型之间的相关性:对2038名ALS患者进行了基因分析,其中1696名散发性ALS(SALS)患者作为基因型-表型分析的对照,1602名SALS患者作为生存分析的对照。统计分析采用逻辑回归和考克斯比例危险模型:共有172名基因突变的ALS患者纳入统计分析(SOD1,n=65;FUS,n=43;TARDBP,n=27;C9orf72,n=37)。SOD1突变在小腿外翻表型中更为常见(OR 7.317,P=0.001),而在球部表型中则较少(OR 0.222,P=0.038)。C9orf72扩增在球部表型中出现的频率较高(OR 2.770,P=0.008)。SOD1和FUS突变与较早的发病年龄显著相关(HR 2.039,pSOD1突变、C9orf72扩增和携带致病性FUS突变者的死亡风险显著增加(HR 2.217,pC9orf72扩增在女性中显著(HR 2.419,p=0.014),但在男性中不显著(HR 1.442,p=0.128)):我们的研究揭示了不同基因型 ALS 患者的不同运动表型倾向,这表明在疾病进展过程中运动神经元的脆弱性存在差异。此外,我们还对不同基因突变的存活率有了新的发现,值得进一步研究。
{"title":"Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.","authors":"Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang","doi":"10.1136/jmg-2024-109909","DOIUrl":"10.1136/jmg-2024-109909","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS.</p><p><strong>Methods: </strong>Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.</p><p><strong>Results: </strong>A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).</p><p><strong>Conclusion: </strong>Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"839-846"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Complex structural variation and nonsense variant in trans cause VPS50-related disorder. 反式中的复杂结构变异和无义变异导致与 VPS50 有关的疾病。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-109983
Laura Hecher, Esther Gorski-Alberts, Matthias Begemann, Johanna Herwig, Eva Lausberg, Georg Hillebrand, Alexander E Volk, Ingo Kurth, Florian Kraft, Kerstin Kutsche

Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.

在两名患有神经发育障碍(小头畸形、癫痫发作和新生儿胆汁淤积症)的无亲属关系的患者中,曾发现过同源的 VPS50 变体。VPS50 编码的亚基是杂四聚体内膜相关再循环蛋白(EARP)复合物所独有的。EARP 复合物的其他亚基,如 VPS51、VPS52 和 VPS53,也与高尔基相关逆行蛋白复合物共享。我们报告了一名 18 个月大的女性患者,她患有双倍性 VPS50 变异。她携带父系遗传的杂合无义 c.13A>T; p.(Lys5*) 变异。通过长线程基因组测序,我们确定了一个结构变异的特征,即母系等位基因的两个断点都有缺失,侧翼有一个 4.3 Mb 的反转。端粒反转断点处的 ~428 kb 缺失包括整个 VPS50 基因。我们在患者来源的成纤维细胞中证实了 VPS50 的缺失,从而证实了这两种 VPS50 变体的功能缺失性质。患者成纤维细胞中的 VPS53 和 VPS52 蛋白水平分别显著降低和缺失。这些数据表明,VPS50和/或EARP缺乏及相关功能缺陷是VPS50致病变体患者表型的基础。VPS50 相关核心表型包括严重发育迟缓、产后小头畸形、胼胝体发育不全、新生儿低γ-谷氨酰转肽酶胆汁淤积症和发育不良。该病在幼儿期可能致命。
{"title":"Complex structural variation and nonsense variant <i>in trans</i> cause <i>VPS50</i>-related disorder.","authors":"Laura Hecher, Esther Gorski-Alberts, Matthias Begemann, Johanna Herwig, Eva Lausberg, Georg Hillebrand, Alexander E Volk, Ingo Kurth, Florian Kraft, Kerstin Kutsche","doi":"10.1136/jmg-2024-109983","DOIUrl":"10.1136/jmg-2024-109983","url":null,"abstract":"<p><p>Homozygous <i>VPS50</i> variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. <i>VPS50</i> encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic <i>VPS50</i> variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire <i>VPS50</i> gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both <i>VPS50</i> variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with <i>VPS50</i> pathogenic variants. The <i>VPS50</i>-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"833-838"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures. IFIH1 变异与发热性癫痫发作前的全身性癫痫有关。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-109950
Wang Song, Wen-Jun Bian, Hua Li, Qing-Hui Guo, Jie Wang, Bin Tang, Jia-Yuan Zhang, Wei Wei, Xiao-Rong Liu, Wei-Ping Liao, Bin Li, Na He

Background: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive.

Methods: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations.

Results: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients.

Conclusions: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.

背景:据报道,IFIH1变异与伴有/不伴有癫痫发作的免疫相关疾病有关。目前尚不清楚IFIH1变异是否与无后天原因的常见癫痫有关,表型变异的机制也仍未确定:方法:对发热性癫痫发作患者或有先兆发热性癫痫发作的癫痫患者进行了基于三重全外显子组测序。方法:对发热性癫痫发作患者或先兆发热性癫痫发作的癫痫患者进行了基于三重全外显子组测序,并系统回顾了之前报道的变异,以研究基因型与表型的关联:结果:在五名先有发热性癫痫发作的全身性癫痫患者中发现了两个新发杂合变异和三个双叶错义变异。硅学工具预测这些变异具有损伤性,并与邻近氨基酸的氢键变化或蛋白质稳定性降低有关。患者的发病年龄较早,且无癫痫发作,预后良好。进一步的分析表明,位于Hel区域的从头错义变异会导致癫痫发作和多种神经系统异常,而位于钳状结构域或C-末端结构域的错义变异则会导致癫痫发作和正常的神经发育,这表明存在亚分子效应。双拷贝错义变体是从未受影响的父母那里遗传来的,在一般人群中等位基因频率较低,与无神经系统异常的癫痫发作有关。截断变异与难治性癫痫和严重发育迟缓有关,这表明基因型与表型之间存在相关性。IFIH1主要在新生儿期表达,成年后急剧下降,这与患者的早期发病年龄和良好的预后是一致的:结论:IFIH1变体可能与先兆发热性癫痫发作的全身性癫痫有关。IFIH1变体的亚分子影响和基因型-表型关联有助于解释IFIH1变体的表型变化。
{"title":"<i>IFIH1</i> variants are associated with generalised epilepsy preceded by febrile seizures.","authors":"Wang Song, Wen-Jun Bian, Hua Li, Qing-Hui Guo, Jie Wang, Bin Tang, Jia-Yuan Zhang, Wei Wei, Xiao-Rong Liu, Wei-Ping Liao, Bin Li, Na He","doi":"10.1136/jmg-2024-109950","DOIUrl":"10.1136/jmg-2024-109950","url":null,"abstract":"<p><strong>Background: </strong><i>IFIH1</i> variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether <i>IFIH1</i> variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations.</p><p><strong>Results: </strong>Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. <i>IFIH1</i> is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients.</p><p><strong>Conclusions: </strong><i>IFIH1</i> variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of <i>IFIH1</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"895-903"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank. 估算英国生物数据库中林奇综合征变异携带者的癌症风险。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2023-109791
Eilidh Fummey, Pau Navarro, John-Paul Plazzer, Ian M Frayling, Sara Knott, Albert Tenesa

BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.

Methods: 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).

Results: Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in path_MMR carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in path_MMR carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic PMS2 variants in UKB.

Conclusion: These results support offering incidentally identified carriers of any path_MMR surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in MLH1, MSH2 and MSH6 would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.

背景林奇综合征(LS)是一种遗传性癌症易感综合征,由影响 DNA 错配修复(MMR)基因 MLH1、MSH2、MSH6 和 PMS2 的遗传变异引起。方法:利用全外显子组序列在 454 756 名英国生物库(UKB)参与者中鉴定出 830 名由 InSiGHT 分类的致病性或可能致病性(path_MMR)MMR 基因变异携带者。采用Nelson-Aalen生存分析法估算结直肠癌、子宫内膜癌和乳腺癌(BC)的累积发病率:结果:与非携带者相比,path_MMR 携带者 70 岁时结直肠癌和子宫内膜癌 (EC) 的累积发病率较高(结直肠癌:11.8%(95% 置信区间 (CI):9.5% 至 14.6%) vs 1.7%(95% 置信区间 (CI):1.6% 至 1.7%);子宫内膜癌:13.4%(95% 置信区间 (CI):9.5% 至 14.6%) vs 1.7%(95% 置信区间 (CI):1.6% 至 1.7%):13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)),但不同基因的发病率增长幅度不同。与非携带者相比,path_MMR携带者70岁时的累积BC发病率并没有升高(8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%))。UKB的累积癌症发病率估计值与前瞻性林奇综合征数据库对所有基因和癌症的估计值相似,但没有证据表明UKB中致病性PMS2变异携带者的EC风险升高:这些结果支持对偶然发现的任何路径_MMR携带者进行监测,以管理结直肠癌风险。偶然发现的MLH1、MSH2和MSH6致病变异携带者也将受益于降低EC风险的干预措施。研究结果表明,BC不是一种与LS相关的癌症。
{"title":"Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank.","authors":"Eilidh Fummey, Pau Navarro, John-Paul Plazzer, Ian M Frayling, Sara Knott, Albert Tenesa","doi":"10.1136/jmg-2023-109791","DOIUrl":"10.1136/jmg-2023-109791","url":null,"abstract":"<p><p>BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i> and <i>PMS2</i> Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.</p><p><strong>Methods: </strong>830 carriers of pathogenic or likely pathogenic (<i>path_MMR</i>) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).</p><p><strong>Results: </strong>Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in <i>path_MMR</i> carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in <i>path_MMR</i> carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic <i>PMS2</i> variants in UKB.</p><p><strong>Conclusion: </strong>These results support offering incidentally identified carriers of any <i>path_MMR</i> surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in <i>MLH1</i>, <i>MSH2</i> and <i>MSH6</i> would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"861-869"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
POT1 and multiple primary melanomas: the dermatological phenotype. POT1 和多发性原发性黑色素瘤:皮肤表型。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2023-109637
Ellie J Maas, Emily DeBortoli, Vaishnavi Nathan, Ned P Freeman, Adam Mothershaw, Darren J Smit, Brigid Betz-Stablein, Lauren G Aoude, Mitchell S Stark, Richard A Sturm, H Peter Soyer, Aideen M McInerney-Leo

POT1 is the second most frequently reported gene (after CDKN2A) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72×10-12) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant POT1 variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.

POT1 是家族性黑色素瘤中第二常见的基因(仅次于 CDKN2A)。致病变体与发病较早和/或多发性原发性黑色素瘤(MPMs)有关。迄今为止,POT1 的表型报告主要局限于相关的恶性肿瘤,对皮肤病的描述也很有限。我们在 384 例(4.7%)无亲属关系的欧洲血统个体(13 例 MPM;5 例单发原发性黑色素瘤)中的 18 例中发现了 10 个变体。与对照人群相比,五个变异在携带者中较为罕见(小等位基因频率×10-12)。大多数黑痣出现在受试者的背部和下肢区域,在这些区域只观察到轻度至中度的紫外线(UV)损伤。相反,头颈部的黑痣数量相对较少,而这两个受试者都有严重的紫外线损伤。我们假设,携带功能显著的 POT1 变体一般与黑痣数量增加有关,特别是与直径大于 5 毫米的黑痣有关,而且这些黑痣的位置与紫外线损伤无关。
{"title":"<i>POT1</i> and multiple primary melanomas: the dermatological phenotype.","authors":"Ellie J Maas, Emily DeBortoli, Vaishnavi Nathan, Ned P Freeman, Adam Mothershaw, Darren J Smit, Brigid Betz-Stablein, Lauren G Aoude, Mitchell S Stark, Richard A Sturm, H Peter Soyer, Aideen M McInerney-Leo","doi":"10.1136/jmg-2023-109637","DOIUrl":"10.1136/jmg-2023-109637","url":null,"abstract":"<p><p><i>POT1</i> is the second most frequently reported gene (after <i>CDKN2A</i>) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, <i>POT1</i> phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72<sup>×10-12</sup>) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant <i>POT1</i> variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"891-894"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
JMG at 60. JMG 第 60 页。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-110287
Huw Dorkins
{"title":"<i>JMG</i> at 60.","authors":"Huw Dorkins","doi":"10.1136/jmg-2024-110287","DOIUrl":"10.1136/jmg-2024-110287","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"823"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of Medical Genetics
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