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Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective. 扩展 X 连锁托恩-卡尔舒尔综合征(TOKAS)的临床范围:从胎儿角度的新见解。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-109854
Silvestre Cuinat, Chloé Quélin, Claire Effray, Christèle Dubourg, Gwenaelle Le Bouar, Anne-Sophie Cabaret-Dufour, Philippe Loget, Maia Proisy, Fanny Sauvestre, Mélie Sarreau, Sophie Martin-Berenguer, Claire Beneteau, Sophie Naudion, Vincent Michaud, Benoit Arveiler, Aurélien Trimouille, Pierre Macé, Sabine Sigaudy, Olga Glazunova, Julia Torrents, Laure Raymond, Marie-Hélène Saint-Frison, Tania Attié-Bitach, Mathilde Lefebvre, Yline Capri, Nicolas Bourgon, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Ange-Line Bruel, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Laurence Faivre, Anne-Claire Brehin, Alice Goldenberg, Sophie Patrier-Sallebert, Alexandre Perani, Benjamin Dauriat, Sylvie Bourthoumieu, Catherine Yardin, Valentine Marquet, Marion Barnique, Maryse Fiorenza-Gasq, Isabelle Marey, Danielle Tournadre, Raïa Doumit, Frédérique Nugues, Tahsin Stefan Barakat, Francisco Bustos, Sylvie Jaillard, Erika Launay, Laurent Pasquier, Sylvie Odent

Introduction: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.

Method: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.

Results: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.

Conclusion: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

简介Tonne-Kalscheuer综合征(TOKAS)是一种由RLIM变异引起的隐性X连锁多发性先天性异常疾病。在报道的 41 例患者中,只有 7 例是产前病例:方法:在一个因 5 名男性胎儿多发性先天性畸形而随访超过 35 年的家庭中,通过外显子组分析对 TOKAS 进行了产前诊断:我们介绍了 TOKAS 产前队列,描述了 6 个法国家庭中的 11 个新病例。我们报告了高发的膈疝(11 例中的 9 例)、性别发育差异(11 例中的 10 例)和各种内脏畸形。我们还报告了一些反复出现的畸形特征,以及以前未在文献中报告过的桥小脑发育不全、耳前皮肤标记和嗅球异常。尽管尚未出现明确的基因型与表型之间的相关性,但我们发现,复发性 p.(Arg611Cys) 变异占胎儿 TOKAS 病例的 66%。我们还报告了 RLIM 中的两个新的可能致病变异,它们位于之前已知的两个突变热点之外:总之,我们展示了首个 TOKAS 胎儿队列,描述了使其成为胎儿病理学检查中可识别综合征的临床特征,并扩展了这一罕见疾病的表型谱和已知基因型。
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引用次数: 0
Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis. 作为肌肉萎缩症病因的大 TRAPPC11 基因缺失及其估计成因。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-110016
Johana Kopčilová, Hana Ptáčková, Tereza Kramářová, Lenka Fajkusová, Kamila Réblová, Jiří Zeman, Tomáš Honzík, Lucie Zdražilová, Josef Zámečník, Patrícia Balážová, Karin Viestová, Miriam Kolníková, Hana Hansíková, Jana Zídková

Background: Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the TRAPPC11 gene. TRAPPC11 structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints.

Methods: Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings.

Results: We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients' skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression.

Conclusion: Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations.

背景:转运蛋白颗粒(TRAPP)是一种多蛋白复合物,具有将蛋白质定位到高尔基区室的功能。TRAPPC11 亚基与影响肌肉、大脑、眼睛和肝脏的疾病有关。我们介绍了三位患者,他们是 TRAPPC11 基因中一个错义变体和一个结构变体的复合杂合子。TRAPPC11 结构变异尚未被描述与疾病相关。为了揭示已确定的结构变异的估计成因,我们对单个断点连接进行了测序,并分析了同源性的程度以及断点内和断点周围是否存在重复元件:方法:我们采用了生化方法,包括血清转铁蛋白和脂蛋白 C-III 等电聚焦法以及线粒体呼吸链复合物活性测量法。对肌肉活检样本进行了组织化学分析。采用下一代测序技术确定与神经肌肉疾病相关的序列变异,并采用桑格测序技术确认研究结果:结果:我们推测非同源末端连接可能是两名患者基因缺失的起源机制,而非等位同源重组可能是一名患者基因缺失的起源机制。对患者骨骼肌线粒体功能的分析表明,线粒体代谢失衡会随着年龄的增长和疾病的进展而恶化:我们的研究结果有助于进一步了解神经肌肉疾病和突变机制。这些知识对于了解人类疾病的分子本质非常重要,并使我们能够改进识别致病突变的策略。
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引用次数: 0
NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study. 与 NF2 相关的分裂瘤病和其他分裂瘤病:最新遗传学和流行病学研究。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-08-29 DOI: 10.1136/jmg-2024-110065
Claire Forde, Miriam J Smith, George J Burghel, Naomi Bowers, Nicola Roberts, Tim Lavin, Jane Halliday, Andrew Thomas King, Scott Rutherford, Omar N Pathmanaban, Simon Lloyd, Simon Freeman, Dorothy Halliday, Allyson Parry, Patrick Axon, Juliette Buttimore, Shazia Afridi, Rupert Obholzer, Roger Laitt, Owen Thomas, Stavros Michael Stivaros, Grace Vassallo, D Gareth Evans

Objectives: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed.

Methods: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed.

Results: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2.

Conclusions: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

目的:2022 年发布了 NF2 相关神经分裂瘤病 (NF2) 的新诊断标准。根据这些标准更新了英国的发病率,重点是新发 NF2 的发病率(遗传咨询中广泛引用的发病率为 50%)。此外,还评估了新发 NF2 病例和家族性 NF2 病例中变异类型的分布情况:英国国家 NF2 数据库从英格兰专业服务机构高度确定的人群中识别出符合最新 NF2 标准的患者。诊断流行率于 2023 年 2 月 1 日进行评估。对血液进行了分子分析,并在可能的情况下对肿瘤标本进行了 NF2、LZTR1 和 SMARCB1 分析:结果:在流行日确定了 1084 名在世的 NF2 患者(相当于 61 332 人中有 1 人)。在英格兰,NF2遗传自患病父母的比例仅为23%。如果排除未确诊的分子诊断或双侧前庭分裂瘤患者,新生NF2患者的比例仍然很高(72%)。在已确定的新生病例中,近一半为镶嵌型。最常见的变异类型是无义变异,占已确定变异者的173/697(24.8%),但只有18/235(7.7%)人患有遗传性NF2致病变异(pLZTR1相关的分裂瘤病和SMARCB1相关的分裂瘤病分别为1/527 000和1/110万,比NF2低8.4-18.4倍):这项工作证实了新发 NF2 的比例远高于之前的报道,并强调了维护患者数据库以提供准确咨询的益处。
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引用次数: 0
Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome. 截短的 MAGEL2 蛋白的亚细胞定位:洞察沙夫-杨综合征的分子病理学。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2024-109898
Mónica Centeno-Pla, Estefanía Alcaide-Consuegra, Sophie Gibson, Aina Prat-Planas, Juan Diego Gutiérrez-Ávila, Daniel Grinberg, Roser Urreizti, Raquel Rabionet, Susanna Balcells

Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.

野生型(WT)或截短的(p.Gln638*)C-端 HA 标记 MAGEL2 的异源表达显示,截短蛋白变体从主要的细胞质定位转变为更多的核定位。现在,我们将这一分析扩展到 N 端 FLAG 标记的 MAGEL2 上的另外六个 SYS 突变。我们的结果重复并扩展了之前的发现,表明所有截短的 MAGEL2 蛋白都始终显示出主要的核定位,而与 C 端或 N 端位置以及标签的化学性质无关。与先天性多关节发育不良相关的变体显示出更明显的核滞留表型,表明临床严重程度与核错位程度之间存在相关性。这些结果表明,截短的MAGEL2具有新形效应,可能有助于SYS的发病。
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引用次数: 0
Carrier testing for partners of MUTYH variant carriers: UK Cancer Genetics Group recommendations. 对 MUTYH 变异携带者的伴侣进行携带者检测:英国癌症遗传学小组建议。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2024-109910
Terri Patricia McVeigh, Fiona Lalloo, Kevin J Monahan, Andrew Latchford, Miranda Durkie, Rachael Mein, Emma L Baple, Helen Hanson
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引用次数: 0
A comparative medical genomics approach may facilitate the interpretation of rare missense variation. 比较医学基因组学方法可能有助于解释罕见的错义变异。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2023-109760
Bushra Haque, George Guirguis, Meredith Curtis, Hera Mohsin, Susan Walker, Michelle M Morrow, Gregory Costain

Purpose: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context.

Methods: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders.

Results: Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity.

Conclusion: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.

目的:确定在人类基因组背景下,驯化物种单焦点性状的可能致病错义变异在多大程度上具有提示致病性的特征:我们从在线动物孟德尔遗传数据库中提取了九种动物(猫、牛、鸡、狗、山羊、马、猪、兔和绵羊)的错义变体,将坐标映射到人类参考基因组,并使用基因组分析工具对变体进行注释。我们还搜索了一个私人商业实验室数据库,该数据库收录了超过 40 万名疑似罕见疾病患者的基因检测结果:在人类基因组中可映射到相同残基和基因的 339 个变异中,有 56 个变异先前已就致病性进行过分类:31 个(55.4%)致病/可能致病,1 个(1.8%)良性/可能良性,24 个(42.9%)不确定/其他。在 ClinVar 中,致病/可能致病分类的几率比为 7.0(95% CI 4.1 至 12.0,p 结论:跨物种比较有助于解释罕见的错义变异。这些结果为比较医学基因组学方法提供了进一步支持,这种方法将人类和兽医遗传学中的大数据计划联系起来。
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引用次数: 0
Comprehensive preimplantation genetic testing for balanced insertional translocation carriers. 针对平衡插入易位携带者的植入前综合基因检测。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2024-109851
Shuo Zhang, Zhenle Pei, Min Xiao, Jing Zhou, Bin Hu, Saijuan Zhu, Xiaoxi Sun, Junping Wu, Caixia Lei, Congjian Xu

Background: Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate.

Methods: A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis. The balanced insertion segments in euploid embryos were inferred from the haplotypes inherited from the carrier parent.

Results: A total of 10 BIT carrier couples were enrolled in our study. 15 in vitro fertilisation cycles were conducted, resulting in 73 blastocysts biopsied and subjected to PGT analysis. Among these, 20 blastocysts displayed rearrangement-related imbalances, 13 exhibited de novo aneuploidies, 15 presented a complex anomaly involving both imbalances and additional aneuploidies, while 25 were euploid. Within the euploid embryos, 12 were balanced carrier embryos and 13 were non-carrier embryos. To date, eight non-carrier and one carrier embryos have been transferred, resulting in seven clinical pregnancies. All pregnancies were recommended to perform prenatal diagnosis, our date revealed complete concordance between fetal genetic testing results and PGT results. Presently, five infants have been born from these pregnancies, and two pregnancies are still ongoing.

Conclusion: The proposed method facilitates comprehensive chromosome screening and the concurrent identification of balanced insertions or normal karyotypes in embryos. This study offers an effective and universally applicable strategy for BIT carriers to achieve a healthy pregnancy and prevent the transmission of BITs to their offspring.

背景:平衡插入易位(BIT平衡插入易位(BIT)可增加配子染色体失衡导致不孕、反复流产或新生儿出生缺陷的风险。然而,针对携带 BITs 患者的植入前基因检测(PGT)研究尚不充分:本研究开发并实施了植入前基因分型和单体型分析方法。进行了全基因组 SNP 基因分型,然后进行了基于核心家系的单倍型分析。从携带者父母遗传的单倍型推断出优倍体胚胎中的平衡插入片段:结果:共有 10 对 BIT 携带者夫妇参加了我们的研究。共进行了 15 个体外受精周期,对 73 个囊胚进行了活组织检查和 PGT 分析。其中,20 个囊胚表现出与重排相关的不平衡,13 个囊胚表现出新的非整倍体,15 个囊胚表现出复杂的异常,包括不平衡和额外的非整倍体,而 25 个囊胚为优倍体。在优倍体胚胎中,12 个是平衡携带者胚胎,13 个是非携带者胚胎。迄今为止,已移植了 8 个非载体胚胎和 1 个载体胚胎,结果有 7 例临床妊娠。我们建议所有孕妇进行产前诊断,结果显示胎儿基因检测结果与产前诊断结果完全一致。目前,这些孕妇中已有五名婴儿出生,还有两名孕妇仍在进行产前诊断:结论:所提出的方法有助于进行全面的染色体筛查,并同时鉴定胚胎中的平衡插入或正常核型。这项研究为 BIT 携带者提供了一种有效且普遍适用的策略,使他们能够健康妊娠,并防止 BIT 遗传给后代。
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引用次数: 0
Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis. 西班牙妇产科学会(Spanish Society of Gynecology and Obstetrics)和西班牙产前诊断协会(Spanish Association of Prenatal Diagnosis)制定的产前诊断 NGS 程序指南。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2024-109878
Anna Abulí, Eugenia Antolín, Antoni Borrell, Maria Garcia-Hoyos, Fe García Santiago, Irene Gómez Manjón, Nerea Maíz, Cristina González González, Laia Rodríguez-Revenga, Irene Valenzuena Palafoll, Javier Suela

Objective: This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care.

Methods: A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals.

Results: This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies.

Conclusions: This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.

目的:本文探讨了下一代测序(NGS)技术在产前基因诊断中的临床应用,旨在制定西班牙的临床实践建议,以确保在产前护理中统一应用这些技术:方法:成立了一个由产科医生和遗传学家专家组成的联合委员会,以审查有关用于遗传诊断的胎儿 NGS 的现有文献,并为西班牙医护人员提出建议:本指南总结了 NGS 技术的技术方面、产前临床适应症、报告结果的注意事项、遗传咨询注意事项以及数据存储和保护政策:本文件提供了在产前诊断中使用 NGS 诊断测试的最新建议。随着我们对 NGS 技术在孕期应用的临床效用的认识不断提高,应定期对这些建议进行审查。
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引用次数: 0
Heterozygous deletion of HOXC10-HOXC9 causes lower limb abnormalities in congenital vertical talus. HOXC10-HOXC9的杂合子缺失会导致先天性垂直距骨的下肢畸形。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2023-109656
Liheng Chen, Shuoyang Zhao, Wenxia Song, Lihong Wang, Zerong Yao, Jianfei Gao, Xiaoze Li
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引用次数: 0
Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers. 在 BRCA1/2 致病变异携带者前瞻性队列中验证 BOADICEA 模型。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-07-19 DOI: 10.1136/jmg-2024-109943
Xin Yang, Thea M Mooij, Goska Leslie, Lorenzo Ficorella, Nadine Andrieu, Karin Kast, Christian F Singer, Anna Jakubowska, Carla H van Gils, Yen Y Tan, Christoph Engel, Muriel A Adank, Christi J van Asperen, Margreet G E M Ausems, Pascaline Berthet, Margriet J Collee, Jackie A Cook, Jacqueline Eason, Karin Y van Spaendonck-Zwarts, D Gareth Evans, Encarna B Gómez García, Helen Hanson, Louise Izatt, Zoe Kemp, Fiona Lalloo, Christine Lasset, Fabienne Lesueur, Hannah Musgrave, Sophie Nambot, Catherine Noguès, Jan C Oosterwijk, Dominique Stoppa-Lyonnet, Marc Tischkowitz, Vishakha Tripathi, Marijke R Wevers, Emily Zhao, Flora E van Leeuwen, Marjanka K Schmidt, Douglas F Easton, Matti A Rookus, Antonis C Antoniou

Background: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres.

Methods: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information.

Results: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options.

Conclusion: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).

背景:迄今为止,BOADICEA多因素乳腺癌风险预测模型尚未专门针对BRCA1/2致病变异(PV)携带者进行过验证。在此,我们评估了 BOADICEA 在通过临床基因中心确定的 BRCA1/2 PV 携带者前瞻性队列中预测 5 年乳腺癌风险的性能:我们在由 1614 名 BRCA1 和 1365 名 BRCA2 PV 携带者(209 例病例)组成的前瞻性 TRANsIBCCS 队列研究中评估了模型校准和判别能力。研究参与者拥有生活方式、生殖、荷尔蒙、人体测量风险因素信息、基于 313 个 SNP 的多基因风险评分以及家族史信息:考虑了家族史和所有其他风险因素的全多因素模型总体校准良好(E/O=1.07,95% CI:0.92 至 1.24),预测风险的五分位数也校准良好。当考虑所有风险因素时,辨别能力达到最大(哈雷尔 C 指数=0.70,95% CI:0.67 至 0.74;曲线下面积=0.79,95% CI:0.76 至 0.82)。单独评估 BRCA1 或 BRCA2 PV 携带者时,模型性能相似。完整模型分别确定了 5.8%、12.9% 和 24.0% 的 BRCA1/2 PV 携带者的 5 年乳腺癌风险:BOADICEA 可用于帮助 BRCA1 和 BRCA2 PV 携带者进行个性化癌症风险管理和决策。它已在免费访问的 CanRisk 工具 (https://www.canrisk.org/) 中实施。
{"title":"Validation of the BOADICEA model in a prospective cohort of <i>BRCA1/2</i> pathogenic variant carriers.","authors":"Xin Yang, Thea M Mooij, Goska Leslie, Lorenzo Ficorella, Nadine Andrieu, Karin Kast, Christian F Singer, Anna Jakubowska, Carla H van Gils, Yen Y Tan, Christoph Engel, Muriel A Adank, Christi J van Asperen, Margreet G E M Ausems, Pascaline Berthet, Margriet J Collee, Jackie A Cook, Jacqueline Eason, Karin Y van Spaendonck-Zwarts, D Gareth Evans, Encarna B Gómez García, Helen Hanson, Louise Izatt, Zoe Kemp, Fiona Lalloo, Christine Lasset, Fabienne Lesueur, Hannah Musgrave, Sophie Nambot, Catherine Noguès, Jan C Oosterwijk, Dominique Stoppa-Lyonnet, Marc Tischkowitz, Vishakha Tripathi, Marijke R Wevers, Emily Zhao, Flora E van Leeuwen, Marjanka K Schmidt, Douglas F Easton, Matti A Rookus, Antonis C Antoniou","doi":"10.1136/jmg-2024-109943","DOIUrl":"10.1136/jmg-2024-109943","url":null,"abstract":"<p><strong>Background: </strong>No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in <i>BRCA1/2</i> pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of <i>BRCA1/2</i> PV carriers ascertained through clinical genetic centres.</p><p><strong>Methods: </strong>We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 <i>BRCA1</i> and 1365 <i>BRCA2</i> PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information.</p><p><strong>Results: </strong>The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in <i>BRCA1</i> or <i>BRCA2</i> PV carriers. The full model identified 5.8%, 12.9% and 24.0% of <i>BRCA1/2</i> PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options.</p><p><strong>Conclusion: </strong>BOADICEA may be used to aid personalised cancer risk management and decision-making for <i>BRCA1</i> and <i>BRCA2</i> PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"803-809"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247237","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}
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Journal of Medical Genetics
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