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.
{"title":"<i>NF2</i>-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study.","authors":"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","doi":"10.1136/jmg-2024-110065","DOIUrl":"10.1136/jmg-2024-110065","url":null,"abstract":"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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 <i>NF2, LZTR1</i> and <i>SMARCB1</i> was performed.</p><p><strong>Results: </strong>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 <i>NF2</i> pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of <i>LZTR1</i>-related schwannomatosis and <i>SMARCB1</i>-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457442","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}
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。
{"title":"Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.","authors":"Mónica Centeno-Pla, Estefanía Alcaide-Consuegra, Sophie Gibson, Aina Prat-Planas, Juan Diego Gutiérrez-Ávila, Daniel Grinberg, Roser Urreizti, Raquel Rabionet, Susanna Balcells","doi":"10.1136/jmg-2024-109898","DOIUrl":"10.1136/jmg-2024-109898","url":null,"abstract":"<p><p>Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in <i>MAGEL2</i> 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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318492","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}
Terri Patricia McVeigh, Fiona Lalloo, Kevin J Monahan, Andrew Latchford, Miranda Durkie, Rachael Mein, Emma L Baple, Helen Hanson
{"title":"Carrier testing for partners of <i>MUTYH</i> variant carriers: UK Cancer Genetics Group recommendations.","authors":"Terri Patricia McVeigh, Fiona Lalloo, Kevin J Monahan, Andrew Latchford, Miranda Durkie, Rachael Mein, Emma L Baple, Helen Hanson","doi":"10.1136/jmg-2024-109910","DOIUrl":"10.1136/jmg-2024-109910","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179437","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}
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。
{"title":"Comprehensive preimplantation genetic testing for balanced insertional translocation carriers.","authors":"Shuo Zhang, Zhenle Pei, Min Xiao, Jing Zhou, Bin Hu, Saijuan Zhu, Xiaoxi Sun, Junping Wu, Caixia Lei, Congjian Xu","doi":"10.1136/jmg-2024-109851","DOIUrl":"10.1136/jmg-2024-109851","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158143","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}
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.
{"title":"Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis.","authors":"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","doi":"10.1136/jmg-2024-109878","DOIUrl":"10.1136/jmg-2024-109878","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247235","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}
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.
{"title":"A comparative medical genomics approach may facilitate the interpretation of rare missense variation.","authors":"Bushra Haque, George Guirguis, Meredith Curtis, Hera Mohsin, Susan Walker, Michelle M Morrow, Gregory Costain","doi":"10.1136/jmg-2023-109760","DOIUrl":"10.1136/jmg-2023-109760","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175023","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}
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/).
{"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":null,"pages":null},"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}
Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis
Background: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.
Methods: DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).
Results: Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).
Conclusions: The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.
背景:在进行种系遗传检测时,有必要对变异进行分类,以便患者及其家属得到适当的治疗。根据美国医学遗传学会(American College of Medical Genetics)和分子病理学协会(Association for Molecular Pathology)推荐的标准和指南,变异可分为致病(P)、可能致病(LP)、意义不确定(VUS)、可能良性(LB)和良性(B),并针对特定基因进行修改。随着文献的迅速扩充和证据的不断积累,以前的分类方法也会随之更新。在本研究中,我们旨在了解安大略省变异基因重新分类的特点:2012年1月至2022年4月期间在安大略省遗传性癌症诊所就诊的患者的DNA样本被提交进行检测。患者符合省级遗传性癌症综合征或多囊肾病检测资格标准。重新分类事件被确定为在其更广泛的重要类别内(B 到 LB 或反之亦然,或 P 到 LP 或反之亦然)或在其更广泛的重要类别外(即从 B/LB 或 VUS 或 P/LP,从 P/LP 到 VUS 或 B/LB,或从 VUS 到任何其他类别的重要重新分类):在纳入本研究的 8075 个独特变异体中,23.7%(1912 个)的变异体接受了重新评估,7.2%(578 个)的变异体被重新分类。其中,351 个(60.7%)变异体被重新分类,超出了其更广泛的重要类别。总体而言,336 个(58.1%)变异体的最终分类有明显不同。重要的是,大多数被重新分类的变异体被降级为更良性的分类(n=245;72.9%)。值得注意的是,大多数重新分类的 VUS 被降级为 B/LB(n=233;84.7%):结论:变异体在重新评估时被重新分类的可能性很高。结论:变异体在重新评估时被重新分类的可能性很高。大多数被重新分类的变异体都被降级为更良性的分类。我们的研究结果凸显了定期进行变异再评估的重要性,以确保为患者及其家属提供及时、适当的治疗。
{"title":"Variant classification changes over time in the clinical molecular diagnostic laboratory setting.","authors":"Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis","doi":"10.1136/jmg-2023-109772","DOIUrl":"10.1136/jmg-2023-109772","url":null,"abstract":"<p><strong>Background: </strong>Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.</p><p><strong>Methods: </strong>DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).</p><p><strong>Results: </strong>Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).</p><p><strong>Conclusions: </strong>The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160573","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}
Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang
Background and aims: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.
Methods: Zfyve19 knockout (Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. ZFYVE19 knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.
Results: The Zfyve19-/- mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, Zfyve19-/- mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from Zfyve19-/- mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.
Conclusions: Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.
{"title":"ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.","authors":"Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang","doi":"10.1136/jmg-2023-109779","DOIUrl":"10.1136/jmg-2023-109779","url":null,"abstract":"<p><strong>Background and aims: </strong>Variants in <i>ZFYVE19</i> underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.</p><p><strong>Methods: </strong><i>Zfyve19</i> knockout (<i>Zfyve19<sup>-/-</sup></i> ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. <i>ZFYVE19</i> knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.</p><p><strong>Results: </strong>The <i>Zfyve19<sup>-/-</sup></i> mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, <i>Zfyve19<sup>-/-</sup></i> mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from <i>Zfyve19<sup>-/-</sup></i> mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.</p><p><strong>Conclusions: </strong>Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179442","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}