Genetics in Medicine Open最新文献

{"title":"Reclassification of VUS in BRCA1 and BRCA2 using the new BRCA1/BRCA2 ENIGMA track set demonstrates the superiority of ClinGen ENIGMA Expert Panel specifications over the standard ACMG/AMP classification system","authors":"Anna Benet-Pagès ,&nbsp;Andreas Laner ,&nbsp;Luis R. Nassar ,&nbsp;Tobias Wohlfrom ,&nbsp;Verena Steinke-Lange ,&nbsp;Maximilian Haeussler ,&nbsp;Elke Holinski-Feder","doi":"10.1016/j.gimo.2024.101961","DOIUrl":"10.1016/j.gimo.2024.101961","url":null,"abstract":"<div><h3>Purpose</h3><div>Variants of uncertain significance (VUS) are considered one of the most significant impediments to the translation of genetic test results into precise clinical recommendations. The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) classification guidelines established a general framework for the assessment and classification of genetic variants; yet, gene-specific specifications are needed to enable better variant classification to reduce the number of VUS. The process of gene-specific adaptations of the ACMG/AMP codes is led and accompanied by ClinGen and implemented by Variant Curation Expert Panels (VCEP). The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) VCEP recently published its specifications for the <em>BRCA1</em> (HGNC:1100) and <em>BRCA2</em> (HGNC:1101) genes. We investigated the differences in reclassification between the ENIGMA specifications and the standard ACMG/AMP classification system in a clinical setting.</div></div><div><h3>Methods</h3><div>We reclassified 121 VUS identified in these genes with the latest annotation data using the standard ACMG/AMP classification system and recommendations from the Sequence Variant Interpretation and the ENIGMA specifications. To simplify the reevaluation process, we have created a University of California Santa Cruz Genome Browser track hub that displays the exact data points required for variant classification using the ENIGMA VCEP specifications at the exon and variant level (<span><span>https://genome.ucsc.edu/s/abenet/BRCA.ENIGMA.hg19</span><svg><path></path></svg></span>).</div></div><div><h3>Results</h3><div>By comparing the codes used and their different weighting in the 2 approaches, we were able to demonstrate the superiority of the application of ENIGMA VCEP specifications, which resulted in a dramatic reduction of VUS (83.5% ENIGMA VCEP vs 20% ACMG/AMP + Sequence Variant Interpretation).</div></div><div><h3>Conclusion</h3><div>For the diagnostic analysis of the <em>BRCA1</em> and <em>BRCA2</em> genes, the use of the ENIGMA VCEP specifications gives the best possible result in the clinical translation of genetic variants. The University of California Santa Cruz Genome Browser <em>BRCA1</em>/<em>BRCA2</em> ENIGMA track set significantly simplified the interpretation process.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101961"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"25: Five new cases of dual IGH translocations in patients with multiple myeloma","authors":"Makenzie L. Fulmer ,&nbsp;Denise I. Quigley ,&nbsp;M. Katharine Rudd ,&nbsp;Erica F. Andersen","doi":"10.1016/j.gimo.2024.101942","DOIUrl":"10.1016/j.gimo.2024.101942","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101942"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"32: A case with germ cell tumor and cutaneous mastocytosis harboring same genomic abnormalities indicating that they arose from a neoplastic progenitor","authors":"Zhongxia Qi","doi":"10.1016/j.gimo.2024.101949","DOIUrl":"10.1016/j.gimo.2024.101949","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101949"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"18: Re-evaluation of genomic CNVs overlapping new dosage sensitive genes at an academic reference laboratory in accordance with ClinGen dosage sensitivity curation","authors":"Denise I. Quigley,&nbsp;Daniel P. Reich,&nbsp;Coumarane Mani,&nbsp;Zoe K. Lewis","doi":"10.1016/j.gimo.2024.101935","DOIUrl":"10.1016/j.gimo.2024.101935","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101935"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"17: Creation of a successful internal cytogenetics training program for the development of future technologists","authors":"Michael Ryan Manning ,&nbsp;Virginia Thurston","doi":"10.1016/j.gimo.2024.101934","DOIUrl":"10.1016/j.gimo.2024.101934","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101934"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"21: Atypical MCC and microarray results from multiple gestation pregnancies","authors":"Saeideh Torabi Dalivandan,&nbsp;Fumin Lin,&nbsp;T. Niroshi Senaratne,&nbsp;Alden Huang,&nbsp;Valerie A. Arboleda,&nbsp;Sung-Hae L. Kang","doi":"10.1016/j.gimo.2024.101938","DOIUrl":"10.1016/j.gimo.2024.101938","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101938"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"15: A search for genetic determinants in neural tube defects using optical genome mapping","authors":"Nikhil Shri Sahajpal ,&nbsp;Benjamin Hilton ,&nbsp;Barbara R. DuPont ,&nbsp;Michael J. Friez ,&nbsp;Roger E. Stevenson","doi":"10.1016/j.gimo.2024.101932","DOIUrl":"10.1016/j.gimo.2024.101932","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101932"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"College of American Pathologists (CAP)/American College of Medical Genetics and Genomics (ACMG) proficiency testing for urinary glycosaminoglycan analysis: A summary of performance","authors":"Kristina Cusmano-Ozog ,&nbsp;Dietrich Matern ,&nbsp;Thomas Long ,&nbsp;Nicola Longo ,&nbsp;Sarah Young","doi":"10.1016/j.gimo.2024.101912","DOIUrl":"10.1016/j.gimo.2024.101912","url":null,"abstract":"<div><h3>Purpose</h3><div>Glycosaminoglycans (GAGs) accumulate in patients with mucopolysaccharidoses (MPS), multiple sulfatase deficiency, and mucolipidoses; measurement of total GAGs and the specific excretion pattern by fractionation can aid in their diagnosis. Since 1993, the College of American Pathologists with the American College of Medical Genetics and Genomics has offered proficiency testing (PT) for urine GAG analysis accessible to laboratories worldwide.</div></div><div><h3>Methods</h3><div>Data from PT surveys administered from 2016 to 2022 were assessed for trends in participation and methodological platforms used, as well as analytical performance and diagnostic accuracy by method and disease.</div></div><div><h3>Results</h3><div>The number of participating laboratories declined from 43 in 2016 to 28 in 2022. Fourteen urine samples with clinical vignettes were distributed; the median of correct diagnoses reported was 91.5% (range: 74%-100%). The best performing methodologies for total GAG analysis and fractionation were dimethylmethylene blue-dye-binding spectrophotometric assay and liquid chromatography-tandem mass spectrometry, respectively. MPS IV samples posed the greatest diagnostic challenge, whereas the overall false-positive rate was low.</div></div><div><h3>Conclusion</h3><div>Based on the data reviewed, best patient care for those at risk of an MPS is achieved by a combination of total GAG analysis and GAG fractionation. Development of liquid-chromatography-tandem-mass-spectrometry-based methods for quantitative, differentiated GAG analysis or disease-specific GAG-derived nonreducing end oligosaccharide fragments in combination with multiplexed lysosomal enzyme assays will likely improve diagnostic accuracy. The decline of laboratories participating in PT is concerning because MPS are increasingly included in newborn screening programs and urinary GAGs can be used to monitor the effectiveness of new therapies.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101912"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer","authors":"Wen Wen ,&nbsp;Sen Zhao ,&nbsp;Yiwen Jiang ,&nbsp;Chengzhu Ou ,&nbsp;Changyuan Guo ,&nbsp;Ziqi Jia ,&nbsp;Jiayi Li ,&nbsp;Yansong Huang ,&nbsp;Hengyi Xu ,&nbsp;Pengming Pu ,&nbsp;Tongxuan Shang ,&nbsp;Lin Cong ,&nbsp;Xiang Wang ,&nbsp;Nan Wu ,&nbsp;Jiaqi Liu","doi":"10.1016/j.gimo.2024.101899","DOIUrl":"10.1016/j.gimo.2024.101899","url":null,"abstract":"<div><h3>Purpose</h3><div>To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond <em>BRCA1/2</em> (HGNC: 1100, 1101) variants.</div></div><div><h3>Methods</h3><div>Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted <em>BRCA1/2</em> variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures.</div></div><div><h3>Results</h3><div>The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in <em>BARD1</em>, <em>ATR</em>, <em>BRIP1</em>, and <em>CHEK2</em> (HGNC: 952, 882, 20473, 16627) among 21 <em>BRCA1/2-</em>negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants (<em>P =</em> 1.10 × 10⁻⁴). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across <em>BRCA1/2-</em>negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development.</div></div><div><h3>Conclusion</h3><div>Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101899"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143162042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"19: Dosage Sensitivity Curation of Recurrent CNVs: A Novel Scoring Metric to Assist Clinical CNV Interpretation","authors":"John Herriges ,&nbsp;Zoe K. Lewis ,&nbsp;Bradley Coe ,&nbsp;Cassandra K. Runke ,&nbsp;Rachel D. Burnside ,&nbsp;Laura K. Conlin ,&nbsp;Benjamin A. Hilton ,&nbsp;Nicole Hoppman ,&nbsp;Vaidehi Jobanputra ,&nbsp;Brynn Levy ,&nbsp;Lucilla Pizzo ,&nbsp;Erin Rooney Riggs ,&nbsp;Andrea K. Vaags ,&nbsp;Shulin Zhang ,&nbsp;Christa Lese Martin ,&nbsp;Erica F. Andersen","doi":"10.1016/j.gimo.2024.101936","DOIUrl":"10.1016/j.gimo.2024.101936","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"3 ","pages":"Article 101936"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}