دورية أكاديمية
أعرض في EDS

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.

التفاصيل البيبلوغرافية
العنوان: Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.
المؤلفون: Block I; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany., Mateu-Regué À; Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Do TTN; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Miceikaite I; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Clinical Genome Center, Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Sdogati D; Lundbeckfonden Center of Excellence NanoCAN, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Molecular Oncology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Larsen MJ; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Clinical Genome Center, Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Hao Q; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Clinical Genome Center, Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Nielsen HR; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Boonen SE; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Skytte AB; Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark., Jensen UB; Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark., Høffding LK; Center for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital, Roskilde, Denmark., De Nicolo A; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Viel A; Unit of Functional Oncogenetics and Genomics, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS, Aviano, (PN), Italy., Tudini E; Population Health Program, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia., Parsons MT; Population Health Program, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia., Hansen TVO; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Rossing M; Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Kruse TA; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Clinical Genome Center, Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Spurdle AB; Population Health Program, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia., Thomassen M; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. mads.thomassen@rsyd.dk.; Clinical Genome Center, Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. mads.thomassen@rsyd.dk.
المصدر: Breast cancer research : BCR [Breast Cancer Res] 2024 Jan 09; Vol. 26 (1), pp. 6. Date of Electronic Publication: 2024 Jan 09.
نوع المنشور: Case Reports; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London, UK : Current Science, c1999-
مواضيع طبية MeSH: Breast Neoplasms* , Fanconi Anemia*/genetics, Humans ; Male ; BRCA1 Protein/genetics ; Exons/genetics ; Mitomycin ; Phenotype
مستخلص: Background: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
Methods: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.
Results: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.
Conclusions: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
(© 2024. The Author(s).)
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معلومات مُعتمدة: APP177524 Australian NHMRC Investigator Fellowship
فهرسة مساهمة: Keywords: BRCA1; Dual carrier; Exon duplication; Fanconi Anemia; Transcription activation domain assay; Variant classification
المشرفين على المادة: 0 (BRCA1 Protein)
0 (BRCA1 protein, human)
50SG953SK6 (Mitomycin)
تواريخ الأحداث: Date Created: 20240109 Date Completed: 20240116 Latest Revision: 20240308
رمز التحديث: 20240309
مُعرف محوري في PubMed: PMC10775606
DOI: 10.1186/s13058-023-01755-9
PMID: 38195559
قاعدة البيانات: MEDLINE
الوصف
تدمد:1465-542X
DOI:10.1186/s13058-023-01755-9