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<p>Pathogenicity assessment of genetic variants is the cornerstone of genetic counselling. Copy gains of exons are challenging, as pathogenicity depends on the localization of the additional exons. Eight patients form six families carried copy gains of <i>BRCA1</i> exons 8–20. For appropriate characterization, long-read sequencing aligned on three distinct reference genome assemblies, optical genomic mapping, short-read and long-read RNA sequencing were performed. All patients shared the same pathogenic structural variant, involving a large segment located downstream in the genome. One breakpoint occurred in a region incorrectly annotated in GRCh37/hg19 and GRCh38/hg38. Alignment to the T2T-CHM13/hs1 assembly was therefore necessary for accurate characterization. This rearrangement caused various <i>BRCA1</i> transcriptomic abnormalities: back-splicing, forward genomic strand transcription by insertion of an ectopic promoter, fusion transcripts with the “Next to <i>BRCA1</i>” gene 1 (<i>NBR1</i>). Our findings underscore the need to combine advanced technologies with the latest genome references to resolve complex rearrangements with significant medical implications.</p>

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A founder BRCA1 exonic duplication involving breakpoint in T2T reference genome-specific region results in constitutional fusion transcript

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Mathias Schwartz,
  • Mathilde Filser,
  • Kevin Merchadou,
  • Elisa Lemaitre,
  • Khadija Abidallah,
  • Henrique Tenreiro,
  • Catherine Dubois D’enghien,
  • Audrey Rapinat,
  • Elise Pierre-Noel,
  • Voreak Suybeng,
  • Marion Espenel,
  • Sylvain Baulande,
  • Séverine Adams,
  • Audrey Remenieras,
  • Crystal Renaud,
  • Camille Aucouturier,
  • Capucine Delnatte,
  • Céline Garrec,
  • Victor Renault,
  • Lisa Golmard,
  • Emmanuelle Fourme,
  • Julien Masliah-Planchon,
  • Sandrine M. Caputo

摘要

Pathogenicity assessment of genetic variants is the cornerstone of genetic counselling. Copy gains of exons are challenging, as pathogenicity depends on the localization of the additional exons. Eight patients form six families carried copy gains of BRCA1 exons 8–20. For appropriate characterization, long-read sequencing aligned on three distinct reference genome assemblies, optical genomic mapping, short-read and long-read RNA sequencing were performed. All patients shared the same pathogenic structural variant, involving a large segment located downstream in the genome. One breakpoint occurred in a region incorrectly annotated in GRCh37/hg19 and GRCh38/hg38. Alignment to the T2T-CHM13/hs1 assembly was therefore necessary for accurate characterization. This rearrangement caused various BRCA1 transcriptomic abnormalities: back-splicing, forward genomic strand transcription by insertion of an ectopic promoter, fusion transcripts with the “Next to BRCA1” gene 1 (NBR1). Our findings underscore the need to combine advanced technologies with the latest genome references to resolve complex rearrangements with significant medical implications.