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Eur J Hum Genet. 2017 Oct;25(10):1147-1154. doi: 10.1038/ejhg.2017.116. Epub 2017 Jul 26.

Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer.

Author information

1
Department of Cancer Biology and Genetics, CLCC François Baclesse, Normandy Centre for Genomic and Personalized Medicine, Caen, France.
2
Inserm U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen, France.
3
Cancéropôle Nord-Ouest Data Processing Centre, CLCC François Baclesse, Caen, France.
4
GenoSplice Technology, iPEPS-ICM, Pitié-Salpétrière Hospital, Paris, France.
5
Department of Genetics, Institut Gustave Roussy, Villejuif, France.
6
Department of Genetics, Institut Curie, Paris, France.
7
Inserm U830, Paris, France.
8
Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.
9
Laboratory of Molecular Genetics, Institut Bergonié, Bordeaux, France.
10
Department of Pathology, CLCC François Baclesse, Caen, France.
11
Tumorothèque de Caen Basse-Normandie, Caen, France.
12
Department of Genetics, University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
13
University of Caen Normandy, Caen, France.

Abstract

Interpretation of variants of unknown significance (VUS) is a major challenge for laboratories performing molecular diagnosis of hereditary breast and ovarian cancer (HBOC), especially considering that many genes are now known to be involved in this syndrome. One important way these VUS can have a functional impact is through their effects on RNA splicing. Here we present a custom RNA-Seq assay plus bioinformatics and biostatistics pipeline to analyse specifically alternative and abnormal splicing junctions in 11 targeted HBOC genes. Our pipeline identified 14 new alternative splices in BRCA1 and BRCA2 in addition to detecting the majority of known alternative spliced transcripts therein. We provide here the first global splicing pattern analysis for the other nine genes, which will enable a comprehensive interpretation of splicing defects caused by VUS in HBOC. Previously known splicing alterations were consistently detected, occasionally with a more complex splicing pattern than expected. We also found that splicing in the 11 genes is similar in blood and breast tissue, supporting the utility and simplicity of blood splicing assays. Our pipeline is ready to be integrated into standard molecular diagnosis for HBOC, but it could equally be adapted for an integrative analysis of any multigene disorder.

PMID:
28905878
PMCID:
PMC5602017
DOI:
10.1038/ejhg.2017.116
[Indexed for MEDLINE]
Free PMC Article

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