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Int. J. Mol. Sci. 2016, 17(12), 2145; doi:10.3390/ijms17122145

A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

1
CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy
2
Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope, via Medina 40, 80133 Naples, Italy
3
Department of Senology, Istituto Nazionale Tumori–IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy
4
International Centre for Genetic Engineering and Biotechnology, Science Park, Padriciano 99, 34149 Trieste, Italy
5
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy
6
IRCCS-Fondazione SDN, via Emanuele Gianturco 113, 80143 Naples, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 28 October 2016 / Revised: 30 November 2016 / Accepted: 14 December 2016 / Published: 21 December 2016
(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)
View Full-Text   |   Download PDF [2586 KB, uploaded 21 December 2016]   |  

Abstract

About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset. View Full-Text
Keywords: breast cancer; BRCA1; next generation sequencing; splicing mutation; partial intron retention breast cancer; BRCA1; next generation sequencing; splicing mutation; partial intron retention
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MDPI and ACS Style

Esposito, M.V.; Nunziato, M.; Starnone, F.; Telese, A.; Calabrese, A.; D’Aiuto, G.; Pucci, P.; D’Aiuto, M.; Baralle, F.; D’Argenio, V.; Salvatore, F. A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA. Int. J. Mol. Sci. 2016, 17, 2145.

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