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Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7–10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.
Highlights
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers [1]
Analysis of III-1 and II-2 were first negative for the BRCA1/BRCA2 pathogenic variant with the Sanger analysis and next-generation sequencing (NGS) analysis
Evidence of the Alu sequence was revealed by Integrative Genomics Viewer (IGV), which showed the presence of chimeric soft-clipped reads coming from the Alu element, some of which are carriers of the polyT stretch (Figure S1)
Summary
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers [1]. The breast cancer associated genes BRCA1 (OMIM #113705) and BRCA2 (OMIM #612555) are the most well-known breast and ovarian cancer susceptibility genes with a lifetime cancer risk in carriers of pathogenic variants estimated at 60–80% for breast cancer and 20–40% for ovarian cancer [2]. Retrotransposons (REs) are genetic mobile elements that can “jump” by retrotransposition and are believed to insert (randomly) in the host genome through an RNA intermediate mechanism. The non-LTR REs include long interspersed elements (LINEs) and short interspersed elements (SINEs), which represent approximately 30% of the human genome. Alu elements are the most abundant SINEs with a typical length of ~300 base pairs (bp). Alu insertion into critical genomic regions could be pathogenic, resulting in many diseases by disrupting gene transcription, splicing, and/or
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