Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements

PLoS One. 2014 Mar 31;9(3):e93306. doi: 10.1371/journal.pone.0093306. eCollection 2014.

Abstract

In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Base Sequence
  • Breast Neoplasms / genetics
  • Exons / genetics
  • Female
  • Gene Rearrangement / genetics*
  • Genetic Testing / methods
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Ovarian Neoplasms / genetics
  • Pedigree
  • Point Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Portugal
  • Sequence Deletion / genetics
  • Spain

Substances

  • BRCA1 Protein
  • BRCA2 Protein

Supplementary concepts

  • Breast Cancer, Familial

Grants and funding

This work was supported by grants to AV from the Xunta de Galicia (10 PXIB 9101 297 PR) and the Fundación Mutua Madrileña. LF is supported by the Isabel Barreto programme of the Xunta de Galicia and the European Social Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.