Identification of rare complete BRCA1 gene deletion using acombination of SNP haplotype analysis, MLPA and array-CGHtechniques

The Large genomic rearrangements (LGR) in BRCA1/2 represent a substantial proportion of disease-causing changes. In our pilot study we demonstrate the specific case of the Slovak breast/ovarian cancer family, where BRCA1 analysis revealed the discrepancy of SNPs haplotypes and primarily indicated the presence of LGR. Initially, the analysis of all exons of BRCA1 was based on the combination of SSCP and sequencing techniques. After the abnormal SNPs haplotypes identification, MLPA analysis was performed. The results were finally proved with array-comparative genomic hybridization (array-CGH). The hemizygous status of 9 SNPs identificated in BRCA1 indicated a possible occurrence of LGR. The MLPA results showed reduction of peaks levels for each BRCA1 exon. Array-CGH method displays a single deletion signal for BRCA1 gene among set of 287 gene probes. Totally, 8 members of the family where analysed, in 3 of them the deletion was confirmed. Two of the LGR carriers suffered with unilateral and bilateral breast cancer respectively; the third carrier of the LGR was affected with an ovarian cancer. We have discovered rare BRCA1 germline LGR affecting complete gene. According to our knowledge, this is the first Slovak family with LGR in BRCA1 gene and second time, when the complete deletion of BRCA1 gene was described worldwide. Concerning the family history it is evident, that clinical effect of LGR is comparable with small deletions/insertions and substitutions and leads to the loss-off gene function. In conclusion, it is also important to note that DNA analysis of BRCA1/2 genes should be performed in all affected members of breast/ovarian cancer families concurrently, since the discrepancy in the SNPs haplotypes may indicate the presence of LGR.