3 research outputs found
High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability.
Mutation screening of the BRCA1 and BRCA2 genes in probands with familial breast/ovarian cancer has been
greatly improved by the multiplex ligation-dependent probe amplification (MLPA) assay able to evidence gene
rearrangements not detectable by standard screening methods. However, no criteria for selection of cases to
be submitted to the MLPA test have been reported yet. We used the BRCAPro software for the selection of
familial breast/ovarian cancer probands investigated with the MLPA approach after negative BRCA1/2
conventional mutation screening. One hundred and seventy-seven probands were investigated for germline
BRCA1/2 mutations after assessment of genetic risk using BRCAPro. Probands were classified as BRCAPro
positive (n = 67) when the carrier probability (CP) was >10% and as BRCAPro negative (n = 110), when the CP
was <10%. Conventional mutational analyses of the BRCA1/2 genes and, in one case, of p53 identified 22
pathogenetic germline mutations, 12 in BRCA1, 9 in BRCA2 and 1 in p53, in 22/177 (12.4%) probands. All the
mutations except one were detected in BRCAPro-positive patients. In the 46 BRCAPro-positive cases that
resulted negative by BRCA1/2 mutation, screening analysis of rearrangements within BRCA1/2 by MLPA was
carried out. Three patients with a very high CP showed BRCA1 deletions, consisting of deletions of exons 1–2 in
two probands and of exon 24 in the third proband. In one case, the exons 1–2 deletion was shown to
cosegregate with disease in the family. No BRCA2 rearrangements were detected, but one patient showed the
1100delC of the CHEK2 gene, whose probe is present in the BRCA2 kit. In our series, the highest carrier
detection rate of mutation screening plus MLPA analysis (52.3%) was in patients with a BRCAPro CP >50%
Two novel mutations affecting splicing in the IRF6 gene associated with van der Woude syndrome.
van der Woude syndrome (VWS) is a rare autosomal dominant oral facial disorder characterized by high penetrance and variable expression, manifesting with lower lip pits, cleft lips with or without cleft palate, and isolated cleft palate. The phenotypic expression of clefts ranges from incomplete to complete. Different studies have demonstrated an association between VWS and mutations of the IRF6 (interferon regulatory factor) gene. In this study, we describe 2 novel Italian families with VWS harboring 2 distinct splice site mutations in the IRF6 gene. These results add to the previous 9 splicing mutations identified in patients with VWS and strengthen the importance of this type of alterations in the pathogenesis of the disease