Several different genetic alterations in the etiology of @entity4309 ( @entity14 [ @entity14 ]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30-50%) of clinicopathologically well-defined @entity14 families, suggesting the presence of other predisposing mechanisms. In a set of probands from 27 @entity4309 families who lacked evidence of a germline mutation in either the @entity4311 or @entity6756 gene, we performed genomic deletion screening with the use of multiplex ligation-dependent probe amplification (MLPA) and sequencing. We used immunohistochemistry (IHC) and @entity124 ( @entity124 ) analyses on samples of the probands of all families. Comparative analysis of mRNA transcripts was performed on blood leukocyte-derived samples from mutation carriers and noncarrier controls. We report that large germline deletions encompassing the last exons of the @entity5960 gene, upstream of @entity4311 , cosegregate with the @entity14 phenotype in 19% (5/27) of families tested. The @entity5 of the carriers show high-level @entity124 and @entity4311 protein loss. We show that these deletions, by removing the transcriptional termination sequences of the upstream gene, give rise to multiple @entity5960 / @entity4311 fusion transcripts. Our results provide evidence that deletions removing the last exon of @entity5960 constitute a distinct class of mutations predisposing to @entity4309 . Thus, analysis of the 3' region of the @entity5960 gene should be included in the routine mutation screening protocols for @entity14 .

Deletions removing the last exon of XXXX constitute a distinct class of mutations predisposing to @entity4309 .

@entity5960 :: ('4072', 'Gene') :: ['TACSTD1'] @entity6756 :: ('4292', 'Gene') :: ['MLH1'] @entity124 :: ('MESH:D053842', 'Disease') :: ['MSI', 'microsatellite instability'] @entity4309 :: ('MESH:D003123', 'Disease') :: ['Lynch syndrome'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumors'] @entity4311 :: ('4436', 'Gene') :: ['MSH2'] @entity14 :: ('MESH:D015179', 'Disease') :: ['hereditary nonpolyposis colorectal cancer', 'HNPCC']
@entity5960 :: (4072,Gene) :: ['TACSTD1']
