caa a22 4500 445331267 CHVBK 20180317142738.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s10689-011-9427-0 doi (NATIONALLICENCE)springer-10.1007/s10689-011-9427-0 Mutation deep within an intron of MSH2 causes Lynch syndrome [Elektronische Daten] [Mark Clendenning, Daniel Buchanan, Michael Walsh, Belinda Nagler, Christophe Rosty, Bryony Thompson, Amanda Spurdle, John Hopper, Mark Jenkins, Joanne Young] Lynch syndrome, a heritable form of cancer predisposition, is caused by germline mutations within genes of the DNA mismatch repair family, and can be rapidly identified in young onset cancer patients through the detection of loss of expression of at least one of these genes in tumour samples. To date, such causative mutations have only been identified within exonic and splice site regions. Though this approach has been successful in the majority of families, a considerable number remain in which no mutation has been found. To address this situation, we used an alternative mutation discovery procedure which involved haplotype analysis of the locus containing the gene lost in the tumour and delineation of segregating haplotypes, followed by an investigation of splicing aberrations to uncover cryptic splice sites which lay outside the genomic regions routinely examined for mutations. In this report, we show that an intronic mutation 478bp upstream of exon 2 in the MSH2 gene causes Lynch syndrome through creation of a novel splice donor site with subsequent pseudoexon activation, thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation. Springer Science+Business Media B.V., 2011 Lynch syndrome nationallicence MSH2 nationallicence Novel mutation mechanism nationallicence Clendenning Mark Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Buchanan Daniel Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Walsh Michael Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Nagler Belinda Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Rosty Christophe Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Thompson Bryony Molecular Cancer Epidemiology, Queensland Institute of Medical Research, Herston, QLD, Australia aut Spurdle Amanda Molecular Cancer Epidemiology, Queensland Institute of Medical Research, Herston, QLD, Australia aut Hopper John Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Parkville, VIC, Australia aut Jenkins Mark Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Parkville, VIC, Australia aut Young Joanne Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut Familial Cancer Springer Netherlands 10/2(2011-06-01), 297-301 1389-9600 10:2<297 2011 10 10689 https://doi.org/10.1007/s10689-011-9427-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10689-011-9427-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Clendenning Mark Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Buchanan Daniel Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Walsh Michael Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Nagler Belinda Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Rosty Christophe Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Thompson Bryony Molecular Cancer Epidemiology, Queensland Institute of Medical Research, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Spurdle Amanda Molecular Cancer Epidemiology, Queensland Institute of Medical Research, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Hopper John Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Parkville, VIC, Australia aut NATIONALLICENCE 700 1- Jenkins Mark Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Parkville, VIC, Australia aut NATIONALLICENCE 700 1- Young Joanne Familial Cancer Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, Australia aut NATIONALLICENCE 773 0- Familial Cancer Springer Netherlands 10/2(2011-06-01), 297-301 1389-9600 10:2<297 2011 10 10689 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer