title: Breakpoint determination of 15 large deletions in Peutz-Jeghers subjects.
abstract: The Peutz-Jeghers Syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers. STK11/LKB1 (hereafter named STK11) germline mutations account for the large majority of PJS cases whereas large deletions account for about 30% of the cases. We report here the first thorough molecular characterization of 15 large deletions identified in a cohort of 51 clinically well-characterized PJS patients. The deletions were identified by MLPA analysis and characterized by custom CGH-array and quantitative PCR to define their boundaries. The deletions, ranging from 2.9 to 180 kb, removed one or more loci contiguous to the STK11 gene in six patients, while partial STK11 gene deletions were present in the remaining nine cases. By means of DNA sequencing, we were able to precisely characterize the breakpoints in each case. Of the 30 breakpoints, 16 were located in Alu elements, revealing non-allelic homologous recombination (NAHR) as the putative mechanism for the deletions of the STK11 gene, which lays in a region with high Alu density. In the remaining cases, other mechanisms could be hypothesized, such as microhomology-mediated end-joining (MMEJ) or non-homologous end-joining (NHEJ). In conclusion we here demonstrated the non-random occurrence of large deletions associated with PJS. All our patients had a classical PJS phenotype, which shows that haploinsufficiency for SBNO2, C19orf26, ATP5D, MIDN, C19orf23, CIRBP, C19orf24,and EFNA2, does not apparently affect their clinical phenotype.
authors.affiliation: Dipartimento di Biomedicina dell'Età Evolutiva, Sezione di Genetica Medica, Università di Bari Aldo Moro, Policlinico Piazza G. Cesare 11, 70124, Bari, Italy. resusc@medgene.uniba.it
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.forename: Rosanna
authors.initials: R
authors.lastname: Bagnulo
authors.forename: Silvana
authors.initials: S
authors.lastname: Beri
authors.forename: Erika
authors.initials: E
authors.lastname: Della Mina
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
authors.forename: Marilidia
authors.initials: M
authors.lastname: Piglionica
authors.forename: Francesco Claudio
authors.initials: FC
authors.lastname: Susca
authors.forename: Ginevra
authors.initials: G
authors.lastname: Guanti
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D020087:Alu Elements / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D021141:Nucleic Acid Amplification Techniques / Q000379:methods; D010580:Peutz-Jeghers Syndrome / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases