Breakpoint determination of 15 large deletions in Peutz-Jeghers subjects

• Published in: Human genetics Vol. 128; no. 4; pp. 373 - 382
• Main Authors: Resta, Nicoletta, Giorda, Roberto, Bagnulo, Rosanna, Beri, Silvana, Mina, Erika Della, Stella, Alessandro, Piglionica, Marilidia, Susca, Francesco Claudio, Guanti, Ginevra, Zuffardi, Orsetta, Ciccone, Roberto
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01-10-2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Alu Elements - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cell cycle; Child; Child, Preschool; Chromosome Breakage; Chromosome Deletion; Chromosomes, Human, Pair 19 - genetics; Classical genetics, quantitative genetics, hybrids; Cytogenetics; Dermatology; DNA Mutational Analysis; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Function; Genes; Genetics of eukaryotes. Biological and molecular evolution; Germ-Line Mutation; Health aspects; Human; Human Genetics; Humans; Infant; Kinases; Male; Medical sciences; Metabolic Diseases; Middle Aged; Molecular Medicine; Mutation; Nucleic Acid Amplification Techniques - methods; Original Investigation; Patients; Peutz-Jeghers Syndrome - genetics; Peutz-Jeghers Syndrome - pathology; Pigmentary diseases of the skin; Polymerase Chain Reaction; Protein-Serine-Threonine Kinases - genetics; Young Adult; Italy; STK11 Mutation; Breakpoint Junction; STK11 Gene; Deletion Breakpoint; Pairwise Sequence Divergence; Chromosomal aberration; Human; Breakpoint; Skin disease; Pigmentation disorder; Lentiginosis; Polyposis; Peutz-Jeghers syndrome; Genetic disease; Deletion; Digestive diseases; Genetics; Benign neoplasm
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-010-0859-7

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.