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Breakpoint determination of 15 large deletions in Peutz–Jeghers subjects

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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.

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Acknowledgments

We thank all the patients and the clinicians Dr. E. Urso, Dr. L. Varesco, Dr. P. Sala, Dr. M. Ponz de Leon, Dr. E. Lapi and Dr. C. Host who provided blood samples for this work. The study was supported by grants: Fondazione Cassa di Risparmio di Puglia “Caratterizzazione molecolare dei geni responsabili di poliposi amartomatose intestinali finalizzata al controllo tempestivo del rischio di neoplasia” and Fondi d’ateneo RS 2007–2008–2009 Università di Bari.

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  1. Dipartimento di Biomedicina dell’Età Evolutiva, Sezione di Genetica Medica, Università di Bari “Aldo Moro”, Policlinico Piazza G. Cesare 11, 70124, Bari, Italy

    Nicoletta Resta, Rosanna Bagnulo, Alessandro Stella & Marilidia Piglionica

  2. Genetica Medica, Università di Pavia, Pavia, Italy

    Erika Della Mina, Orsetta Zuffardi & Roberto Ciccone

  3. Molecular Biology, “E. Medea” Scientific Institute, Bosisio Parini, LC, Italy

    Roberto Giorda & Silvana Beri

  4. Dipartimento di Medicina Interna e Medicina Pubblica, Sezione di Genetica Medica, Università di Bari “Aldo Moro”, Policlinico Piazza G. Cesare 11, 70124, Bari, Italy

    Francesco Claudio Susca & Ginevra Guanti

  5. IRCCS C. Mondino Scientific Institute, Pavia, Italy

    Orsetta Zuffardi

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  1. Nicoletta Resta
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  2. Roberto Giorda
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Correspondence to Nicoletta Resta.

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N. Resta and R. Giorda contributed equally to this work.

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Resta, N., Giorda, R., Bagnulo, R. et al. Breakpoint determination of 15 large deletions in Peutz–Jeghers subjects. Hum Genet 128, 373–382 (2010). https://doi.org/10.1007/s00439-010-0859-7

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