Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearran...

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Veröffentlicht in:	PLoS genetics Jg. 7; H. 7; S. e1002173
Hauptverfasser:	Bonaglia, Maria Clara, Giorda, Roberto, Beri, Silvana, De Agostini, Cristina, Novara, Francesca, Fichera, Marco, Grillo, Lucia, Galesi, Ornella, Vetro, Annalisa, Ciccone, Roberto, Bonati, Maria Teresa, Giglio, Sabrina, Guerrini, Renzo, Osimani, Sara, Marelli, Susan, Zucca, Claudio, Grasso, Rita, Borgatti, Renato, Mani, Elisa, Motta, Cristina, Molteni, Massimo, Romano, Corrado, Greco, Donatella, Reitano, Santina, Baroncini, Anna, Lapi, Elisabetta, Cecconi, Antonella, Arrigo, Giulia, Patricelli, Maria Grazia, Pantaleoni, Chiara, D'Arrigo, Stefano, Riva, Daria, Sciacca, Francesca, Dalla Bernardina, Bernardo, Zoccante, Leonardo, Darra, Francesca, Termine, Cristiano, Maserati, Emanuela, Bigoni, Stefania, Priolo, Emanuela, Bottani, Armand, Gimelli, Stefania, Bena, Frederique, Brusco, Alfredo, di Gregorio, Eleonora, Bagnasco, Irene, Giussani, Ursula, Nitsch, Lucio, Politi, Pierluigi, Martinez-Frias, Maria Luisa, Martínez-Fernández, Maria Luisa, Martínez Guardia, Nieves, Bremer, Anna, Anderlid, Britt-Marie, Zuffardi, Orsetta
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 01.07.2011 Public Library of Science (PLoS)
Schlagworte:	Adolescent Adult Aged Aged, 80 and over Base Sequence Biology Child Child, Preschool Chromosome Deletion Chromosome Disorders - genetics Chromosomes Chromosomes, Human, Pair 22 - genetics Comparative Genomic Hybridization Cytogenetics Diagnosis Female Genetic aspects Genetics Humans Hypotheses In situ hybridization Infant Infant, Newborn Male Medicine Mental retardation Middle Aged Molecular Sequence Data Parents Phelan-McDermid syndrome Polymerase chain reaction Ring Chromosomes Sequence Deletion - genetics Social interaction Translocation, Genetic Young Adult Italy
ISSN:	1553-7404, 1553-7390, 1553-7404
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Zusammenfassung:	In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed on behalf of the 22q13 Clinical Study Group. Conceived and designed the experiments: MC Bonaglia, R Giorda, O Zuffardi. Performed the experiments: MC Bonaglia, R Giorda, S Beri, C De Agostini, F Novara, M Fichera, L Grillo, O Galesi, A Vetro, R Ciccone. Analyzed the data: MC Bonaglia, R Giorda, S Beri, C De Agostini, F Novara, M Fichera, L Grillo, O Galesi, A Vetro, R Ciccone. Contributed reagents/materials/analysis tools: MT Bonaglia, S Giglio, R Guerrini, S Osimani, S Marelli, C Zucca, R Grasso, R Borgatti, E Mani, C Motta, M Molteni, C Romano, D Greco, S Reitano, A Baroncini, E Lapi, A Cecconi, G Arrigo, MG Patricelli, C Pantaleoni, S D'Arrigo, D Riva, F Sciacca, B Dalla Bernardina, L Zoccante, F Darra, C Termine, E Maserati, S Bigoni, E Priolo, A Bottani, S Gimelli, F Bena, A Brusco, E di Gegorio, I Bagnasco, U Giussani, L Nitsch, P Politi, ML Martinez-Frias, ML Martínez-Fernández, N Martínez Guardia, A Bremer, B-M Anderlid. Wrote the paper: MC Bonaglia, R Giorda, O Zuffardi.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1002173