Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with phelan/mcdermid syndrome

Maria Clara Bonaglia, Roberto Giorda, Silvana Beri, Cristina de Agostini, Francesca Novara, Marco Fichera, Lucia Grillo, Ornella Galesi, Annalisa Vetro, Roberto Ciccone, Maria Teresa Bonati, Sabrina Giglio, Renzo Guerrini, Sara Osimani, Susan Marelli, Claudio Zucca, Rita Grasso, Renato Borgatti, Elisa Mani, Cristina MottaMassimo Molteni, Corrado Romano, Donatella Greco, Santina Reitano, Anna Baroncini, Elisabetta Lapi, Antonella Cecconi, Giulia Arrigo, Maria Grazia Patricelli, Chiara Pantaleoni, Stefano D'Arrigo, Daria Riva, Francesca Sciacca, Dalla Bernardo Bernardina, Leonardo Zoccante, Francesca Darra, Cristiano Termine, Emanuela Maserati, Stefania Bigoni, Emanuela Priolo, Armand Bottani, Stefania Gimelli, Frederique Bena, Alfredo Brusco, Eleonora Gregorio, Irene Bagnasco, Ursula Giussani, Lucio Nitsch, Pierluigi Politi, Maria Luisa Martinez-Frias, Maria Luisa Martínez-Fernández, Nieves Guardia, Anna Bremer, Britt Marie Anderlid, Orsetta Zuffardi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere1002173
JournalPLoS Genetics
Issue number7
Publication statusPublished - Jul 2011

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)


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