title: Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome.
abstract: 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.
authors.affiliation: Cytogenetics Laboratory, Scientific Institute E. Medea, Bosisio Parini, Italy. clara.bonaglia@bp.lnf.it
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Bonaglia
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.forename: Silvana
authors.initials: S
authors.lastname: Beri
authors.forename: Cristina
authors.initials: C
authors.lastname: De Agostini
authors.forename: Francesca
authors.initials: F
authors.lastname: Novara
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Lucia
authors.initials: L
authors.lastname: Grillo
authors.forename: Ornella
authors.initials: O
authors.lastname: Galesi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bonati
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Sara
authors.initials: S
authors.lastname: Osimani
authors.forename: Susan
authors.initials: S
authors.lastname: Marelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Zucca
authors.forename: Rita
authors.initials: R
authors.lastname: Grasso
authors.forename: Renato
authors.initials: R
authors.lastname: Borgatti
authors.forename: Elisa
authors.initials: E
authors.lastname: Mani
authors.forename: Cristina
authors.initials: C
authors.lastname: Motta
authors.forename: Massimo
authors.initials: M
authors.lastname: Molteni
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Donatella
authors.initials: D
authors.lastname: Greco
authors.forename: Santina
authors.initials: S
authors.lastname: Reitano
authors.forename: Anna
authors.initials: A
authors.lastname: Baroncini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lapi
authors.forename: Antonella
authors.initials: A
authors.lastname: Cecconi
authors.forename: Giulia
authors.initials: G
authors.lastname: Arrigo
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Patricelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
authors.forename: Stefano
authors.initials: S
authors.lastname: D'Arrigo
authors.forename: Daria
authors.initials: D
authors.lastname: Riva
authors.forename: Francesca
authors.initials: F
authors.lastname: Sciacca
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dalla Bernardina
authors.forename: Leonardo
authors.initials: L
authors.lastname: Zoccante
authors.forename: Francesca
authors.initials: F
authors.lastname: Darra
authors.forename: Cristiano
authors.initials: C
authors.lastname: Termine
authors.forename: Emanuela
authors.initials: E
authors.lastname: Maserati
authors.forename: Stefania
authors.initials: S
authors.lastname: Bigoni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Priolo
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.forename: Frederique
authors.initials: F
authors.lastname: Bena
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
authors.forename: Eleonora
authors.initials: E
authors.lastname: di Gregorio
authors.forename: Irene
authors.initials: I
authors.lastname: Bagnasco
authors.forename: Ursula
authors.initials: U
authors.lastname: Giussani
authors.forename: Lucio
authors.initials: L
authors.lastname: Nitsch
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Politi
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Martinez-Frias
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Martínez-Fernández
authors.forename: Nieves
authors.initials: N
authors.lastname: Martínez Guardia
authors.forename: Anna
authors.initials: A
authors.lastname: Bremer
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Anderlid
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010290:Parents; D012303:Ring Chromosomes; D017384:Sequence Deletion / Q000235:genetics; D014178:Translocation, Genetic; D055815:Young Adult