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Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome
Open accessAbstract
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.
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“Similarly, in other cases with almost identical small microdeletions (<100 kb) including SHANK3, neurobehavioral phenotypes were quite variable (Boccuto et al., 2013; Bonaglia et al., 2011; Dhar et al., 2010).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Bonaglia et al., 2011
In the citing paper
“By comparison, for point mutations such as missense mutation and small intragenic deletions identified in SHANK2 and SHANK3, the pathogenic mechanism is less clear (Bonaglia et al., 2011; Durand et al., 2011; Moessner et al., 2007).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Bonaglia et al., 2011
In the citing paper
“The Δex4-9 (Bozdagi et al., 2010) and Δex4-7 mutations in mouse (Peca et al., 2011) are closest to patients with intragenic exon 1-9 deletion and splice mutation of intron 5 in SHANK3 (Bonaglia et al., 2011; Hamdan et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Bonaglia et al., 2011
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McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A. S., Zackai, E. H., Emanuel, B. S., Vermeesch, J. R., Morrow, B. E., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.71 · Cited by 2,236
Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsäter, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1933 · Cited by 1,602
Chromosome instability is common in human cleavage-stage embryos
Vanneste, E., Voet, T., Le Caignec, C., Ampe, M., Konings, P., Melotte, C., Debrock, S., Amyere, M., Vikkula, M., Schuit, F., et al. (2009) · Nature Medicine · doi:10.1038/nm.1924 · Cited by 880
Hastings, P. J., Ira, G., & Lupski, J. R. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000327 · Cited by 818
Contribution of SHANK3 Mutations to Autism Spectrum Disorder
Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J., Zwaigenbaum, L., Fernandez, B., Roberts, W., Szatmari, P., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/522590 · Cited by 681
Conlin, L. K., Thiel, B. D., Bönnemann, C. G., Medne, L., Ernst, L. M., Zackai, E. H., Deardorff, M. A., Krantz, I. D., Hakonarson, H. H., & Spinner, N. B. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq003 · Cited by 475
The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)
Phelan, K., & McDermid, H. E. (2011) · Molecular Syndromology · doi:10.1159/000334260 · Cited by 460
Non-B DNA structure-induced genetic instability and evolution
Zhao, J., Bacolla, A., Wang, G., & Vásquez, K. M. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0131-2 · Cited by 421
Wilson, H. L., Wong, A. C. C., Shaw, S. R., Tse, W.-Y., Stapleton, G. A., Phelan, M. C., Hu, S., Marshall, J., & McDermid, H. E. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.8.575 · Cited by 377
Gauthier, J., Champagne, N., Lafrenière, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Côté, M., Noreau, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906232107 · Cited by 369
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Xu, N., Lv, H., Yang, T., Du, X., Sun, Y., Xiao, B., Fan, Y., Luo, X., Zhan, Y., Wang, L., et al. (2020) · doi:10.22541/au.159225088.85197462
Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.003.0002
Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.003.0019
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Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.003.0008
Phelan—McDermid syndrome associated with a novel heterozygous mutation in the SHANK3 gene
I, D. V., & Proskokova, T. N. (2023) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2023123081124
Barišić, I., & Pohovski, L. M. (2013) · Paediatria Croatica · doi:10.13112/pc.663
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Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.005.0002
Ideograms of Human Chromosomes, and Haploid Autosomal Lengths
Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.005.0001
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(2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.002.0007
(2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.002.0005
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Gardner, R. J. M., & Amor, D. J. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780199329007.005.0003
Pandey, S., Hajikazemi, M., Zacheja, T., Schalbetter, S. A., Baxter, J., Guryev, V., Hofmann, A., Heermann, D. W., Juranek, S., & Paeschke, K. (2021) · Figshare · doi:10.6084/m9.figshare.17056724
Additional file 1 of Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome
Kolevzon, A., Breen, M. S., Siper, P. M., Halpern, D., Frank, Y., Rieger, H., Weismann, J., Trelles, M. P., Lerman, B., Rapaport, R., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19561676
Additional file 2 of Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome
Kolevzon, A., Breen, M. S., Siper, P. M., Halpern, D., Frank, Y., Rieger, H., Weismann, J., Trelles, M. P., Lerman, B., Rapaport, R., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19561679
Schenkel, L. C., Aref-Eshghi, E., Rooney, K., Kerkhof, J., Levy, M. A., McConkey, H., Rogers, R. C., Phelan, K., Sarasua, S. M., Jain, L., et al. (2021) · TigerPrints (Clemson University) · doi:10.6084/m9.figshare.13533178
Pandey, S., Hajikazemi, M., Zacheja, T., Schalbetter, S. A., Baxter, J., Guryev, V., Hofmann, A., Heermann, D. W., Juranek, S., & Paeschke, K. (2021) · Figshare · doi:10.6084/m9.figshare.17056712
Pandey, S., Hajikazemi, M., Zacheja, T., Schalbetter, S. A., Baxter, J., Guryev, V., Hofmann, A., Heermann, D. W., Juranek, S., & Paeschke, K. (2021) · Figshare · doi:10.6084/m9.figshare.17056721
Pandey, S., Hajikazemi, M., Zacheja, T., Schalbetter, S. A., Baxter, J., Guryev, V., Hofmann, A., Heermann, D. W., Juranek, S., & Paeschke, K. (2021) · Figshare · doi:10.6084/m9.figshare.17056727
Pandey, S., Hajikazemi, M., Zacheja, T., Schalbetter, S. A., Baxter, J., Guryev, V., Hofmann, A., Heermann, D. W., Juranek, S., & Paeschke, K. (2021) · Figshare · doi:10.6084/m9.figshare.17056718
Xue, H., Dai, Y., Ye, X. Z., Zhang, L., Guo, Q., Lin, N., Huang, H., & Xu, L. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15187130
Metadata
- Authors
- Bonaglia, M. C., Giorda, R., Beri, S., De Agostini, C., Novara, F., Fichera, M., Grillo, L., Galesi, O., Vetro, A., Ciccone, R., Bonati, M. T., Giglio, S., Guerrini, R., Osimani, S., Marelli, S., Zucca, C., Grasso, R., Borgatti, R., Mani, E., Motta, C., Molteni, M., Romano, C., Greco, D., Reitano, S., Baroncini, A., Lapi, E., Cecconi, A., Arrigo, G., Patricelli, M. G., Pantaleoni, C., D'Arrigo, S., Riva, D., Sciacca, F., Dalla Bernardina, B., Zoccante, L., Darra, F., Termine, C., Maserati, E., Bigoni, S., Priolo, E., Bottani, A., Gimelli, S., Bena, F., Brusco, A., di Gregorio, E., Bagnasco, I., Giussani, U., Nitsch, L., Politi, P., Martinez-Frias, M. L., Martínez-Fernández, M. L., Martínez Guardia, N., Bremer, A., Anderlid, B.-M., & Zuffardi, O.
- Affiliations
- IRCCS Eugenio Medea (IT)
- University of Pavia (IT)
- Oasi Maria SS (IT)
- IRCCS Istituto Auxologico Italiano (IT)
- Meyer Children's Hospital (IT)
- IRCCS Ospedale San Raffaele (IT)
- Ospedale Santa Maria Annunziata (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- University of Verona (IT)
- University of Insubria (IT)
- University of Ferrara (IT)
- Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT)
- Canton of Geneva (CH)
- University of Turin (IT)
- Ospedale Martini (IT)
- University of Naples Federico II (IT)
- Karolinska Institutet (SE)
- ORCID
- Giorda, Roberto
- 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
- Borgatti, Renato
- Mani, Elisa
- Molteni, Massimo
- Romano, Corrado
- Greco, Donatella
- Baroncini, Anna
- Patricelli, Maria Grazia
- Pantaleoni, Chiara
- Riva, Daria
- Sciacca, Francesca
- Zoccante, Leonardo
- Darra, Francesca
- Termine, Cristiano
- Maserati, Emanuela
- Bigoni, Stefania
- Bottani, Armand
- Brusco, Alfredo
- Nitsch, Lucio
- Politi, Pierluigi
- Anderlid, Britt-Marie
- Zuffardi, Orsetta
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-07-14
- Volume
- 7
- Issue
- 7
- Pages
- e1002173
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3136441
- OpenAlex
- W2144839123
- Cited by
- 224
- References
- 51
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 11 · 2022: 15 · 2021: 28 · 2020: 16 · 2019: 10 · 2018: 51 · 2017: 12 · 2016: 11 · 2015: 15 · 2014: 13 · 2013: 10 · 2012: 21
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- IrInSubria (University of Insubria) (submittedVersion, other-oa)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Regione Lombardia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Phelan-McDermid syndrome, ring chromosomes, unbalanced translocation, interstitial deletion, breakpoint junctions, non-homologous end joining, microhomology-mediated break-induced replication, neurological deterioration
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Base Sequence, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 22, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Molecular Sequence Data, Parents, Ring Chromosomes, Translocation, Genetic, Sequence Deletion, Chromosome Disorders, Comparative Genomic Hybridization, Young Adult
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