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Cited by 377Genomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental DisordersDown syndrome and intellectual disability research

Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms

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Wilson, H L, Wong, A C C, Shaw, S R, Tse, W-Y, Stapleton, G A, Phelan, M C, Hu, S, Marshall, J +1 more·2003·Journal of Medical Genetics
DOI 10.1136/jmg.40.8.575PMC PMC1735560
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Abstract

Methods : The 22q13 deletion syndrome (MIM 606232) is characterised by moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features. We have determined the deletion size and parent of origin in 56 patients with this syndrome. Results: Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions vary widely in size, from 130 kb to over 9 Mb; however all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene. The molecular structure of SHANK3 was further characterised. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate to deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. Conclusion : Our analysis therefore supports haploinsufficiency of the gene SHANK3 , which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome.

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  • Disruption of Shank3 is thought to cause the core neurodevelopmental and neurobehavioural deficits of 22q13 deletion syndrome (Phelan-McDermid syndrome), an autism spectrum disorder.

    “Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan-McDermid syndrome), an autism spectrum disorder9–11.”

    From Shank3 mutant mice display autistic-like behaviours and striatal dysfunction (2011) · cites this paper as [11]

  • Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders.

    “Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders.”

    From Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication (2010) · cites this paper as [22]

  • Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis.

    “Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis (Wilson et al., 2003).”

    From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wilson et al., 2003

  • SHANK3 maps to the critical region of 22q13.3 deletion syndrome (Phelan-McDermid syndrome).

    “SHANK3 maps to the critical region of 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMS) (Figure 1A) (Wilson et al., 2003).”

    From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wilson et al., 2003

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Research works printed but not linked: 8

  1. Botto LD, Campbell RM, Coleman K, Correa A, Elixson EM, Erickson JD, Fernhoff P, May K, Merritt R, O'Leary L, Rasmussen SA. A population-based study of the 22q11.2 deletion. Am J Hum Genet 2001;69:583A.
  2. Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, Shaw SR, Clayton J, Willis J, Kelly DP. 22q13 deletion syndrome. Am J Med Genet 2001;101:91-9.
  3. Goizet C, Excoffier E, Taine L, Taupiac E, El Moneim AA, Arveiler B, Bouvard M, Lacombe D. Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. Am J Med Genet 2000;96:839-44.
  4. Wilson H, Wong A, Tsi WY, McDermid HE. PROSAP2: a possible candidate gene for neurological abnormalities in the 22q13 deletion syndrome. Am J Hum Genet 2000;67:376.
  5. Zwaigenbaum L, Siegel-Bartelt J, Teshima I, Ho C. Two patients with 22q13.3 deletions have similar facies and developmental patterns. Am J Hum Genet 1990;47:A45.
  6. Eydoux P, Sanderson D, Treacy E, Scriver C, Teebi AS. HHH-like syndrome and dysmorphic features associated with 22q deletion. Am J Hum Genet 1996;59:A117.
  7. Feldman G, Wiktor A, Conard J, Van Dyke DL. Identification by FISH of a del(22)(q13.3) in a patient with de novo 22qs. Am J Hum Genet 1995;57:A113.
  8. Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. Preferential loss of the paternal alleles in the 18q-syndrome. Am J Med Genet 1997;69:280-6.

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Authors
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.
Affiliations
  • University of Alberta (CA)
  • Greenville Children's Hospital (US)
  • Greenwood Genetic Center (US)
  • Children’s Hospital at Erlanger (US)
Corresponding author
McDermid, H E
ORCID
Wilson, H L
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2003-08
Volume
40
Issue
8
Pages
575-584
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmg.40.8.575
PMC
PMC1735560
OpenAlex
W2172267891
Cited by
377
References
62
Citations by year
2026: 10 · 2025: 8 · 2024: 6 · 2023: 18 · 2022: 20 · 2021: 23 · 2020: 18 · 2019: 16 · 2018: 17 · 2017: 18 · 2016: 20 · 2015: 16 · 2014: 18 · 2013: 24 · 2012: 20
FWCI
5.28
Type
journal article
Language
en
Open access
Locations
  • Journal of Medical Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council Canada
  • Canadian Institutes of Health Research
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
22q13 deletion syndrome, SHANK3, haploinsufficiency, paternal uniparental disomy, deletion size, intellectual disability, speech delay, postsynaptic density, parent of origin
MeSH terms
Base Sequence, Carrier Proteins, Developmental Disabilities, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 22, Female, Haplotypes, Humans, Infant, Language Development Disorders, Male, Intellectual Disability, Molecular Sequence Data, Nerve Tissue Proteins, Patents as Topic, Phenotype, Syndrome, Cytogenetic Analysis

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