22q13 deletion syndrome

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22q13 deletion syndrome
Classification and external resources
OMIM 606232

22q13 Deletion Syndrome (spoken as twenty two q one three), also known as Phelan-McDermid Syndrome, is a genetic disorder caused by a microdeletion on chromosome 22. The deletion occurs at the terminal end of the chromosome at the location designated q13.3. This microdeletion is rarely uncovered by typical genetic screening, therefore a fluorescence in situ hybridization, or FISH, test is recommended to confirm the diagnosis.

This genetic disorder is characterized by general hypotonia, absent to delayed speech, and global developmental delays. It has a prevalence estimated at 2.5-10 per million births, though this is thought to be a gross underestimate[citation needed].

Contents

[edit] Characteristics

Individuals with a 22q13 deletion can suffer from a range of symptoms, with mild to very serious physical and behavioral characteristics. Possible symptoms are[1]:

Physical

  • Absent to severely delayed speech: 99%
  • Hypotonia (poor muscle tone): 97%
  • Normal to accelerated growth: 95%
  • Increased tolerance to pain: 86%
  • Thin, flaky toenails: 78%
  • Large, fleshy hands: 68%
  • Prominent, poorly formed ears: 65%
  • Pointed chin: 62%
  • Dolicocephaly (elongated head): 57%
  • Ptosis (droopy eyelids): 57%
  • Tendency to overheat and lack of perspiration: 51%

Behavioral

  • Chewing on non food items (clothing, bedding, toys):70%
  • Teeth grinding: (percent undetermined)
  • Tongue thrusting: (percent undetermined)
  • Hair pulling: (percent undetermined)
  • Aversion to clothes: (percent undetermined)
  • Autistic behaviors: (percent undetermined)

[edit] Etiology

The deletion affects the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases), from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the deletion is variable and can go from 130kbp (130,000 base pairs) to 9Mbp (9,000,000 base pairs). While some clinical signs correlate with the size of the deletion, the main traits of the syndrome appear to be independent of the deletion size, and only related to the presence of the Shank3 gene [2]. The haploinsufficiency of Shank3 is thought to be the responsible for the neurological deficits of the syndrome (Wilson et al., 2003).

The proteins encoded by the Shank genes assemble glutamate receptors with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density. They are important for the formation and stabilisation of synapses:

  • Experimentally induced expression of Shank3 has been shown to be sufficient to induce functional dendritic spines in aspiny cerebellar neurons (Roussignol et al., 2005).
  • Neural network activity up- or down regulates large groups of postsynaptic proteins through ubiquitin-mediated protein degradation. Shank proteins were identified as one of the few postsynaptic density proteins that can be degraded by ubiquitination (Waites et al., 2005)

In 2006, a group lead by Thomas Bourgeron from the Pasteur Institute in France, found anomalies of the 22q13 locus in five children with diagnosis of autism and Asperger syndrome. While the absence of the Shank3 gene was found in children with the typical characteristics of the Phelan-McDermid syndrome, its duplication was found in one child diagnosed with Asperger syndrome,[3][4] a type of high-functioning autism.

Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13 [5]. Wnt7b acts through Dvl1 to the regulation of dendritic development. Rosso et al. (2005) found that its overexpression resulted in increased dendritic branching in cultured mouse hippocampal neurons. Knockout mice for Dvl1 are viable, fertile and structurally normal, but show reduced social interaction and abnormal sleeping patterns (Lijam et al, 1997)

[edit] Incidence

The incidence of the 22q13 deletion syndrome is uncertain. The advanced genetic technique essential for diagnosis, fluorescent in situ hybridization (FISH), has only been available since 1998, and currently requires specialized laboratory facilities. Current thinking is that 22q13 deletion syndrome remains largely under-diagnosed, and may be one of the principal causes of idiopathic mental retardation.

[edit] See also

[edit] Notes

  1. ^ 22q13 Deletion Syndrome / Phelan-McDermid Syndrome
  2. ^ SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3
  3. ^ Gene linked to autism discovered
  4. ^ Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders
  5. ^ WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 7B; WNT7B

[edit] References

  • Bonaglia MC, Giorda R, Mani E, Aceti G, Anderlid BM, Baroncini A, Pramparo T, Zuffardi O (2005) Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet (Epub ahead of print) PMID 16284256.
  • Manning MA, Cassidy SB, Clericuzio C, Cherry AM, Schwartz S, Hudgins L, Enns GM, Hoyme HE (2004) Pediatrics 114(2):451-7. PMID 15286229
  • Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, Shaw SR, Claytor J, Willis J, Kelly DP (2001) 22q13 deletion syndrome. Am J Med Genet, Vol. 101, No. 2., pp. 91-99. PMID 11391650.
  • Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nature Neurosci. 8: 34-42, 2005. PMID 15608632
  • Roussignol G, Ango F, Romorini S, Tu JC, Sala C, Worley PF, Bockaert J, Fagni L (2005) Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci, Vol. 25, No. 14., pp. 3560-3570. PMID 15814786
  • Van Bokhoven H, Kissing J, Schepens M, van Beersum S, Simons A, Riegman P, McMahon J A, McMahon AP, Brunner HG (1997) Assignment of WNT7B to human chromosome band 22q13 by in situ hybridization. Cytogenet. Cell Genet. 77: 288-289. PMID 9284940
  • Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci, Vol. 28, pp. 251-274. PMID 16022596.
  • Wilson HL, Wong ACC, Shaw SR, Tse WY, Stapleton GA, Phelan MC, Hu S, Marshall J, McDermid HE (2003) Molecular characerisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSASP2 in the major neurological symptoms. J Med Genet 40:575-584. PMID 12920066
  • 22q13.org "22q13 deletion syndrome home"

[edit] External links