22q13 deletion syndrome

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. Recent work indicates Phelan-McDermid Syndrome may also be caused by errors in a single gene (SHANK3/PROSAP2) in the q13.3 region. Errors on the same gene have been associated with Autism Spectrum Disorder (ASD).

This genetic disorder is characterized by general hypotonia, absent to delayed speech, and global developmental delays. There are approximately 600 reported cases of Phelan-McDermid Syndrome worldwide.

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%
• Dolichocephaly (elongated head): 57%
• Ptosis (eyelid) (droopy eyelids): 57%
• Poor thermoregulation: 51%

Behavioral

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

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.^[3]

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.^[4]
• 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 ^[5]

In 2006, a group led 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,^[6][7] a type of high-functioning autism.

Van Bokhoven et al. (1997)^[8] have also assigned the WNT7B gene to 22q13.^[9] Wnt7b acts through Dvl1 to the regulation of dendritic development.^[10] 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.^[3] Heterozygous knockout mice for Shank3 are viable.^[11] Bangash et al. created a gain-of-function transgenic mouse bearing a deletion at the C terminus of Shank3 that mimics clinical mutations and define a biochemical pathway linking mutant Shank3 to the proteasomal degradation of Shank3 and NMDA type glutamate receptors subunit NR1. PMID 21565394 The heterozygous mutant mice display autism-like behavioral deficits and also exhibit schizophrenia-like phenotypes, consistent with altered glutamate receptor function.^[12] Consistent with this, the mice have deficits in NMDA LTP, LTD and enhanced mGluR LTD similar to Fragile-X. These results suggest that NMDA receptor degradation could be a shared feature of both Autism and Schizophrenia. Homozygous PDZ domain knockout mice from another lab also display autistic-like behaviours and striatal dysfunction.^[13]

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.

See also

• 22q11.2 deletion syndrome

Notes

References

• Bonaglia MC, Giorda R, Mani E, et al. (2006). "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". J. Med. Genet. 43 (10): 822–8. doi:10.1136/jmg.2005.038604. PMC 2563164. PMID 16284256. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2563164. 
• Manning MA, Cassidy SB, Clericuzio C, et al. (2004). "Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum". Pediatrics 114 (2): 451–7. doi:10.1542/peds.114.2.451. PMID 15286229. http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=15286229. 
• Phelan MC, Rogers RC, Saul RA, et al. (2001). "22q13 deletion syndrome". Am. J. Med. Genet. 101 (2): 91–9. doi:10.1002/1096-8628(20010615)101:2<91::AID-AJMG1340>3.0.CO;2-C. PMID 11391650. 
• 22q13.org "22q13 deletion syndrome home"

External links

• DECIPHER database entry for 22q13 deletion syndrome
• GeneReviews: 22q13.3 deletion syndrome
• 22q13.org, Support group for families of children affected by the 22q13 deletion syndrome.
• Alliance22 (in French)