The deletion of the tip of the chromosome 22 is related to autistic behaviour, moderate to severe developmental delay and mental retardation. It is known as 22q13 deletion syndrome or Phelan-McDermid syndrome. A genetic deletion is a genetic aberration in which part of a chromosome is missing. ... Chromosome 22 is one of the 23 pairs of chromosomes in humans. ... Autism is classified by the World Health Organization (WHO) and American Psychological Association as a developmental disability that results from a disorder of the human central nervous system. ... Mental retardation is a term for a pattern of persistently slow learning of basic motor and language skills (milestones) during childhood, and a significantly below-normal global intellectual capacity as an adult. ...

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 ^[1]. The haploinsufficiency of Shank3 is thought to be the responsible for the neurological deficits of the syndrome (Wilson et al., 2003). A genetic deletion is a genetic aberration in which part of a chromosome is missing. ... Figure 1: A representation of a condensed eukaryotic chromosome, as seen during cell division. ... A father is the male parent of a child. ... In genetics, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair (often abbreviated bp). ... Haploinsufficiency occurs when a diploid organism only has a single copy of a wild-type gene, with the other copy being inactivated by hereditary mutation or another mechanism. ...

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: Glutamate is a neurotransmitter in nerve cells which binds to all glutamate receptors located on neuron membranes, and is an example of a transmembrane receptor. ... The postsynaptic density (PSD) is a cytoskeletal specialization at neuronal synapses that was originally identified as an electron-dense region at the membrane of a postsynaptic neuron, as viewed by electron microscopy. ... Illustration of the major elements in a prototypical synapse. ...

• 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 Institut Pasteur 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 children diagnosed with Asperger's Syndrome^[2][3], a type of high functioning autism. Close up of the dendrite of a striatal medium spiny neuron. ... Ubiquitin is a very conserved small regulatory protein that is ubiquitous in eukaryotes. ... The postsynaptic density (PSD) is a cytoskeletal specialization at neuronal synapses that was originally identified as an electron-dense region at the membrane of a postsynaptic neuron, as viewed by electron microscopy. ... Ubiquitin is a very conserved small regulatory protein that is ubiquitous in eukaryotes. ... Asperger described his patients as little professors. Aspergers syndrome (AS, or the more common shorthand Aspergers), is characterized as one of the five pervasive developmental disorders, and is commonly referred to as a form of high functioning autism. ... High-functioning autism (HFA) is the condition of individuals who display symptoms of autism and are able to function close to a normal level in society. ...

Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13.3 ^[4]. 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)

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 (Manning and al. 2004). A metaphase cell positive for the bcr/abl rearrangement using FISH. The chromosomes can be seen in blue. ...

Description

Almost all children affected by the 22q13 deletion have absent or severely delayed speech. They exhibit only minor facial dysmorphism; thin, flaky toenails (78%); large, fleshy hands (68%); large feet; prominent, poorly formed ears (65%); and other characteristics which are not visually apparent: hypotonia (97%); normal to accelerated growth (95%); increased tolerance to pain (86%); seizures (unknown percentage); strabismus; anomalies of the spine; poor central vision [1]. A deformity, dysmorphism, or dysmorphic feature is a major difference in the shape of the body a body part, or a body organ (internal or external) compared to the average shape for the part in question. ...

These are videos of children with 22q13del

See also

• 22q11.2 deletion syndrome
• http://www.alliance22.org
• http://monsite.orange.fr/le-monde-de-camille/

22q11. ...

References and Sources

• 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"

Notes

External links

• 22q13.org "22q13 deletion syndrome home" Support group for families of children affected by the 22q13 deletion syndrome.
• "Chromosome 22 central" Description and Full-text links to related articles.
• "The rare chromosome disorder group support". Support group for rare chromosome disorders in the UK.
• Emory University Genetic Challenge Would you be able to diagnose a 22q13 deletion? Take the genetic challenge!