22q13 deletion syndrome

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22q13 Deletion Syndrome
Classification and external resources
ICD-10 Q93
OMIM 606232

22q13 Deletion syndrome (spoken as twenty-two q thirteen[1]), also known as Phelan-McDermid syndrome (abbreviated PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Some terminal deletions can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small (microdeletions). The availability of DNA microarray technology, and microarray's utility in looking for multiple genetic problems simultaneously, have made this technology the diagnostic tool of choice. However, fluorescence in situ hybridization (FISH) tests are valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenetic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology, below).

Phelan-McDermid syndrome is characterized by global developmental delay, absent or severely delayed speech, and neonatal hypotonia.[2] There are approximately 600 reported cases of Phelan-McDermid syndrome worldwide.

Characteristics[edit]

The core characteristics of 22q13 Deletion syndrome (listed above) have a major impact on the individual. However, in addition to these characteristics, there are other manifestations than may range from mild to severe:

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[edit]

Various deletions affect 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 terminal deletion is variable and can go from 130 kbp (130,000 base pairs) to 9 Mbp (9,000,000 base pairs). At one time it was thought that deletion size was not related to the core clinical features.[3] That observation lead to an emphasis on the SHANK3 gene, which resides close to the terminal end of chromosome 22. Interest in SHANK3 grew as it became associated with Autism Spectrum Disorder (ASD) and Schizophrenia.[4] At one point, it was suggested that Phelan-McDermid syndrome was a monogenetic genetic disorder. Although appealing, this hypothesis has not held up. Recent studies with larger cohorts demonstrate that the core features do depend upon deletion size.[5] Further, there are now just as many published cases of Phelan-McDermid syndrome that do not affect SHANK3 as there are published cases of localized SHANK3 deletions/mutations. [6] [7] A landmark study of iPS neurons cultured from patients with Phelan-McDermid syndrome shows that restoration of the SHANK3 protein levels can rescue fewer than half the glutamate neurons of neocortex.[8]

Although SHANK3 is probably important in rare cases of PMS (e.g., terminal deletions smaller than about 130 kbp), there is growing interest in the MAPK8IP2 (also called IB2) lost in most cases of Phelan-McDermid syndrome.[9] MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.[10] The genes SULT4A1 and PARVB may cause Phelan-McDermid syndrome in cases of more proximal interstitial and large terminal deletions.[11] There are over 250 known genes and gene regulator sites in the 22q13 region.[12] A group of genes (MPPED1, CYB5R3, FBLN1, NUP50, C22orf9, KIAA1644, PARVB, TRMU, WNT7B and ATXN10), as well as microRNAs may all contribute to loss of language, a feature that generally varies with deletion size.[13] The same study found that macrocephaly seen in Phelan-McDermid syndrome patients may be associated with WNT7B.


Incidence[edit]

The incidence of the 22q13 deletion syndrome is uncertain. The National Institutes of Health Office of Rare Diseases (http://rarediseases.info.nih.gov/) lists Phelan-McDermid syndrome as a rare disease.

See also[edit]

Notes[edit]

  1. ^ Technically, it should be spoken as twenty-two q one three
  2. ^ Phelan MC, McDermid HE (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome).". Mol Syndromol. 2 (1): 186–201. doi:10.1159/000334260. PMID 22670140. 
  3. ^ Wilson HL, Wong AC, Shaw SR, et al. (2003). "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms". J. Med. Genet. 40 (8): 575–84. doi:10.1136/jmg.40.8.575. PMC 1735560. PMID 12920066. 
  4. ^ Gauthier et al. (2010). "De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.". Proc. Natl. Acad. Sci. USA 107 (17): 7863–8. doi:10.1073/pnas.0906232107. PMID 20385823. 
  5. ^ Sarasua SM et al. (2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).". J Med Genet. 48 (11): 761–6. doi:10.1136/jmedgenet-2011-100225. PMID 21984749. 
  6. ^ Simenson K et al. (2013). "A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region.". Am J Med Genet A. doi:10.1002/ajmg.a.36358. PMID 24375995. 
  7. ^ Disciglio V et al. (2014). "Interstitial 22q13 Deletions Not Involving SHANK3 Gene: A New Contiguous Gene Syndrome.". Am J Med Genet A. doi:10.1002/ajmg.a.36513. PMID 24700646. 
  8. ^ Shcheglovitov A et al. (2013). "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.". Nature 503 (7475): 267–71. doi:10.1038/nature12618. PMID 24132240. 
  9. ^ Aldinger KA et al. (2013). "Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion.". Am J Med Genet A 161 (1): 131–6. doi:10.1002/ajmg.a.35700. PMID 23225497. 
  10. ^ Giza J et al. (2010). "Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2.". J Neurosci. 30 (44): 14805–16. doi:10.1523/JNEUROSCI.1161-10.2010. PMC 3200367. PMID 21048139. 
  11. ^ Disciglio V et al. (2014). "Interstitial 22q13 Deletions Not Involving SHANK3 Gene: A New Contiguous Gene Syndrome.". Am J Med Genet A. doi:10.1002/ajmg.a.36513. PMID 24700646. 
  12. ^ http://genome.ucsc.edu/
  13. ^ Sarasua SM et al. (2014). "Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome.". Human Genetics. doi:10.1007/s00439-014-1423-7. PMID 24481935. 

References[edit]

External links[edit]