22q13 deletion syndrome

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22q13 Deletion Syndrome
Classification and external resources
Specialty medical genetics
ICD-10 Q93
OMIM 606232
DiseasesDB 34793
MeSH C536801

22q13 Deletion syndrome (spoken as twenty-two q one three[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. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) should be diagnosed as PMS. 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 1000 diagnosed cases of Phelan-McDermid Syndrome worldwide.


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:



  • Chewing on non food items: 85%
  • Delayed or unreliable toileting: 76%
  • Impulsive behaviors: 47%
  • Biting (self or others): 46%
  • Problems sleeping: 46%
  • Hair pulling: 41%
  • Autistic behaviors: 31%
  • Episodes of non-stop crying before age 5: 30%
  • Teeth grinding: (unknown) %


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] SHANK3 mutations and microdeletions can produce a phenotype similar to PMS. However, recent work suggests that the phenotype associated with SHANK3 microdeletions and mutations may result from a molecular mechanism very different from that originally described for PMS. The phenotype may result from an over-expression of isoforms (e.g., Shank3b and Shank3e) that interfere with spine development.[5] The mechanism of PMS is whole gene loss (haploinsufficiency).

The core features of PMS depend upon deletion size (dosage dependent) and does not depend on the loss of SHANK3.[6][7][8] 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, another indication of the dosage-dependence effects of other genes on chromosome 22.[9]

There is growing interest in the impact of MAPK8IP2 (also called IB2), lost in most cases of Phelan-McDermid syndrome.[10] MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.[11] The genes SULT4A1[12] and PARVB[13] may cause Phelan-McDermid syndrome in cases of more proximal interstitial and large terminal deletions.[8] There are over 250 known genes and gene regulator sites in the 22q13 region.[14] A group of genes (MPPED1,[15] CYB5R3,[16] FBLN1,[17] NUP50,[18] C22orf9,[19] KIAA1644,[20] PARVB,[13] TRMU,[21] WNT7B[22] and ATXN10[23]), as well as microRNAs may all contribute to loss of language, a feature that generally varies with deletion size.[24] The same study found that macrocephaly seen in Phelan-McDermid syndrome patients may be associated with WNT7B.


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]


  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. PMC 3366702. 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. PMC 2867875. PMID 20385823. 
  5. ^ Wang X et al. (2014). "Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice.". Mol Autism 5 (30). doi:10.1186/2040-2392-5-30. PMID 25071925. 
  6. ^ 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. 
  7. ^ 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. 164A (3): 806–9. doi:10.1002/ajmg.a.36358. PMID 24375995. 
  8. ^ a b Disciglio V et al. (2014). "Interstitial 22q13 Deletions Not Involving SHANK3 Gene: A New Contiguous Gene Syndrome.". Am J Med Genet A. 164 (7): 1666–76. doi:10.1002/ajmg.a.36513. PMID 24700646. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=SULT4A1&search=a909593f05863155b816a8fb7654c03b
  13. ^ a b http://www.genecards.org/cgi-bin/carddisp.pl?gene=PARVB&search=6f331a34c3511163f07d03211274ad96
  14. ^ http://genome.ucsc.edu/
  15. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=MPPED1&search=af0348b2e8f8bbe07815c7c4c35e1f8e
  16. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=CYB5R3&search=f30516afb414af5d738f38bfdee0a8b4
  17. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=FBLN1&search=31c50040405215fff62221f468762f78
  18. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=NUP50&search=ebf7ec6b4ee48d75243c7b448aa489a8
  19. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=KIAA0930&search=7fe64f97e1b1ff3046fce6978ce05ceb
  20. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=KIAA1644&search=7699c1245c9f84709a4902cb2643f900
  21. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=TRMU&search=dfaeaec9ab390a77b7713cddf9e0d842
  22. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=WNT7B&search=b9a837acec2f26b76076ecd2d3887361
  23. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN10&search=8085643553fd43eaabcf7fac1618ef13
  24. ^ Sarasua SM et al. (2014). "Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome.". Human Genetics 133 (7): 847–59. doi:10.1007/s00439-014-1423-7. PMID 24481935. 


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