22q13 deletion syndrome

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22q13 deletion syndrome
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22q13 deletion syndrome (spoken as twenty-two q one three[1]) 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) typical of a terminal deletion should be diagnosed as 22q13 deletion syndrome. 22q13 deletion syndrome is often placed in the more general category of Phelan-McDermid Syndrome (abbreviated PMS), which includes some mutations and microdeletions. The PMS name is less precise, since there is disagreement among researchers as to which variants belong in the PMS category.[2] The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that excludes terminal deletions.[3] This latter definition of PMS is incompatible with the definition of 22q13 deletion syndrome by those who first described 22q13 deletion syndrome.[4]

A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology, below).

22q13 deletion syndrome is characterized by global developmental delay, absent or severely delayed speech, and neonatal hypotonia.[4] There are approximately 1300 diagnosed cases of 22q13 deletion syndrome worldwide.

Characteristics

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

Behavioral

  • 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) %

Etiology

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 Kb (130,000 base pairs) to 9 Mb. Deletions smaller than 1 Mb are very rare (about 3%). The remaining 97% of terminal deletions impact about 30 to 190 genes (see list, below). At one time it was thought that deletion size was not related to the core clinical features.[5] 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.[6] Since then, twelve other genes on 22q13 (MAPK8IP2,[7] CHKB,[8] SCO2,[9] SBF1,[10] PLXNB2,[11] MAPK12,[12] PANX2,[13] BRD1,[14] CELSR1,[15] WNT7B,[16] TCF20[17]) have been associated with Autism Spectrum Disorder and/or Schizophrenia (see references below). Some mutations of SHANK3 mimic 22q13 deletion syndrome, but SHANK3 mutations and microdeletions have quite variable impact. Most mutations may not reflect loss of the entire gene.[18][19][20][21]

Some of the core features of 22q13 deletion syndrome are dependent upon deletion size, and do not depend on the loss of SHANK3.[22][23][24] As noted above, the distal 1 Mb of 22q is a gene rich region. There are too few clinical cases to statistically measure the relationship between deletion size and phenotype in this region. A landmark study of induced pluripotent stem cell neurons cultured from patients with 22q13 deletion syndrome shows that restoration of the SHANK3 protein levels can rescue fewer than half the glutamate neurons of neocortex, another indication of the strong impact of other genes in the distal 1 Mb of chromosome 22.[25]

There is an interest in the impact of MAPK8IP2 (also called IB2) in 22q13 deletion syndrome.[26] MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.[27] The genes SULT4A1[28] and PARVB[29] may cause 22q13 deletion syndrome in cases of more proximal interstitial and large terminal deletions.[24] There are about 187 protein coding genes in the 22q13 region.[30] A group of genes (MPPED1,[31] CYB5R3,[32] FBLN1,[33] NUP50,[34] C22orf9,[35] KIAA1644,[36] PARVB,[29] TRMU,[37] WNT7B[38] and ATXN10[39]), as well as microRNAs may all contribute to loss of language, a feature that varies notably with deletion size.[40] The same study found that macrocephaly seen in 22q13 deletion syndrome patients may be associated with WNT7B.

Table of protein coding genes involved in 22q13 deletion syndrome (based on Human Genome Browser – hg38 assembly [41]). Underline identifies 13 genes that are associated with autism.[42][43][44][45] Bold identifies genes associated with hypotonia (based on Human Phenotype Browser [46] search for 'hypotonia' and the OMIM database [47]).

RABL2B ACR SHANK3 ARSA MAPK8IP2 CHKB CPT1B SYCE3 KLHDC7B ODF3B TYMP SCO2
NCAPH2 LMF2 MIOX ADM2 SBF1 PPP6R2 DENND6B PLXNB2 MAPK11 MAPK12 HDAC10 TUBGCP6
SELO TRABD PANX2 MOV10L1 MLC1 IL17REL PIM3 CRELD2 ALG12 ZBED4 BRD1 FAM19A5
FLJ32756 TBC1D22A CERK GRAMD4 CELSR1 TRMU BC069212 GTSE1 TTC38 PKDREJ CDPF1 PPARA
WNT7B ATXN10 FBLN1 RIBC2 SMC1B FAM118A UPK3A KIAA0930 NUP50 PHF21B PRR5-ARHGAP8 LDOC1L
KIAA1644 PARVG TRNA_SeC PARVB SAMM50 PNPLA3 PNPLA5 SULT4A1 EFCAB6 MPPED1 SCUBE1 TTLL12
TSPO MCAT BIK TTLL1 PACSIN2 ARFGAP3 A4GALT ATP5L2 DL490307 CYB5R3 RNU12 POLDIP3
SERHL2 RRP7A NFAM1 TCF20 CYP2D6 NDUFA6 SMDT1 FAM109B NAGA WBP2NL CENPM TNFRSF13C
SHISA8 SREBF2 CCDC134 MEI1 C22orf46 NHP2L1 XRCC6 DESI1 PMM1 CSDC2 POLR3H ACO2
PHF5A TOB2 TEF ZC3H7B RANGAP1 CHADL L3MBTL2 EP300 RBX1 DNAJB7 XPNPEP3 ST13
SLC25A17 MCHR1 MKL1 SGSM3 ADSL TNRC6B FAM83F GRAP2 ENTHD1 CACNA1I RPS19BP1 ATF4
SMCR7L MGAT3 TAB1 SNORD43 RPL3 PDGFB CBX7 APOBEC3H APOBEC3F APOBEC3D APOBEC3C APOBEC3B
CBX6 NPTXR DNAL4 SUN2 GTPBP1 JOSD1 TOMM22 CBY1 FAM227A DMC1 DDX17 KDELR3
KCNJ4 CSNK1E TMEM184B MAFF MAFF PLA2G6 BAIAP2L2 SLC16A8 PICK1 SOX10 POLR2F C22orf23
MICALL1 EIF3L ANKRD54 GALR3 GCAT H1F0 TRIOBP NOL12 LGALS1 SH3BP1 GGA1 LGALS2
CDC42EP1 CARD10 MFNG ELFN2 CYTH4

Incidence

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

See also

Notes

  1. ^ Technically, it should be spoken as twenty-two q one three
  2. ^ "Letter to the editor regarding Disciglio et al.: interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome". Am J Med Genet A. 167 (7): 1679–80. 2015. doi:10.1002/ajmg.a.36788. PMID 26295085. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  3. ^ https://www.rarediseasesnetwork.org/cms/dsc/About-Us (downloaded 21-September-2015)
  4. ^ a b "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)". Mol Syndromol. 2 (1): 186–201. 2011. doi:10.1159/000334260. PMC 3366702. PMID 22670140. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  5. ^ "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. 2003. doi:10.1136/jmg.40.8.575. PMC 1735560. PMID 12920066. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  6. ^ "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. 2010. doi:10.1073/pnas.0906232107. PMC 2867875. PMID 20385823. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  7. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=MAPK8IP2&keywords=mapk8ip2
  8. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=CHKB&keywords=CHKB
  9. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=SCO2&keywords=sco2
  10. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=SBF1&keywords=SBF1
  11. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=PLXNB2&keywords=plxnb2
  12. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=MAPK12&keywords=mapk12
  13. ^ http://www.genecards.org/Search/Keyword?queryString=panx2
  14. ^ http://www.genecards.org/Search/Keyword?queryString=brd1
  15. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=CELSR1&keywords=CELSR1
  16. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=WNT7B&keywords=wnt7b
  17. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF20&keywords=tcf20
  18. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Zhou Y; et al. (2016). "Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects". Neuron. 89 (1). doi:10.1016/j.neuron.2015.11.023. PMID 26687841.
  20. ^ Jaramillo TC; et al. (2015). "Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism". Autism Res. doi:10.1002/jcph.679. PMID 26626443.
  21. ^ "Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals". J Neurochem ([Epub ahead of print]). 2016. doi:10.1111/jnc.13523. PMC 2867875. PMID 26725465. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  22. ^ "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. 2011. doi:10.1136/jmedgenet-2011-100225. PMID 21984749. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  23. ^ "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. 2013. doi:10.1002/ajmg.a.36358. PMID 24375995. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  24. ^ a b "Interstitial 22q13 Deletions Not Involving SHANK3 Gene: A New Contiguous Gene Syndrome". Am J Med Genet A. 164 (7): 1666–76. 2014. doi:10.1002/ajmg.a.36513. PMID 24700646. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=SULT4A1&search=a909593f05863155b816a8fb7654c03b
  29. ^ a b http://www.genecards.org/cgi-bin/carddisp.pl?gene=PARVB&search=6f331a34c3511163f07d03211274ad96
  30. ^ http://genome.ucsc.edu/
  31. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=MPPED1&search=af0348b2e8f8bbe07815c7c4c35e1f8e
  32. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=CYB5R3&search=f30516afb414af5d738f38bfdee0a8b4
  33. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=FBLN1&search=31c50040405215fff62221f468762f78
  34. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=NUP50&search=ebf7ec6b4ee48d75243c7b448aa489a8
  35. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=KIAA0930&search=7fe64f97e1b1ff3046fce6978ce05ceb
  36. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=KIAA1644&search=7699c1245c9f84709a4902cb2643f900
  37. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=TRMU&search=dfaeaec9ab390a77b7713cddf9e0d842
  38. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=WNT7B&search=b9a837acec2f26b76076ecd2d3887361
  39. ^ http://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN10&search=8085643553fd43eaabcf7fac1618ef13
  40. ^ 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.
  41. ^ https://genome.ucsc.edu/index.html
  42. ^ https://gene.sfari.org/autdb/HG_Home.do
  43. ^ Napoli E; et al. (2012). "Mitochondrial Dysfunction in Pten Haplo-Insufficient Mice with Social Deficits and Repetitive Behavior: Interplay between Pten and p53". PLoS One. 7 (8): 1–13. doi:10.1371/journal.pone.0042504. PMID 22900024.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  44. ^ Iossifov I; et al. (2015). "Low load for disruptive mutations in autism genes and their biased transmission". Proc Natl Acad Sci U S A. 112 (41): E5600-7. doi:10.1073/pnas.1516376112. PMID 26401017.
  45. ^ Davis LK; et al. (2012). "Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci". Mol Autism. 3 (1). doi:10.1186/2040-2392-3-3. PMID 22591576.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  46. ^ http://www.human-phenotype-ontology.org/
  47. ^ http://www.omim.org/

References

External links

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