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Schizophrenia 4(SCZD4)

MedGen UID:
371517
Concept ID:
C1833247
Disease or Syndrome
Synonyms: SCHIZOPHRENIA SUSCEPTIBILITY LOCUS, CHROMOSOME 22q11-RELATED; SCHIZOPHRENIA, SUSCEPTIBILITY TO, 4; SCZD4
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): PRODH (22q11.21)
OMIM®: 600850

Clinical features

Schizophrenia
MedGen UID:
48574
Concept ID:
C0036341
Mental or Behavioral Dysfunction
Schizophrenia is highly heritable, as shown by family, twin, and adoption studies. For example, for identical twins, if one twin develops schizophrenia, the other twin has about a 50% chance of also developing the disease. The risk of the general population developing the schizophrenia is about 0.3-0.7% worldwide. The search for “schizophrenia genes” has been elusive. Initial linkage studies looked at parts of the genome associated with schizophrenia, and many candidate genes were identified, including APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53, and TPH1. However, some of these have later been questioned. Microdeletions and microduplications have been found to be three times more common in individuals with schizophrenia, compared to controls. Because these deletions and duplications are in genes that are overexpressed in pathways related to brain development, it is possible that the inheritance of multiple rare variants may contribute to the development of schizophrenia. Several genetic disorders feature schizophrenia as a clinical feature. The 22q11.2 Deletion Syndrome comprises many different syndromes, of which one of the most serious is DiGeorge syndrome. Children born with DiGeorge syndrome typically have heart defects, cleft palate, learning difficulties, and immune deficiency. Schizophrenia is a late manifestation, affecting around 30% of individuals. Microdeletions and duplications in chromosome 1, 2, 3, 7, 15 and 16 have also been associated with schizophrenia. In 2014, a genome-wide association study looked at the genomes of over 35,000 patients and 110,00 controls. The study identified 108 SNPs that were associated with schizophrenia, 83 of which had not been previously reported. As expected, many of these loci occurred in genes that are expressed in the brain. For example, the SNPs included a gene that encodes the dopamine D2 receptor, DRD2 (the target of antipsychotic drugs), and many genes involved in glutamine neurotransmitter pathways and synaptic plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1). More surprisingly, however, associations were also enriched among genes expressed in tissues with important immune functions. In 2016, a study based on nearly 65,000 people investigated the association between schizophrenia and variation in the Major Histocompatibility Complex (MHC) locus—a region on chromosome 6 that is important for immune function. The study focused on the C4 gene (complement component 4) that exists as two distinct genes: C4A and C4B, which encode particularly structurally diverse alleles. The study found that the alleles which promoted greater expression of C4A in the brain were associated with a greater risk of schizophrenia. By using mice models, the study showed that C4 is involved in the elimination of synapses during brain maturation. In humans, “synaptic pruning” is most active during late adolescence, which coincides with the typical onset of symptoms of schizophrenia. It is therefore possible that the inheritance of specific C4A alleles could lead to “run away” synaptic pruning, increasing the risk of schizophrenia. Further research may even determine C4 as a potential therapeutic target.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding

Recent clinical studies

Etiology

Misawa F, Suzuki T, Fujii Y
J Clin Psychopharmacol 2017 Dec;37(6):664-668. doi: 10.1097/JCP.0000000000000798. PMID: 29045304
Friedman JH
Clin Neuropharmacol 2017 Jul/Aug;40(4):157-159. doi: 10.1097/WNF.0000000000000219. PMID: 28622212
Karbasforoushan H, Woodward ND
Curr Top Med Chem 2012;12(21):2404-14. PMID: 23279179
Sarlon E, Duburcq A, Neveu X, Morvan-Duru E, Tremblay R, Rouillon F, Falissard B
Rev Epidemiol Sante Publique 2012 Jun;60(3):197-203. Epub 2012 May 16 doi: 10.1016/j.respe.2011.11.001. PMID: 22608012
Robinson DG, Woerner MG, Napolitano B, Patel RC, Sevy SM, Gunduz-Bruce H, Soto-Perello JM, Mendelowitz A, Khadivi A, Miller R, McCormack J, Lorell BS, Lesser ML, Schooler NR, Kane JM
Am J Psychiatry 2006 Dec;163(12):2096-102. doi: 10.1176/ajp.2006.163.12.2096. PMID: 17151160

Diagnosis

Friedman JH
Clin Neuropharmacol 2017 Jul/Aug;40(4):157-159. doi: 10.1097/WNF.0000000000000219. PMID: 28622212
Nesvåg R, Jönsson EG, Bakken IJ, Knudsen GP, Bjella TD, Reichborn-Kjennerud T, Melle I, Andreassen OA
BMC Psychiatry 2017 Mar 14;17(1):93. doi: 10.1186/s12888-017-1256-8. PMID: 28292279Free PMC Article
Golenkov A, Large M, Nielssen O, Tsymbalova A
Asian J Psychiatr 2016 Oct;23:87-92. Epub 2016 Jul 20 doi: 10.1016/j.ajp.2016.07.015. PMID: 27969086
Sarlon E, Duburcq A, Neveu X, Morvan-Duru E, Tremblay R, Rouillon F, Falissard B
Rev Epidemiol Sante Publique 2012 Jun;60(3):197-203. Epub 2012 May 16 doi: 10.1016/j.respe.2011.11.001. PMID: 22608012
Josman N, Schenirderman AE, Klinger E, Shevil E
Schizophr Res 2009 Dec;115(2-3):270-7. Epub 2009 Oct 22 doi: 10.1016/j.schres.2009.09.015. PMID: 19850451

Therapy

Chu KY, Huang CY, Ouyang WC
BMC Psychiatry 2018 Mar 7;18(1):62. doi: 10.1186/s12888-018-1611-4. PMID: 29514660Free PMC Article
Misawa F, Suzuki T, Fujii Y
J Clin Psychopharmacol 2017 Dec;37(6):664-668. doi: 10.1097/JCP.0000000000000798. PMID: 29045304
Friedman JH
Clin Neuropharmacol 2017 Jul/Aug;40(4):157-159. doi: 10.1097/WNF.0000000000000219. PMID: 28622212
Sarlon E, Duburcq A, Neveu X, Morvan-Duru E, Tremblay R, Rouillon F, Falissard B
Rev Epidemiol Sante Publique 2012 Jun;60(3):197-203. Epub 2012 May 16 doi: 10.1016/j.respe.2011.11.001. PMID: 22608012
Robinson DG, Woerner MG, Napolitano B, Patel RC, Sevy SM, Gunduz-Bruce H, Soto-Perello JM, Mendelowitz A, Khadivi A, Miller R, McCormack J, Lorell BS, Lesser ML, Schooler NR, Kane JM
Am J Psychiatry 2006 Dec;163(12):2096-102. doi: 10.1176/ajp.2006.163.12.2096. PMID: 17151160

Prognosis

Wangel AM, Molin J, Moghaddassi M, Stman M
J Psychosom Obstet Gynaecol 2011 Dec;32(4):189-97. Epub 2011 Oct 31 doi: 10.3109/0167482X.2011.626940. PMID: 22040006
Kawakubo Y, Suga M, Tochigi M, Yumoto M, Itoh K, Sasaki T, Kano Y, Kasai K
PLoS One 2011;6(10):e24929. Epub 2011 Oct 11 doi: 10.1371/journal.pone.0024929. PMID: 22022368Free PMC Article
Nordentoft M, Mortensen PB, Pedersen CB
Arch Gen Psychiatry 2011 Oct;68(10):1058-64. doi: 10.1001/archgenpsychiatry.2011.113. PMID: 21969462
Crespo-Facorro B, Pelayo-Terán JM, Pérez-Iglesias R, Ramírez-Bonilla M, Martínez-García O, Pardo-García G, Vázquez-Barquero JL
J Psychiatr Res 2007 Oct;41(8):659-66. Epub 2006 Jun 23 doi: 10.1016/j.jpsychires.2006.05.002. PMID: 16797591
Robinson DG, Woerner MG, Napolitano B, Patel RC, Sevy SM, Gunduz-Bruce H, Soto-Perello JM, Mendelowitz A, Khadivi A, Miller R, McCormack J, Lorell BS, Lesser ML, Schooler NR, Kane JM
Am J Psychiatry 2006 Dec;163(12):2096-102. doi: 10.1176/ajp.2006.163.12.2096. PMID: 17151160

Clinical prediction guides

Wang R, Wang Y, Hu R, Chen X, Song M, Wang X
Neurosci Lett 2015 Oct 8;606:220-4. Epub 2015 Sep 10 doi: 10.1016/j.neulet.2015.09.010. PMID: 26365407
Degli Esposti L, Sangiorgi D, Mencacci C, Spina E, Pasina C, Alacqua M, la Tour F
BMC Psychiatry 2014 Oct 14;14:282. doi: 10.1186/s12888-014-0282-z. PMID: 25312446Free PMC Article
Nordgaard J, Parnas J
Schizophr Bull 2014 Nov;40(6):1300-7. Epub 2014 Jan 29 doi: 10.1093/schbul/sbt239. PMID: 24476579Free PMC Article
Karbasforoushan H, Woodward ND
Curr Top Med Chem 2012;12(21):2404-14. PMID: 23279179
Robinson DG, Woerner MG, Napolitano B, Patel RC, Sevy SM, Gunduz-Bruce H, Soto-Perello JM, Mendelowitz A, Khadivi A, Miller R, McCormack J, Lorell BS, Lesser ML, Schooler NR, Kane JM
Am J Psychiatry 2006 Dec;163(12):2096-102. doi: 10.1176/ajp.2006.163.12.2096. PMID: 17151160

Recent systematic reviews

Chu KY, Huang CY, Ouyang WC
BMC Psychiatry 2018 Mar 7;18(1):62. doi: 10.1186/s12888-018-1611-4. PMID: 29514660Free PMC Article
Wang AK, Miller BJ
Schizophr Bull 2018 Jan 13;44(1):75-83. doi: 10.1093/schbul/sbx035. PMID: 28338954Free PMC Article
Desmedt M, Vertriest S, Hellings J, Bergs J, Dessers E, Vankrunkelsven P, Vrijhoef H, Annemans L, Verhaeghe N, Petrovic M, Vandijck D
Value Health 2016 Sep - Oct;19(6):892-902. Epub 2016 Jun 29 doi: 10.1016/j.jval.2016.05.001. PMID: 27712719
Armenteros JL, Davies M
Eur Child Adolesc Psychiatry 2006 Mar;15(3):141-8. Epub 2006 Feb 9 doi: 10.1007/s00787-005-0515-2. PMID: 16470340
Jönsson EG, Flyckt L, Burgert E, Crocq MA, Forslund K, Mattila-Evenden M, Rylander G, Asberg M, Nimgaonkar VL, Edman G, Bjerkenstedt L, Wiesel FA, Sedvall GC
Psychiatr Genet 2003 Mar;13(1):1-12. doi: 10.1097/01.ypg.0000051094.88669.4b. PMID: 12605094

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