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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
 
Gene (location): PRODH (22q11.21)
 
Monarch Initiative: MONDO:0010943
OMIM®: 600850

Definition

A schizophrenia that has material basis in an autosomal dominant mutation of PRODH on chromosome 22q11.21. [from MONDO]

Clinical features

From HPO
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.
Hyperprolinemia
MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
An increased concentration of proline in the blood.

Professional guidelines

PubMed

Manninen M, Koivukangas J, Holm M, Lindgren M
Child Abuse Negl 2022 Sep;131:105765. Epub 2022 Jun 25 doi: 10.1016/j.chiabu.2022.105765. PMID: 35763955
Chang ET, Zulman DM, Nelson KM, Rosland AM, Ganz DA, Fihn SD, Piegari R, Rubenstein LV
JAMA Netw Open 2020 Jun 1;3(6):e208120. doi: 10.1001/jamanetworkopen.2020.8120. PMID: 32597993Free PMC Article
Ajnakina O, Horsdal HT, Lally J, MacCabe JH, Murray RM, Gasse C, Wimberley T
Schizophr Res 2018 Jul;197:294-297. Epub 2018 Feb 19 doi: 10.1016/j.schres.2018.02.017. PMID: 29472163

Recent clinical studies

Etiology

Lan KC, Chiang HJ, Huang TL, Chiou YJ, Hsu TY, Ou YC, Yang YH
J Assist Reprod Genet 2021 Jan;38(1):85-93. Epub 2020 Aug 30 doi: 10.1007/s10815-020-01936-x. PMID: 32862335Free PMC Article
Nagel M, Jansen PR, Stringer S, Watanabe K, de Leeuw CA, Bryois J, Savage JE, Hammerschlag AR, Skene NG, Muñoz-Manchado AB; 23andMe Research Team, White T, Tiemeier H, Linnarsson S, Hjerling-Leffler J, Polderman TJC, Sullivan PF, van der Sluis S, Posthuma D
Nat Genet 2018 Jul;50(7):920-927. Epub 2018 Jun 25 doi: 10.1038/s41588-018-0151-7. PMID: 29942085
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
Karbasforoushan H, Woodward ND
Curr Top Med Chem 2012;12(21):2404-14. doi: 10.2174/156802612805289863. PMID: 23279179
Silverstein SM, Bellack AS
Clin Psychol Rev 2008 Oct;28(7):1108-24. Epub 2008 Mar 18 doi: 10.1016/j.cpr.2008.03.004. PMID: 18420322

Diagnosis

Lu W, Srijeyanthan J, Mueser KT, Yanos PT, Parrott JS, Siriram A, Gottlieb JD, Marcello S, Silverstein SM
Psychiatry Res 2022 Nov;317:114892. Epub 2022 Oct 13 doi: 10.1016/j.psychres.2022.114892. PMID: 36257204
Lan KC, Chiang HJ, Huang TL, Chiou YJ, Hsu TY, Ou YC, Yang YH
J Assist Reprod Genet 2021 Jan;38(1):85-93. Epub 2020 Aug 30 doi: 10.1007/s10815-020-01936-x. PMID: 32862335Free PMC Article
Zheng W, Li W, Qi H, Xiao L, Sim K, Ungvari GS, Lu XB, Huang X, Ning YP, Xiang YT
J Affect Disord 2020 Apr 15;267:123-130. Epub 2020 Jan 21 doi: 10.1016/j.jad.2020.01.096. PMID: 32063563
Harvey PD, Khan A, Atkins A, Walker TM, Keefe RSE
Schizophr Res 2019 Aug;210:30-38. Epub 2019 Jun 10 doi: 10.1016/j.schres.2019.05.040. PMID: 31196736
Silverstein SM, Bellack AS
Clin Psychol Rev 2008 Oct;28(7):1108-24. Epub 2008 Mar 18 doi: 10.1016/j.cpr.2008.03.004. PMID: 18420322

Therapy

Adachi N, Ito M
Epilepsy Behav 2022 Feb;127:108520. Epub 2022 Jan 6 doi: 10.1016/j.yebeh.2021.108520. PMID: 34999502
Zheng W, Li W, Qi H, Xiao L, Sim K, Ungvari GS, Lu XB, Huang X, Ning YP, Xiang YT
J Affect Disord 2020 Apr 15;267:123-130. Epub 2020 Jan 21 doi: 10.1016/j.jad.2020.01.096. PMID: 32063563
Nagel M, Jansen PR, Stringer S, Watanabe K, de Leeuw CA, Bryois J, Savage JE, Hammerschlag AR, Skene NG, Muñoz-Manchado AB; 23andMe Research Team, White T, Tiemeier H, Linnarsson S, Hjerling-Leffler J, Polderman TJC, Sullivan PF, van der Sluis S, Posthuma D
Nat Genet 2018 Jul;50(7):920-927. Epub 2018 Jun 25 doi: 10.1038/s41588-018-0151-7. PMID: 29942085
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
Turkington D, Kingdon D, Weiden PJ
Am J Psychiatry 2006 Mar;163(3):365-73. doi: 10.1176/appi.ajp.163.3.365. PMID: 16513854

Prognosis

Lu W, Srijeyanthan J, Mueser KT, Yanos PT, Parrott JS, Siriram A, Gottlieb JD, Marcello S, Silverstein SM
Psychiatry Res 2022 Nov;317:114892. Epub 2022 Oct 13 doi: 10.1016/j.psychres.2022.114892. PMID: 36257204
Chang ET, Zulman DM, Nelson KM, Rosland AM, Ganz DA, Fihn SD, Piegari R, Rubenstein LV
JAMA Netw Open 2020 Jun 1;3(6):e208120. doi: 10.1001/jamanetworkopen.2020.8120. PMID: 32597993Free PMC Article
Laursen TM, Agerbo E, Pedersen CB
J Clin Psychiatry 2009 Oct;70(10):1432-8. Epub 2009 Jun 16 doi: 10.4088/JCP.08m04807. PMID: 19538905
Turkington D, Kingdon D, Weiden PJ
Am J Psychiatry 2006 Mar;163(3):365-73. doi: 10.1176/appi.ajp.163.3.365. PMID: 16513854
Lara DR
Cell Mol Neurobiol 2002 Jun;22(3):239-47. doi: 10.1023/a:1020759615977. PMID: 12469867

Clinical prediction guides

Adachi N, Ito M
Epilepsy Behav 2022 Feb;127:108520. Epub 2022 Jan 6 doi: 10.1016/j.yebeh.2021.108520. PMID: 34999502
Shibata M, Pattabiraman K, Lorente-Galdos B, Andrijevic D, Kim SK, Kaur N, Muchnik SK, Xing X, Santpere G, Sousa AMM, Sestan N
Nature 2021 Oct;598(7881):483-488. Epub 2021 Oct 1 doi: 10.1038/s41586-021-03953-x. PMID: 34599305Free PMC Article
Zheng W, Li W, Qi H, Xiao L, Sim K, Ungvari GS, Lu XB, Huang X, Ning YP, Xiang YT
J Affect Disord 2020 Apr 15;267:123-130. Epub 2020 Jan 21 doi: 10.1016/j.jad.2020.01.096. PMID: 32063563
Karbasforoushan H, Woodward ND
Curr Top Med Chem 2012;12(21):2404-14. doi: 10.2174/156802612805289863. PMID: 23279179
Irie F, Yamaguchi Y
Front Biosci 2004 May 1;9:1365-73. doi: 10.2741/1325. PMID: 14977552

Recent systematic reviews

Zheng W, Li W, Qi H, Xiao L, Sim K, Ungvari GS, Lu XB, Huang X, Ning YP, Xiang YT
J Affect Disord 2020 Apr 15;267:123-130. Epub 2020 Jan 21 doi: 10.1016/j.jad.2020.01.096. PMID: 32063563
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
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

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