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Protection From Schizophrenia—Too Much 22q11.2 Is a Good Thing

November 22, 2013. Duplications of the 22q11.2 chromosomal region seem to protect against schizophrenia, according to a study published online November 12 in Molecular Psychiatry. Led by Michael Owen and Michael O’Donovan of Cardiff University, United Kingdom, the study surveyed the genomes of 47,005 people and found that the frequency of large 22q11.2 duplications in people with schizophrenia was much lower than in people without the disorder. In fact, a person having the duplication had only about one-sixth the chance of developing schizophrenia that people without the duplication did. As the well-known counterpart deletion of 22q11.2 confers risk for schizophrenia, the results suggest that the dosage of genes within this region contributes to a sliding scale of risk or protection.

Previous meta-analyses have found common alleles with protective effects against schizophrenia (Allen et al., 2008), but this is the first time a large, structural variation has been identified. Though some losses or gains of chromosome regions, or copy number variations (CNVs), seem harmless enough (e.g., Sebat et al., 2004), rare and large CNVs greater than 100 kb turn up more frequently in several brain disorders, including intellectual disability (ID), autism, epilepsy, and schizophrenia (Malhotra et al., 2012). In the limited reports to date, duplications or deletions of the same chromosomal regions—called “reciprocal” CNVs, such as those found at 16p11.2—appear to increase risk for different disorders (see SRF related news story) rather than producing the bi-directional risk-protective effect found in the new study.

Large (1.5-3 Mb) deletions of 22q11.2 cause velocardiofacial syndrome (also known as DiGeorge syndrome), which has a wide variety of symptoms, and 22q11.2 deletions are also associated with autism and ID. About 25 percent of people carrying the 22q11.2 deletion—which contains at least 30 genes—develop psychosis and receive a diagnosis of schizophrenia, making it one of the most potent genetic risk factors for schizophrenia. Carriers of the reciprocal duplication also display a spectrum of phenotypes, including ID, autism, and even fairly normal (Ou et al., 2008). The new study, however, is the first to specifically survey people with schizophrenia for these duplications and found they were conspicuously missing.

Clues from 22q
First author Elliot Rees and colleagues began by genotyping 6,882 people with schizophrenia and 11,255 controls with single nucleotide polymorphism (SNP) arrays. They found no 22q11.2 duplications in the schizophrenia group, but 10 in the controls. In contrast, they detected 20 22q11.2 deletions in the schizophrenia group, but none in the controls, as expected. Looking in additional cohorts, the researchers found three people with schizophrenia who carried 22q11.2 duplications, but this frequency still remained lower than that in the control group. When combining these results with the original discovery cohort, they found that, in 47,005 people surveyed, 22q11.2 duplications turned up in 22 (0.085 percent) of 25,867 controls but only in three (0.014 percent) of 21,138 people with schizophrenia. Though rare in both cases, they were significantly more rare in schizophrenia (p = 0.00086).

Although the protective effect was not complete, the three people with schizophrenia who also carried 22q11.2 had relatively late ages of onset (28, 34, and 43). They did not carry other known risk CNVs. Of the 22 controls with the duplications, there was information available about psychiatric histories for only six, but these did not show anything resembling schizophrenia, schizoaffective disorder, or major affective disorder.

This apparent bi-directional effect for schizophrenia, with duplications decreasing risk and deletions increasing it, is not found for other disorders. For autism and ID, for example, the researchers noted that both 22q11.2 deletions and duplications were more frequent in cases than in controls. This disassociation suggests that genes within 22q11.2 underlie some schizophrenia-specific molecular effects.

Consistent with this notion, gene expression varied with gene dosage in a subset of samples tested. Lymphoblasts from a subset of duplication and deletion carriers, surveyed with RNA sequencing, showed the expected increases and decreases in expression of genes within the 22q11.2 region, but not in genes immediately flanking the region. This supports the idea that genes within the region confer the protective or risk effects, rather than that the CNV disrupts chromatin elsewhere in the genome.

The finding may intensify the hunt for the operative gene(s) for mental illness in the 22q11.2 region. Previous research focused on the candidate genes COMT, PRODH, GNB1L, and TBX1 (see SRF related news story), but the new protective effect could give researchers another phenotype to work with in their efforts to find the relevant genes. It may also provide a clue to understanding the varied penetrance and expressivity that comes with CNVs.—Michele Solis.

Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J, Szatkiewicz J, O'Dushlaine C, Richards AL, Green EK, Jones I, Davies G, Legge SE, Moran JL, Pato C, Pato M, Genovese G, Levinson D, Duan J, Moy W, Göring HH, Morris D, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A; Wellcome Trust Case Control Consortium, Craddock N, Sklar P, Hultman C, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol Psychiatry. 2013 Nov 12. Abstract

Comments on News and Primary Papers
Comment by:  Bernard Crespi
Submitted 27 November 2013
Posted 27 November 2013
  I recommend the Primary Papers

Reciprocal CNVs at 22q11.2: New Insights Into Protection Versus Risk for Neurodevelopmental Disorders

The discovery of factors that protect against schizophrenia has immediate and important implications for prevention and treatment of this condition, as well as providing useful insights into the relationship of schizophrenia with other disorders. The recent finding that duplications of the 22q11.2 chromosome region protect against schizophrenia (Rees et al., 2013) provides an outstanding case in point, because the reciprocal deletion of this region represents one of the most highly penetrant and well-documented causes of schizophrenia uncovered to date. Of particular interest with regard to deletions and duplications of 22q11.2 is that, whereas deletions are strongly associated with schizophrenia risk, duplications of 22q11.2 not only protect against schizophrenia, but also increase risk for autism (Crespi et al., 2010; Sanders et al., 2011; Crespi and Crofts, 2012; Rees et al., 2013).

Comparable findings have been reported for 16p11.2: Whereas a 0.6 Mb deletion in this chromosomal region is strongly associated with risk of autism (Sanders et al., 2011), the reciprocal duplication is strongly associated with risk of schizophrenia (McCarthy et al., 2009). For both of these loci, the schizophrenia-associated CNV has also been linked with ASD, but these findings remain controversial because relatively severe premorbidity to schizophrenia may present as ASD in childhood, such that these autism spectrum diagnoses could represent false positives (Eliez, 2007; Crespi et al., 2010; Crespi and Crofts, 2012; Angkustsiri et al., 2013; Karayiorgou, 2013).

Why, then, should reciprocal CNVs predispose to autism on one hand, but schizophrenia on the other? Why should an autism risk factor protect against schizophrenia? And most importantly, how can these findings help to guide future research on these conditions?

The simplest explanation for why autism and schizophrenia may be mediated by reciprocal CNVs is that they represent, in some sense, "reciprocal" or "diametric" disorders (Crespi and Badcock, 2008). The idea of diametric disorders is novel to psychiatry, but it represents a straightforward application of the concept that biological systems may generally be perturbed in two opposite directions, towards, for example, lower versus higher levels of some gene product, lower versus higher activation of some pathway, or smaller versus larger size for a given structure. Here, the "system" is neurological and social-behavioral development. In this context, autism involves, in part, underdeveloped social cognition and behavior (Lai et al., 2013). By contrast, schizophrenia, and related psychotic-affective conditions, involve, in part, "hyper-developed" social cognition and behavior, expressed in such exaggerated social phenotypes as paranoia, auditory hallucinations, mania, megalomania, high levels of guilt and shame, and dysregulated, chaotic speech and language (Frith, 2004; Crespi and Badcock, 2008).

This diametric model will remain overly simplistic, and contentious, until its neurodevelopmental basis has been better elucidated and evaluated. However, it provides a straightforward hypothesis that, on face value, provides the clearest account to date for the observed psychiatric effects of these reciprocal CNVs. Directly comparable reciprocal risk and protective factors have also been reported for X chromosome dosage effects: Klinefelter syndrome (usually XXY) involves increased risk of schizophrenia and schizotypy (DeLisi et al., 2005; van Rijn et al., 2006), but Turner syndrome (XO) involves increased risk of autism but decreased risk of schizophrenia and bipolar disorder (Mors et al., 2001; Knickmeyer and Davenport, 2011).

The primary usefulness of the diametric model for autism spectrum and psychotic-affective conditions is that it makes novel, specific, and testable predictions regarding causes, protective factors, and potential therapies for both autism and schizophrenia. Such predictions are valuable because they allow for reciprocal illumination of the causes, correlates, and treatments of both sets of disorders, whose study has proceeded virtually independently for many decades.

Consider as examples:

1. Prenatal valproate represents a well-validated model for autism (Rinaldi et al., 2007), but in adulthood valproate serves as a therapeutic treatment for some psychotic-affective conditions (Haddad et al., 2009).

2. One of the best validated factors protecting against schizophrenia is congenital blindness (Landgraf and Osterheider, 2013; Silverstein et al., 2012); by contrast, congenital blindness represents a well-studied risk factor for autism (Hobson and Bishop, 2003).

3. mGluR5 antagonists represent one of the most promising new treatments for the autistic syndrome fragile X (Gürkan and Hagerman, 2012; Pop et al., 2013); by contrast, quite independently, mGluR5 agonists are under development and trials as treatment for schizophrenia (Lindsley and Stauffer, 2013).

4. Agonists of nicotinic acetylcholine receptors, the receptors that individuals with schizophrenia self-stimulate via their extraordinarily high rates of cigarette smoking (Mobascher and Winterer, 2008), are being developed and tested for schizophrenia (Deutsch et al., 2013). Again quite independently, antagonists of the same receptor have been proposed as therapeutic agents for autism, based on a variety of evidence including low rates of smoking in autism (Lippiello, 2006).

5. Deletions of the SHANK3 gene represent a strong risk factor for autism (Betancur and Buxbaum, 2013), but duplications of this gene are associated with schizophrenia (Crespi et al., 2010), and SHANK3 overexpression causes mania-like behavior in mice (Han et al., 2013).

With regard to CNVs at 22q11.2, and protection from schizophrenia in individuals with duplications, it is of notable interest that 1) selective prefrontal overexpression of COMT, a key 22q11.2-region gene, rescues schizophrenia-like symptoms in a mouse model of deletion of 22q11.2 (Kimoto et al., 2012), and 2) an allele linked to low COMT expression is associated with psychosis among individuals with 22q11.2 deletions (Gothelf et al., 2013). If higher COMT expression protects against schizophrenia, might it also represent a risk factor for autism? In turn, might therapies that reduce COMT expression or effects help to alleviate symptoms of autism?

Testing the diametric model, in comparison to models that posit overlap between schizophrenia and autism, requires strong inference tests of alternative predictions. Such tests must also carefully take into account possible confounding of autism spectrum disorder with childhood premorbidity to schizophrenia (especially for relatively penetrant risk factors) and confounding of autistic social deficits with negative symptoms of schizophrenia that are superficially but not causally similar.

Most importantly, joint, integrated study of autism and schizophrenia should generate new insights into both sets of conditions, including factors that increase risk as well as the remarkable ones that protect.


Angkustsiri K, Goodlin-Jones B, Deprey L, Brahmbhatt K, Harris S, Simon TJ. Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype? J Autism Dev Disord. 2013 Sep 18. Abstract

Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013 Jun 11;4(1):17. Abstract

Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci. 2008 Jun;31(3):241-61; discussion 261-320. Abstract

Crespi BJ, Crofts HJ. Association testing of copy number variants in schizophrenia and autism spectrum disorders. J Neurodev Disord. 2012 May 30;4(1):15. Abstract

Crespi B, Stead P, Elliot M. Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1736-41. Abstract

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Deutsch SI, Schwartz BL, Schooler NR, Brown CH, Rosse RB, Rosse SM. Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy. Schizophr Res. 2013 Aug;148(1-3):138-44. Abstract

Eliez S. Autism in children with 22q11.2 deletion syndrome. J Am Acad Child Adolesc Psychiatry. 2007 Apr;46(4):433-4. Abstract

Frith CD. Schizophrenia and theory of mind. Psychol Med. 2004 Apr;34(3):385-9. Abstract

Gothelf D, Law AJ, Frisch A, Chen J, Zarchi O, Michaelovsky E, Ren-Patterson R, Lipska BK, Carmel M, Kolachana B, Weizman A, Weinberger DR. Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome. Biol Psychiatry. 2013 Aug 27. Abstract

Gürkan CK, Hagerman RJ. Targeted treatments in autism and Fragile x syndrome. Res Autism Spectr Disord. 2012 Oct 1;6(4):1311-1320. Abstract

Haddad PM, Das A, Ashfaq M, Wieck A. A review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol. 2009 May;5(5):539-51. Abstract

Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H, Tang J, Wu Z, Hao S, Cheung SW, Yu P, Sun H, Breman AM, Patel A, Lu HC, Zoghbi HY. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013 Nov 7;503(7474):72-7. Abstract

Hobson RP, Bishop M. The pathogenesis of autism: insights from congenital blindness. Philos Trans R Soc Lond B Biol Sci. 2003 Feb 28;358(1430):335-44. Abstract

Karayiorgou M. Dosage effects of 22q11 chromosomal region.

Kimoto S, Muraki K, Toritsuka M, Mugikura S, Kajiwara K, Kishimoto T, Illingworth E, Tanigaki K. Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome. Transl Psychiatry. 2012 Aug 7;2:e146. Abstract

Knickmeyer RC, Davenport M. Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders. J Neurodev Disord. 2011 Dec;3(4):293-306. Abstract

Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2013 Sep 25. Abstract

Landgraf S, Osterheider M. "To see or not to see: that is the question." The "Protection-Against-Schizophrenia" (PaSZ) model: evidence from congenital blindness and visuo-cognitive aberrations. Front Psychol. 2013 Jul 1;4:352. Abstract

Lindsley CW, Stauffer SR. Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012). Pharm Pat Anal. 2013 Jan;2(1):93-108. Abstract

Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses. 2006;66(5):985-90. Abstract

McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009 Nov;41(11):1223-7. Abstract

Mobascher A, Winterer G. The molecular and cellular neurobiology of nicotine abuse in schizophrenia. Pharmacopsychiatry. 2008 Sep;41 Suppl 1:S51-9. Abstract

Mors O, Mortensen PB, Ewald H. No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes. Psychol Med. 2001 Apr;31(3):425-30. Abstract

Pop AS, Gomez-Mancilla B, Neri G, Willemsen R, Gasparini F. Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacology (Berl). 2013 Nov 15. Abstract

Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J, Szatkiewicz J, O'Dushlaine C, Richards AL, Green EK, Jones I, Davies G, Legge SE, Moran JL, Pato C, Pato M, Genovese G, Levinson D, Duan J, Moy W, Göring HH, Morris D, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A; Wellcome Trust Case Control Consortium, Craddock N, Sklar P, Hultman C, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol Psychiatry. 2013 Nov 12. Abstract

Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13501-6. Abstract

Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011 Jun 9;70(5):863-85. Abstract

Silverstein SM, Wang Y, Keane BP. Cognitive and neuroplasticity mechanisms by which congenital or early blindness may confer a protective effect against schizophrenia. Front Psychol. 2012 Jan 21;3:624. Abstract

van Rijn S, Aleman A, Swaab H, Kahn R. Klinefelter's syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. Br J Psychiatry. 2006 Nov;189:459-60. Abstract

View all comments by Bernard Crespi

Comments on Related News

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 5 November 2005
Posted 5 November 2005

The fact that the PRODH alteration studied in Gogos et al. leads to alterations in glutamate release, and this corresponds to deficits in associative learning and response to psychotomimetics, provides a nice parallel to the human condition. The Reiss paper examines humans with the 22q11.2 deletion, and shows that the COMT low-activity allele of this deletion syndrome correlates with cognitive decline, PFC volume, and development of psychotic symptoms. This is a nice addition to the Weinberger and Bilder papers about how COMT can lead to psychosis vulnerability.

View all comments by Anthony Grace

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Caterina Merendino
Submitted 5 November 2005
Posted 5 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Leboyer Marion
Submitted 6 November 2005
Posted 6 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anne Bassett
Submitted 7 November 2005
Posted 7 November 2005
  I recommend the Primary Papers

I echo Jeff Lieberman's comment regarding previous reports of a weak association between the Val COMT functional allele and schizophrenia. Notably, the most recent meta-analysis (Munafo et al., 2005) shows no significant association. Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al. (1999) have reported that there is no association between COMT genotype and schizophrenia, and Bearden et al. reported that Val-hemizygous patients performed significantly worse than Met-hemizygous patients on executive cognition ( 2004) and childhood behavioral problems (2005). Though important as an initial prospective study, there is a risk in the Gothelf et al. small sample size and multiple testing for type 1 errors. Certainly, there is little evidence, even in 22qDS, for COMT (or PRODH) as “key” risk factors for schizophrenia. There may be some evidence for small effects on cognitive or other measures. Regardless, there is not “extreme deficiency” in COMT activity in the many individuals with Met-hemizygosity in 22qDS, or Met-Met homozygosity in the general population.

Regarding the news item, there are a few widely held misconceptions about 22qDS. Our recent article (Bassett et al., 2005) shows that, accounting for ascertainment bias, the rate of schizophrenia was 23 percent, and congenital heart defects was 26 percent. Of the other 41 common lifetime features of 22qDS (found in 5 percent or more patients), neuromuscular palatal anomalies were common but overt cleft palate was so rare it did not meet inclusion criteria; intellectual disabilities ranged from severe mental retardation (rare) to average intellect (rare) with most patients falling in the borderline range of intellect; and on average, patients had nine of 43 common features. We propose clinical practice guidelines for adults with 22qDS which may be directly applicable to the 1-2 percent of patients with a 22qDS form of schizophrenia.

Bassett AS, Chow EWC, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005 Nov 1;138(4):307-13. Abstract

Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry . 2004 Sep;161(9):1700-2. Abstract

Bearden CE, Jawad AF, Lynch DR, Monterossso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Feb;11(1):109-17. Abstract

Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug;10(8):765-70. Abstract

Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct 1;56(10):940-5. Abstract

View all comments by Anne Bassett