Aetiological diagnosis for patients with schizophrenia was long thought to be impossible. However, genomic abnormalities with clear causal relevance can now be identified in a consistent minority of cases using chromosomal microarray analysis (CMA; also known as array Comparative Genomic Hybridization or array-CGH).  Analogous to a karyotype but with dramatically improved genome-wide resolution, CMA can inform diagnosis and clinical management by identifying sub-microscopic segments of missing (deleted) or additional (duplicated) chromosomal material known as copy number variants (CNVs).  CMA is sensitive, reliable, and widely available in clinical laboratories around the world, including major medical centres in the developing world.  Costs are competitive with other investigations such as neuroimaging.  CMA is now a standard first-line diagnostic test for intellectual disability and autism where 10-20% of affected individuals have a clinically-relevant deletion or duplication (1).   Widespread application of CMA testing in these populations has increased confidence in diagnostic interpretation, enhanced the prognostic evidence base, and facilitated research progress (2).  In our view, the time has come to translate replicated research findings with proven clinical utility into routine diagnostic practice for patients with schizophrenia

Baker, Kate

Bassett, Anne S

Costain, Gregory

Fung, Wai Lun Alan

The Lancet Psychiatry

Kate Baker

Gregory Costain

Wai Lun Alan Fung

Anne S Bassett

Crossref

Chromosomal microarray analysis—a routine clinical genetic test for patients with schizophrenia

Apollo (Cambridge)

Baker et al – Chromosomal Microarray in Schizophrenia    1 Manuscript Word Count: Text without references 878 Number of Figures: 0  Number of Tables: 1  Chromosomal microarray analysis  - a routine clinical genetic test for patients with schizophrenia Kate Baker MRCPCH PhD1 Gregory Costain PhD2 Wai Lun Alan Fung MD ScD 2,3,4 Anne S. Bassett MD FRCPCP 2,3,4 1Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom. 2 Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 3 The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome, University Health Network, Toronto, Ontario, Canada 4 Department of Psychiatry, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada.  Corresponding authors: Kate Baker, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom, E-mail: kb488@cam.ac.uk and Anne S. Bassett, Centre for Addiction and Mental Health, 33 Russell Street, Room 1100, Toronto, Ontario, Canada M5S 2S1, E-mail: anne.bassett@utoronto.ca  Conflicts of interest: The authors declare no conflicts of interest  Contributors: All authors contributed to the writing this CommentBaker et al – Chromosomal Microarray in Schizophrenia    2 Aetiological diagnosis for patients with schizophrenia was long thought to be impossible. However, genomic abnormalities with clear causal relevance can now be identified in a consistent minority of cases using chromosomal microarray analysis (CMA; also known as array Comparative Genomic Hybridization or array-CGH).  Analogous to a karyotype but with dramatically improved genome-wide resolution, CMA can inform diagnosis and clinical management by identifying sub-microscopic segments of missing (deleted) or additional (duplicated) chromosomal material known as copy number variants (CNVs).  CMA is sensitive, reliable, and widely available in clinical laboratories around the world, including major medical centres in the developing world.  Costs are competitive with other investigations such as neuroimaging.  CMA is now a standard first-line diagnostic test for intellectual disability and autism where 10-20% of affected individuals have a clinically-relevant deletion or duplication (1).   Widespread application of CMA testing in these populations has increased confidence in diagnostic interpretation, enhanced the prognostic evidence base, and facilitated research progress (2).  In our view, the time has come to translate replicated research findings with proven clinical utility into routine diagnostic practice for patients with schizophrenia. The rationale for chromosomal microarray testing in schizophrenia Clinically-relevant deletions or duplications are present amongst individuals with schizophrenia with a collective prevalence of 5% or more (3-5).  These encompass three broad groups of CNVs, each of which can occur de novo or can be inherited: (A) 22q11.2 deletions (~1% of schizophrenia; lifetime schizophrenia risk amongst deletion carriers ~25% (6)); (B) other recurrent deletions and duplications associated with schizophrenia, e.g. 1q21.1 deletions, 15q11-q13 duplications (~3-4% collectively of schizophrenia); (C) other Baker et al – Chromosomal Microarray in Schizophrenia    3 individually rarer abnormalities.  The first study of CMA application in a community-based sample of schizophrenia showed that 1 in 13 patients within a single geographical catchment had a clinically-relevant deletion or duplication: diagnostic yield 8.1% (95% CI 5.2–12.2%)(7). Those with pathogenic genetic anomalies diagnosed via CMA were indistinguishable from the remainder of patients with respect to basic clinical variables.  Hence, if CMA is only offered to patients with additional features such as intellectual disability or dysmorphology, many individuals with clinically-significant deletions or duplications will remain undiagnosed.   Maximising clinical utility  Identification of a pathogenic CNV can improve holistic physical and mental health care for patients with schizophrenia.   Taking the example of 22q11.2 deletion syndrome, there are clinical practice guidelines to aid lifetime management (8).  These include clear recommendations for baseline medical assessments (e.g. cardiac and immunological assessments) and annual checks (e.g. thyroid function tests and serum calcium monitoring).   These CNV-specific assessments frequently uncover hidden health problems in adult patients, leading to a range of interventions from dietary advice to pharmacological treatments which significantly improve well-being and reduce risk of serious complications.  Diagnosis of 22q11.2 deletion syndrome can also influence psychiatric treatment:  antipsychotic choice may be modified according to safety profiles; seizure risk can be reduced by early use of anticonvulsants and by identifying and treating hypocalcaemia.  For other recurrent schizophrenia-associated CNVs, there are systematic efforts to establish similar evidence bases (9-11).  Genetic counselling after diagnosis of any clinically-significant Baker et al – Chromosomal Microarray in Schizophrenia    4 deletion or duplication is important because offspring are at 50% risk of inheriting the CNV, with inherent medical, neurodevelopmental and psychiatric implications.   Recognising limitations  Genomic abnormalities interact with biological and social factors to mediate psychiatric risk, and an overly reductionist approach is unrealistic.  However, this complexity is not unique to psychiatric illness or schizophrenia.  As for most genetic diagnoses, the clinical problems associated with pathogenic deletions and duplications vary from person to person, even within families. Variable expression encompasses physical manifestations, cognitive impairments and psychiatric symptoms, and it is difficult to predict which individuals with clinically-significant CNVs will experience specific problems in each area.  For very rare CNVs, limited prognostic information will be available until more cases are diagnosed.  A further limitation is that some CMA findings will be reported as variants of uncertain significance (VUS) when there is insufficient current evidence to classify a CNV as either benign or pathogenic.   Practicalities of chromosomal microarray testing for patients with schizophrenia CMA testing and genetic diagnosis have been shown to be desirable and acceptable amongst patients with schizophrenia and their families, even amongst the majority who did not receive a genetic diagnosis (12;13).  The process of obtaining informed consent is in essence no different for patients with schizophrenia than for any other population, once capacity has been evaluated.  A simple pre-test discussion should outline the purposes, benefits and limitations of testing (Table 1).  It is desirable to involve family members so that awareness is shared amongst individuals for whom test results are potentially relevant.  Baker et al – Chromosomal Microarray in Schizophrenia    5 However, lack of availability of family members should not preclude testing that may be of great individual benefit.   Looking ahead A genetic diagnosis can have multiple practical and psychological values for patients, their partners, relatives, clinicians and wider society.  Further research that integrates CNV diagnosis with cognitive neuroscience has the potential to illuminate diverse pathways from risk to symptoms (14, 15).   The benefits of genetic diagnosis and risks inherent in under-investigation considerably outweigh limitations of CMA testing.  CMA is a natural step in the evolution of biologically-informed clinical management of schizophrenia – clinical exome and whole genome sequencing is on its way (16).  This eventuality mandates a concerted effort to address knowledge gaps, remove discriminatory barriers, and increase opportunities for individualized care for adults with severe mental illness.   Baker et al – Chromosomal Microarray in Schizophrenia    6 Reference List  (1)  Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010 May 14;86(5):749-64.  (2)  Baker K, Raymond FL, Bass N. Genetic investigation for adults with intellectual disability: opportunities and challenges. Curr Opin Neurol 2012 Apr;25(2):150-8.  (3)  Hochstenbach R, Buizer-Voskamp JE, Vorstman JA, Ophoff RA. Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenet Genome Res 2011;135(3-4):174-202.  (4)  Grozeva D, Conrad DF, Barnes CP, Hurles M, Owen MJ, O'Donovan MC, et al. Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr Res 2012 Mar;135(1-3):1-7.  (5)  Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 2012 Feb;17(2):142-53.  (6)  Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree MB, et al. Psychiatric Disorders From Childhood to Adulthood in 22q11.2 Deletion Syndrome: Results From the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 2014 Jun 1;171(6):627-39.  (7)  Costain G, Lionel AC, Merico D, Forsythe P, Russell K, Lowther C, et al. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. Hum Mol Genet 2013 Nov 15;22(22):4485-501.  (8)  Bassett AS, Donald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, Habel A, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011 Aug;159(2):332-9.  (9)  Dolcetti A, Silversides CK, Marshall CR, Lionel AC, Stavropoulos DJ, Scherer SW, et al. 1q21.1 Microduplication expression in adults. Genet Med 2013 Apr;15(4):282-9.  (10)  Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet 2012 Oct;49(10):660-8.  (11)  Lowther C, Costain G, Stavropoulos DJ, Melvin R, Silversides CK, Andrade DM, et al. Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.  Genet Med 2014, in press.  (12)  Costain G, Esplen MJ, Toner B, Scherer SW, Meschino WS, Hodgkinson KA, et al. Evaluating genetic counseling for individuals with schizophrenia in the molecular age. Schizophr Bull 2014 Jan;40(1):78-87. Baker et al – Chromosomal Microarray in Schizophrenia    7  (13)  Costain G, Chow EW, Ray PN, Bassett AS. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome. J Intellect Disabil Res 2012 Jun;56(6):641-51  (14) Insel, T. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry 2014 Apr 1;171(4):395-7.     (15) Baker K and Vorstman JA. Is there a core neuropsychiatric phenotype in 22q11.2 deletion syndrome? Curr Opin Neurol 2012 Apr;25(2):131-7   (16)  Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014 Feb 13;506(7487):179-84.  Baker et al – Chromosomal Microarray in Schizophrenia    8 TABLE 1: CMA testing for patients with schizophrenia – aims, benefits, limitations, strategies AIMS Identification of causal factors Awareness of associated medical risks Tailored psychiatric care Genetic counselling Potential benefits   Detection of clinically-significant deletion or duplication (CNV) in 5-8% of patients with schizophrenia  Surveillance and interventions for treatable conditions e.g. cardiac, endocrine, neurological  Reduction in health inequalities, improvement in quality of life  Enhanced understanding of the patient’s illness  Improved safety and effectiveness of treatments for schizophrenia  Individualised, evidence-based counselling  Education and empowerment   Genetic testing options for at-risk relatives  Limitations and challenges  No clinically-significant CNV in the majority of cases  Variants of uncertain significance   Incidental findings  Limited evidence base for rare CNVs   Variability in clinical expression   Few specific treatment recommendations for rare CNVs  Adjustment of patient, family and clinician to new knowledge  Questions around childhood testing and prenatal testing Strategies   Submission of CNV data to international databases to enhance interpretation of variants  Genome sequencing to increase diagnostic yield  Submission of phenotype data to international databases to enhance prognostic evidence base  Research into medical comorbidities, surveillance approaches, interventions and outcomes  Continue standard treatments unless change indicated  Research into psychiatric presentations, treatment responses and outcomes  Potential for new aetiology-specific, mechanism-informed therapies  Enhanced liaison between psychiatry and clinical genetics   Clinician education to increase confidence in initiating testing, pre-test discussion, managing results   

Chromosomal microarray analysis-a routine clinical genetic test for patients with schizophrenia.

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Chromosomal microarray analysis-a routine clinical genetic test for patients with schizophrenia.

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