Read the Co-Authors of the ISPG Genetic Testing Statement Here
Summary of Recommendations
Background & Aims
As the major scientific society focused on the genetics of psychiatric disorders, the International Society of Psychiatric Genetics (ISPG) recognizes the growing attention given to clinical genetic testing and the questions raised about the value of such testing in psychiatry. We have convened an expert panel to review the available evidence and provide some guidance for clinicians in the mental health and general medical communities. This statement is based on the best available published evidence to date and will be reviewed periodically to keep pace with this rapidly changing field.
Views are still evolving about several related issues that we will not address here. These include the extent and format of genetic test data made available to patients and referring clinicians, prenatal genetic testing, and genetic testing in newborns. Our recommendations assume that all testing will be done in accordance with local laws and regulations. We discuss the use of informed consent for genetic testing. Issues surrounding genetic testing in individuals who cannot provide informed consent are not covered here.
The main measures for a diagnostic test are analytic validity (does the test accurately measure what it is supposed to measure?) and clinical validity (is there adequate scientific evidence to support the correlation between the genetic variant and a particular health condition or risks?). Regular quality control measures in clinical laboratories are needed to assure analytic validity. Replication is a critically important criterion for clinical validity. A valid test can then be evaluated for clinical utility (is the test likely to provide unique information to improve patient outcomes?). For a detailed discussion of these issues see ref 1.
Genetic Tests to Assist Diagnosis and Characterize Risk
There is a history of successful use of genetic tests for the identification of neurodevelopmental and neurodegenerative disorders that often manifest psychiatric symptoms. Examples include phenylketonuria (PKU), Fragile X syndrome, Down syndrome (Trisomy 21), Huntington Disease (HD), and some rare forms of Alzheimer Disease or other dementias (ref 2). Depending on the condition, such tests can be used to (1) screen at-risk individuals before onset of symptoms or clinical diagnosis, thus providing critical information for primary prevention, clinical trials of new treatments, genetic counseling, and long-term life planning, or (2) establish a molecular diagnosis after symptoms have appeared. The widely used tests for these conditions have clearly established analytical and clinical validity as well as clinical utility. Although there are as yet no cures for these conditions, dietary modification is effective for PKU, and molecular diagnosis may provide the patient, family, and clinician with useful information regarding prognosis, planning for long-term care, and risk to relatives. With respect to late-onset Alzheimer disease, common variants of the APOE gene can have substantial effects on risk, but the magnitude of these effects is not such that testing can be used to predict or confirm the diagnosis (ref 2).
Many genetic causes of intellectual disability (ID) and autism spectrum disorder (ASD) have been identified. There are now several hundred genes in which copy number and single-gene variants with large effects on brain function cause syndromic or non-syndromic ID and/or ASD. Fragile X molecular testing and chromosomal microarray analysis (CMA), which detects copy number variation across the entire genome, have long been considered standard of care for the etiological evaluation of global developmental delay, ID, and/or ASD (ref 3). If such tests fail to establish a diagnosis, a targeted gene panel or whole exome sequencing (WES) may be indicated. Although consensus recommendations await publication, WES is available clinically in many countries and is increasingly used as a first-tier test for the evaluation of ID or ASD. Multiple studies have shown that a combination of CMA and WES provides a genetic diagnosis in at least 25% of patients with these conditions (refs). A molecular diagnosis can have important clinical implications and personal utility for patients, and may help inform life planning, access to public benefits, and recurrence risk assessment in relatives (ref 3).
In contrast to the disorders mentioned above, major adult psychiatric and substance use disorders are only rarely explained by rare pathogenic copy number or single gene variants, although research in this area is ongoing. Research-based genome-wide association studies (GWAS) have found numerous common genetic variants that are reproducibly correlated with these disorders at accepted levels of statistical significance. Individually, such common variants have very small effects on risk that are of no clinical significance. However, when large numbers of these variants are considered in aggregate, known as polygenic risk scores (PRS) or risk allele burden testing, the cumulative effect on risk is more substantial (ref 5). PRS informed by GWAS are currently considered research analyses and are not recommended for clinical use. We do not recommend that this kind of information be used in the clinic to identify high-risk individuals or help diagnose psychiatric patients, but this may change in the future as research advances. PRS are strongly influenced by ancestry; if they are to form part of future clinical practice it will be essential to obtain informative sets of markers for people of diverse ancestries so that valid testing can be offered in an equitable fashion.
Genetic technologies such as next generation sequencing permit readout of an individual’s whole exome or whole genome sequence. Limited information is available on single-gene causes of adult psychiatric disorders, as there have so far been few WES or whole genome sequencing studies published in large case samples. WES studies have made progress in identifying very rare DNA sequence variants which can have substantial effects on risk for schizophrenia. Such studies have also identified genes that contribute to a broad spectrum of neurodevelopmental and adult-onset psychiatric disorders (ref 6). Pathogenic variants that disrupt these genes in an individual with schizophrenia can be regarded as significant contributing risk factors, even in the absence of comorbid ID, developmental delay, or ASD.
Chromosomal microdeletions and microduplications lead to loss or gain of one or many genes within a particular chromosomal region and may result in large deleterious effects on brain function. CNVs may be inherited or arise anew (de novo) during human reproduction. Some inherited and de novo CNVs, such as deletion of chromosome 22q11.2, can confer a substantial risk for adult-onset psychiatric illnesses, intellectual disability, ASD, ID, or epilepsy (ref 7). These and other CNVs may also occur in apparently healthy people. Although CNVs that confer high risk are individually rare, taken together they may contribute to a small but significant fraction of adult-onset psychiatric disorders such as schizophrenia. Additional large, population-based and family-based studies are needed to establish the lifetime risk for psychiatric disorders in individuals who carry specific CNVs. When a history of neurodevelopmental problems, e.g., childhood intellectual disability, is present in adults with schizophrenia, ADHD, or other mental illnesses, pathogenic CNVs may be more common. Some CNVs are associated with other health problems. The identification of these CNVs may have clinical implications for general medical care. The Committee did not reach consensus on the use of CNV analysis in most adults with mental illness but agreed that identification of pathogenic CNVs in adults with major mental illness may help patients and their families to better understand and accept the diagnosis within a medical context and could provide useful information about risk to relatives.
Reporting of Incidental or Secondary Findings
Genetic technologies such as next generation sequencing permit readout of an individual’s whole exome or whole genome sequence, and chromosomal microarray screening detects copy number variation across the entire genome. While useful in some contexts, genome-wide diagnostic tests such as CMA and WES may also generate secondary or incidental findings of potential importance for medical conditions unrelated to the clinical complaint for which these tests were originally performed. Such findings may highlight a preventable illness that could benefit from early intervention but may also identify risk for a disease with no available treatment.
There is as yet no general consensus about reporting such findings back to patients or study participants. Some authorities, such as the American College of Medical Genetics (ACMG), recommend that clinicians report to patients actionable findings in genes that cause diseases with established interventions aimed at preventing or significantly reducing morbidity and mortality (ref 8). In its statement, however, the ACMG also emphasized that the recommendations should not be seen as strict instructions for action but rather as support for a meaningful clinical decision. The attending physician must consider the specific clinical and psychosocial situation of each patient. The return of incidental and secondary findings to study participants in research settings remains controversial, and recommendations are still developing.
While we concur with the ACMG recommendations regarding reporting of actionable findings to the referring clinician, a decision to inform a patient about such finding(s) must weigh several factors. These include (1) the seriousness of the implicated disease, (2) potential medical consequences of nondisclosure, (3) and the potential negative impacts of disclosure on the patient’s psychological condition, insurability and quality of life, along with (4) the patient’s stated wish to be informed about such findings, capacity to appreciate the prognostic implications, and ability to participate in any preventive or therapeutic interventions.
Studies have so far found little evidence that returning genetic results poses substantial psychological or behavioral harms (ref 9). However, these studies primarily focused on individuals who were not at high risk for adverse psychological consequences. More research is needed to understand how patients with active psychiatric disorders respond to the unanticipated disclosure of a genetic finding with major implications for health or longevity for themselves and their close family members.
In general, the Committee supports informing patients of potentially actionable secondary or incidental findings unless there are compelling reasons to withhold this information. For example, when test results become available during the active phase of an episodic psychotic illness, it may be reasonable to postpone disclosure of non-urgent findings until psychiatric stabilization has been achieved. Also, individuals who do not wish to be informed of genetic test results may have a right not to know (ref 10).
Psychological, Ethical and Clinical Implications in Genetic Testing
Ethical concerns affect diagnostic testing, especially pre-symptomatic testing undertaken before recognized onset of disease (ref 11). When any genetic testing is considered, there is a difficult balance between the risks and benefits of acting on a test result. Although psychological preparation for diagnosis and treatment may be among the potential benefits of genetic testing, possible risks include stopping or avoiding beneficial treatments, or loss of control over private information. These risks can have adverse effects on an individual or a family, such as changing life plans or deciding to terminate a pregnancy, particularly when subject to misinformation, incomplete data, or misinterpretation. Genetic test results, like all medical records, are private data but are at risk for unauthorized disclosure. To address this risk, entities that store genetic testing results in conjunction with personally identifiable data must employ advanced encryption and other computer security measures.
Professional counseling is an important means to help patients understand these issues and ameliorate negative effects. The interpretation of genetic risk involves expertise in clinical genetics; supportive, psychotherapeutic, educational, or reproductive counseling may also be needed. Scalability of individual genetic counseling will be a challenge and needs to be addressed as the use of genetic testing increases. While we acknowledge that genetic counseling resources are limited in the context of mental health care, we recommend that any genetic tests ordered for diagnostic purposes and all genome-wide screens should include informed consent procedures and counseling by a professional skilled in both mental health and the interpretation of genetic test results.
Direct-to-consumer (DTC) genetic tests, which can be obtained without a physician’s order, are often used recreationally by people interested in learning more about their ancestry or common traits, as well as genetic variants associated with medical disorders or treatment. The use of DTC genetic tests for medical purposes, however, is prohibited in many countries. The risks posed by medical DTC genetic testing have been addressed in previous statements from the American Society of Human Genetics, the European Society of Human Genetics, and the European Academy of Sciences (ref 12). Major risks include lack of informed consent and misinterpretation of results. While more research is needed, we do not recommend DTC genetic testing for medical purposes in patients with psychiatric illness or their families, or in healthy individuals concerned about risk or treatment for psychiatric disorders.
Need for Public and Professional Education
We advocate the development and dissemination of clinical and community education programs on psychiatric genetics and pharmacogenetics. Residency training and continuing education programs aimed at mental health professionals should provide sufficient background in genetics so that clinicians can critically evaluate the relevant medical literature, know when to recommend genetic testing, and be able to provide informed counseling to their patients and clients on the proper use and interpretation of genetic information in psychiatric care. We recommend materials developed by the ISPG Residency Education Taskforce and the Global Genetics and Genomics Community (ref 13). Excellent textbooks are also available (ref 14).
Community education should seek to minimize stigma or other disadvantages related to life and health insurance or job security that individuals with psychiatric conditions could experience if they chose to obtain genetic testing. Community education is more effective if done in cooperation with patients and their families.
Pharmacogenetic Tests to Guide Optimal Treatment
Studies of genetic testing to guide treatment in psychiatry have almost exclusively focused on drug therapies rather than behavioral (e.g., cognitive behavioral therapy) or neurostimulation therapies (e.g., electroconvulsive therapy). Genome-wide association studies of drug response have been limited in their ability to identify clinically useful genetic markers, suggesting response to treatment is likely a complex, polygenic trait.
However, targeted studies over the last two decades have identified several genes influencing drug metabolism. Most notably, it has been shown that allelic variation in the genes encoding the CYP2D6 and CYP2C19 enzymes leads to differences in the metabolism of numerous medications relevant to psychiatry, in particular antidepressants and antipsychotics. Individuals with genetic variants causing extreme drug metabolism phenotypes are at increased risk for adverse events, and some evidence suggests such patients are less likely to respond to treatment (ref 15)
Other studies have found that carriers of certain uncommon HLA alleles are at substantially increased risk of severe cutaneous adverse reactions when treated with carbamazepine or oxcarbazepine (ref 17). The implicated alleles are referred to as HLA-B*15:02 and HLA-A*31:01.
In view of these findings, expert groups (ref 18) have published clinical guidelines for interpreting and implementing pharmacogenetic testing results into practice. While it does not make recommendations for the use of tests in clinical care, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed detailed clinical practice guidelines through a standardized, evidence-based, peer-reviewed process by international experts with diverse backgrounds. A full list of CPIC guidelines are freely available at the CPIC website or at the Pharmacogenetics Knowledge base, which also maintains information on guidelines developed by other groups. Allele nomenclature that is frequently utilized for pharmacogenetic test reporting can be freely accessed at the Pharmacogene Variation Consortium website.
To date, pharmacogenetic-based guidelines and drug labels with pharmacogenetic information are available for many antidepressants (i.e., SSRIs including vortioxetine, TCAs, and venlafaxine), several antipsychotics (aripiprazole, brexpiprazole, clozapine, haloperidol, iloperidone risperidone, zuclopenthixol), and the ADHD medication atomoxetine. Mood stabilizers and medications for treating addictions are under active investigation. Other drug classes relevant to psychiatry, such as anticonvulsants (i.e., carbamazepine, oxcarbazepine, phenytoin) and pain medications (i.e., codeine, oxycodone, tramadol) also have pharmacogenetic-based guidelines available.
The implementation of the pharmacogenetic-based drug therapy most relevant to psychiatry requires at a minimum the availability of genetic information for CYP2D6, CYP2C19, HLA-A, and HLA-B. Here we provide examples of some of the recommendations included in the CPIC guidelines for these genes. The full guidelines should, however, be consulted and drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) need to be considered prior to clinical implementation. CPIC recommends clinicians avoid prescribing tricyclics to people known to carry CYP2D6 or CYP2C19 alleles associated with unusually rapid or slow metabolism. Among carriers of alleles associated with very high or low metabolism, CPIC recommends use of an SSRI that is not predominantly metabolized by these enzymes. For carriers of CYP2C19 alleles associated with ultrarapid metabolism, citalopram and escitalopram are not recommended, while carriers of CYP2C19 alleles associated with poor drug metabolism should receive a 50% reduction in starting dose. Carriers of HLA-B*15:02 or HLA-A*31:01 should avoid carbamazepine and oxcarbazepine (ref 17).
Unanswered questions that remain include where to obtain pharmacogenetic testing and how to address cost coverage or reimbursement of testing. While an increasing number of clinics have implemented routine pharmacogenetic testing, the majority of testing performed is by commercial laboratories with clinical certifications, such as the Clinical Laboratory Improvement Amendments (CLIA). Current pharmacogenetic-based dosing guidelines assume that the genetic results were derived from a laboratory test with good analytical and clinical validity. As such, the quality of the laboratory designing and/or performing the test is imperative. There is no standardization of the gene or variant allele content of pharmacogenetic tests, so test results may differ by laboratory. Therefore, the selection of a pharmacogenetic testing provider should be done with caution.
Current guidelines provide no advice on when, or to whom, genetic testing should be offered. Clinical trials to date have suggested testing might be most beneficial for individuals who have experienced an adverse drug reaction or inadequate response to a previous antidepressant trial (ref 16). Several major medical centers across the world offer pharmacogenetic testing before or at the same time as prescribing a medication. Current estimates of the number needed to test from the published randomized, double-blind clinical trials of pharmacogenetic testing for antidepressants suggest about one in every 12 patients will benefit from testing (ref 19). The number needed to test for other drug classes (e.g., antipsychotics, mood stabilizers) are currently unavailable but are anticipated in the coming years as ongoing pharmacogenetic trials are completed. Ongoing and future studies are also expected to assist in determining the optimal time to offer pharmacogenetic testing and for which individuals this testing will have the greatest likelihood of benefit.
Pharmacogenetic testing should be viewed as a decision-support tool to assist in thoughtful implementation of good clinical care, enhancing rather than offering an alternative to standard protocols. In this context, genetic markers can supplement demographic (e.g., age, sex, family history), clinical (e.g., concomitant medications), and lifestyle (e.g., diet, smoking) information to help guide treatment decisions. Genetic testing for HLA-B*15:02 has become mandatory by way of national regulations in Taiwan and Hong Kong while testing is freely available in Thailand in order to avoid serious side effects (e.g., Stevens-Johnson Syndrome) to carbamazepine. At this time, evidence does not support widespread use of other pharmacogenetic testing, but when genetic information is available, we recommend that such information should be considered when making medication selection and dosing decisions. We also recommend that clinicians and patients educate themselves or consult an expert prior to ordering a pharmacogenetic test and encourage the use of freely available resources to assist in the interpretation and implementation of test results. Useful but not exhaustive lists of pharmacogenetic tests are maintained by the NIH Genetic Testing Registry and the US Food and Drug Administration (ref 20). With growing numbers of testing platforms available, increasing uptake in genome sequencing and population-level precision medicine initiatives underway, we anticipate a fluid state of development of this area in coming years.
- Common genetic variants alone are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia. Genotypes from large numbers of common variants can be combined to produce an overall genetic risk score which can identify individuals at higher or lower risk, but at present it is not clear that this has clinical value.
- There is growing evidence that rare, pathogenic variants with large effects on brain function play a causative role in a significant minority of individuals with psychiatric disorders and may be a major cause of illness in some families. Identification of known pathogenic variants may help diagnose rare conditions that have important medical and psychiatric implications for individual patients and may inform family counseling. Identification of de novo mutations and copy number variants (CNVs) may also have a place in the management of serious psychiatric disorders. CNV testing may also prove useful for persons requesting counseling on familial risk. While the Committee did not reach consensus on widespread use of CNV testing in adult-onset disorders, most agreed that such tests may have value in cases that present atypically or in the context of intellectual disability, autism spectrum disorder, learning disorders, or certain medical syndromes.
- Professional counseling can play an important role in the decision to undergo genetic testing and in the interpretation of genetic test results. We recommend that diagnostic or genome-wide genetic testing should include counseling by a professional with expertise in both mental health and the interpretation of genetic tests. Consultation with a medical geneticist is recommended, if available, when a recognized genetic disorder is identified or when findings have reproductive or other broad health implications.
- Whenever genome-wide testing is performed, the possibility of incidental (secondary) findings must be communicated in a clear and open manner. Procedures for dealing with such findings should be made explicit and should be agreed with the patient or study participant in advance. The autonomy of competent individuals regarding preferences for notification of incidental findings should be respected.
- Genetic test results, like all medical records, are private data and must be safeguarded against unauthorized disclosure with advanced encryption and computer security systems.
- We advocate the development and dissemination of education programs and curricula to enhance knowledge of genetic medicine among trainees and mental health professionals, increase public awareness of genetics and genetic testing, and reduce stigma.
- Expanded research efforts are needed to identify relevant genes and clarify the proper role of genetic testing and its clinical utility in psychiatric care.
- Pharmacogenetic testing should be viewed as a decision-support tool to assist in thoughtful implementation of good clinical care. We recommend HLA-A and HLA-B testing prior to use of carbamazepine and oxcarbazepine, in alignment with regulatory agencies and expert groups. Evidence to support widespread use of other pharmacogenetic tests at this time is still inconclusive, but when pharmacogenetic testing results are already available, providers are encouraged to integrate this information into their medication selection and dosing decisions. Genetic information for CYP2C19 and CYP2D6 would likely be most beneficial for individuals who have experienced an inadequate response or adverse reaction to a previous antidepressant or antipsychotic trial.
- The ACCE Model Project developed the first publicly-available analytical process for evaluating scientific data on emerging genetic tests. The ACCE framework has guided or been adopted by various entities in the United States and worldwide. www.cdc.gov/genomics/gtesting/ACCE/index.htm.
- Cohn-Hokke et al. 2011; Goldman et al. 2011; Sorbi et al. 2012; Loy et al. 2014
- Schaefer et al. 2013; Mefford et al. 2012; Moeschler & Shevell 2014; Vissers et al. 2016
- Tammimies, Marshal, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314:895-903; Anazi, Maddirevula et al. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2017;22:615.
- Ott 2015; Torkamani et al 2018; Khera et al. 2018
- Reviewed in Coelewij & Curtis 2018
- Gershon & Alliey-Rodriguez, 2013; Costain et al. 2013; Marshall & CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, 2016; Olsen et al. 2018
- Green et al. 2013: Original ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing; updated in Kalia et al 2017; McGuire, Joffe et al. Ethics and genomic incidental findings. Science. 2013;340:1047-1048; Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, DC. bioethics.gov/sites/default/files/FINALAnticipateCommunicate_PCSBI_0.pdf, 2013
- Green et al. 2009 Pubmed; Bloss, Christensen et al. 2011 Pubmed; Wakefield, Francke et al. 2016 Pubmed; Francke, Dijamco, et al. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ. 2013;1:e8.
- Sapp et al.: Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. AJHG 103:358-366, 2018. This last reference is the only one which specifically refers to patients’ responses to incidental findings.
- Hoge & Appelbaum 2012 Pubmed
- Appelbaum & Benston 2017
- See www.ashg.org/pdf/dtc_statement.pdf; www.eshg.org/fileadmin/www.eshg.org/documents/PPPC/2010-ejhg2010129a.pdf; and www.easac.eu/fileadmin/Reports/EASAC_Genetic_Testing_Web_complete.pdf
- See https://ispg.net/resources/educational-presentations/; genomicscases.net/en; Nurnberger, Austin, et al. What Should a Psychiatrist Know About Genetics? Review and Recommendations From the Residency Education Committee of the International Society of Psychiatric Genetics. J Clin Psychiatry. 2018 Nov 27;80(1); Besterman, Moreno-De-Luca, et al. 21st-Century Genetics in Psychiatric Residency Training: How Do We Get There? JAMA Psychiatry. 2019
- Nurnberger & Berrettini 2012; Schulze & McMahon 2018; Folkersen 2018
- Bousman et al 2018; Rosenblatt et al 2018 In these two papers meta-analyses of pharmacogenetic-guided antidepressant prescribing trials were performed. Both papers concluded pharmacogenetic-guided antidepressant prescribing was superior to treatment as usual.
- Phillips et al. 2018 In this article the Clinical Pharmacogenetic Implementation Consortium summarizes the evidence linking HLA-A and HLA-B genetic variants to severe adverse reactions following exposure to carbamazepine or oxcarbazepine. It also provides recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.
- Hicks et al 2017; See also cpnds.ubc.ca; cpicpgx.org; www.pharmgkb.org; pharmvar.org
- Winner et al. 2013; Singh 2015; Pérez et al. 2017; Bradley et al. 2018 These articles represent the four published randomized controlled trials of pharmacogenetic-guided prescribing of antidepressants. Data reported from these trials were used to calculate the number needed to test.
- See www.ncbi.nlm.nih.gov/gtr/; ww.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/