Genetic Testing Statement

Genetic Testing and Psychiatric Disorders

A Statement from the International Society of Psychiatric Genetics
(based on a draft proposed by the appointed Task Force to Review the Genetic Testing for Psychiatric Disorders Statement of 3/20/13; revised 7/12/13; further revised and augmented by members of the Genetic Testing Working Group and sent to the Board of Directors, 4/4/2014; approved 4/22/14)

Members of the ISPG Genetic Testing Taskforce

Summary of Recommendations

Background & Aims
As the primary and largest scientific society focused on the genetics of psychiatric disorders
worldwide, the International Society of Psychiatric Genetics recognizes the growing attention given
to clinical genetic testing and the questions raised about the value of such testing in psychiatry. We
convened an expert panel to review the available evidence and produce a statement that we hope
will provide some guidance for the general public and the medical community. 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 handle 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 children. Our recommendations assume informed consent for
all genetic testing; testing in individuals who cannot provide informed consent is not covered here.
We will revisit these issues in future statements.

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 assure analytic
validity. Replication is a critically important criterion for clinical validity. A valid test can then
be evaluated for clinical utility (i.e. is the test likely to improve patient outcomes?). For a
detailed discussion of these issues see ref 1.

Genetic Tests to assist Diagnosis and Identification of High-Risk Individuals
There is a history of successful use of genetic tests for several neuropsychiatric disorders,
including developmental disorders (e.g., phenylketonuria or PKU, Fragile X syndrome, and
Down syndrome or Trisomy 21) and some neurodegenerative diseases (e.g., Huntingtons
disease or HD). Depending on the disease, such tests can be used (1) to screen at-risk
individuals prior to symptoms or clinical diagnosis to help guide preventive treatment or longterm
planning, or (2) to help establish the diagnosis of someone with symptoms. The widely
used tests for PKU, Fragile X and HD have clearly established analytical and clinical validity as
well as clinical utility. Although there are no effective therapies yet for HD, confirming the
diagnosis provides the clinician and the family with useful information about how the patient™s
illness is likely to progress and therefore can help predict the needs of the patient and their

In contrast to the disorders mentioned above, major adult psychiatric and substance use
disorders, like other common disorders, are generally not caused by single genes or mutations.
Genome-wide association studies have found numerous DNA variants that change a single DNA
base and which are reproducibly correlated with schizophrenia, bipolar disorder, or nicotine
dependence at accepted levels of statistical significance. However, none of the variants found so
far are necessary or sufficient to bring about a psychiatric disorder. Instead, they increase or
decrease risk by a small fraction (usually less than 2-fold). Hence, testing one or a few of these
polymorphisms in isolation is not clinically relevant and not worth pursuing for diagnostic use.
More research is needed to determine if testing large numbers of low-risk variants in aggregate
may offer some utility for clinical practice.

[Patients with dementia are often cared for by psychiatrists. However, there does not appear to be
a consensus in the field regarding the appropriate use of genetic tests, such as APOe4, in
differential diagnosis of symptomatic individuals with dementia. This subject will not be
addressed here. We defer to other sources for the evolving expert opinion in this area, e.g., ref 2.]

A different scenario is presented by chromosomal microdeletions and microduplications (also
known as copy number variants or CNVs), which lead to loss or gain of one or many genes
within a particular chromosomal region. CNVs may be inherited or arise anew (de novo) during
human reproduction. Both inherited and de novo CNVs can confer a substantial risk for disease.
However, known CNVs lack diagnostic specificity: a given CNV may increase risk for a range
of psychiatric illnesses, intellectual disabilities, autism spectrum disorders, and epilepsy, and
may occur in normal healthy people. Large population-based studies are needed to establish the
lifetime risk for psychiatric disorder in individuals who carry of specific CNVs.

Although CNVs conferring high risks are rare, taken together they may contribute to a
significant fraction of cases of certain psychiatric disorders such as schizophrenia (ref 3). In the US, CNV analysis by microarray is already part of the recommended diagnostic workup for children with autism spectrum disorder, developmental delays, congenital anomalies, or intellectual disability (refs 4-6). Identification of CNVs may also help diagnose recognized disorders that have important medical and psychiatric implications for individual patients and may inform family counseling. Examples include DiGeorge, Phelan-McDermid, and Prader-Willi syndromes.

Genetic Tests to Guide Optimal Treatment
There is a growing list of genetic markers associated with effectiveness and adverse events of
various drugs. In some situations, pharmacogenetic markers can supplement clinical information
to help guide treatment decisions for psychiatric disorders, reducing the risk of treatment failure
and serious adverse events. For example, in patients of Asian ancestry who receive
carbamazepine, the HLA-B*1502 marker substantially increases risk of serious skin disorders
(Stevens Johnson Syndrome and toxic epidermal necrolysis; ref 7).

Some CYP450 enzymes (e.g., CYP2D6, CYP2C19) are highly involved in metabolism of drugs,
including antidepressants and antipsychotics. Variation in the genes that encode these enzymes
can lead to differences in drug metabolism that can be predicted by genetic markers. Individuals
with genetic markers of poor or rapid metabolism may be at higher risk for non-response,
adverse events, or drug-drug interactions. In view of these findings, expert panels have started to
publish guidelines for use of CYP450 testing in psychiatry (ref 8). We generally concur with these guidelines, which do notrecommend genetic testing on a global level, but provide guidance if genotype data are already available. Other gene-drug pairings are under active investigation. In addition, other factors that influence drug outcome (such as diet, use of other medications, or treatment resistance) need to be taken into account and studied further. Randomized, doubleblind clinical trials are needed to establish the clinical utility of genetic testing in psychiatric drug treatment.

We recommend clinicians follow good medical practice and stay current on changes to drug
labeling and adverse event reports. One useful (but not necessarily exhaustive) list of
pharmacogenetic tests is maintained by the US Food and Drug Administration (ref 9).

Reporting of Incidental or Secondary findings
Genetic technologies such as next generation sequencing permit readout of an individuals
whole exome or whole genome sequence, while chromosomal microarray screening detects
copy number variation across the entire genome. Genome-wide screens such as these may
generate secondary or incidental findings of potential importance for medical conditions
unrelated to the clinical complaint for which these tests were originally performed. Such
secondary findings may highlight a preventable illness or one that could benefit from early
intervention. Some authorities, such as the American College of Medical Genetics (ACMG),
recommend that clinicians report some secondary findings back to individual patients (ref 1010),
although this recommendation was not intended for, and remains controversial in, purely
research settings.

While we concur with the ACMG recommendations regarding reporting of actionable secondary
findings to the referring clinician, a decision to inform a patient about such finding(s) must
weigh the seriousness of the implicated disease, the potential medical consequences of
nondisclosure, the patient stated wish to be informed about secondary/incidental findings
(ideally established during pre-test counselling), the patients ability to rationally appreciate the
prognostic implications of such finding(s) and participate in any preventive or therapeutic
interventions that might be recommended, and the potential negative impact of disclosure on the
patients psychological condition and quality of life.

Studies have so far found no evidence that returning genetic results poses substantial
psychological or behavioral harms (ref 11). However, these studies primarily focused on individuals
at low-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 for their close family
members. In general, we support informing patients unless there are compelling reasons to
withhold potentially actionable findings. In situations where results become available during the
active phase of an episodic illness, such as major depression, it is reasonable to postpone
disclosure of non-urgent incidental findings until psychiatric stabilization has been achieved.

Psychological, ethical and clinical implications in genetic testing
When offering any genetic testing, there is a difficult balance between risks and benefits of acting
on a test result. Although psychological preparation for diagnosis and treatment may be among
the potential positive benefits, possible negative effects include taking unnecessary or unproven
treatments, stopping or avoiding needed treatments, changing life plans, or terminating a
pregnancy. All of these can have adverse impacts on an individual or a family, particularly when
subject to misinformation, incomplete data, or misinterpretation. Professional counseling is an
important means to help recipients understand these issues and ameliorate negative effects. The
interpretation of genetic risk may involve expertise in clinical genetics, and supportive,
psychotherapeutic, educational, and reproductive counseling may also be needed. Scalability of
individual counseling will be a challenge and needs to be addressed as the use of genetic testing
increases. In psychiatry especially, effective use of limited counseling resources will be crucial.

Direct-to-consumer (DTC) genetic tests, which can be obtained without a physicians order, are
prohibited in some countries, but allowed in others. The risks posed by 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 12-14).
Research is needed on the immediate and long-term effects of such testing in patients with
psychiatric illness and their families to inform the safe use of these tests in this specific
population. We recommend that all genetic tests with health implications — whether ordered by a
physician or directly by the consumer — should be accompanied by professional genetic

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 counsel their patients and clients on the proper use of genetic
testing. Community education should seek to minimize stigma or other disadvantages related to
life/health insurance or job security that individuals with psychiatric conditions could
experience if they chose to obtain genetic testing in clinical settings. Genetic test results, like all
medical records, are private data and must be safeguarded against unauthorized disclosure.

Summary Recommendations
1. As a basic principle, informed consent plays a crucial role in genetic testing. Tests
should only be carried out if patients have been informed about potential risks
(including significant implications for their daily life) and have consented to the
2. For major adulthood psychiatric disorders such as depression, bipolar disorder,
substance dependence, and schizophrenia, single genetic variants are not sufficient to
cause disease, and there are no genetic tests that can establish a diagnosis or predict
individual risk.
3. Although they lack diagnostic specificity, certain copy number variants (CNVs) are
more prevalent in individuals with autism spectrum disorders, schizophrenia, or other
psychiatric disorders. Identification of these CNVs in such patients may help diagnose
rare conditions that have important medical and psychiatric implications for
individual patients and may inform family counseling. Identification of de novo CNVs
may also have a place in counseling for certain psychiatric disorders.
4. Agencies such as the US FDA have begun to include pharmacogenomic information in
drug labeling and recommend genetic testing for some specific psychiatric drugs. We
suggest clinicians consider such recommendations in treatment decisions.
5. Evidence remains inconclusive as to the possible clinical utility of CYP450 genetic
testing in psychiatry, but more research is needed.
6. Professional genetic counseling is important when considering genetic testing or
returning genetic test results to individuals. We recommend that all genetic tests with
health implications should be accompanied by professional genetic counseling. For
patients with psychiatric illness, or for tests that relate to psychiatric conditions,
counseling by professionals with clinical expertise in mental health is important.
7. In genome-wide testing, the possibility of incidental or secondary findings must be
communicated in a clear and open manner and procedures for dealing with such
findings should be made explicit
8. We advocate the development and dissemination of clinical and community education
programs to educate mental health professionals in genetic medicine, safeguard the
privacy of individuals™ genetic testing results, and reduce stigma in the community.
9. Expanded research efforts are needed to clarify the role of genetic testing in

2. Sorbi et al. 2012; Goldman et al. 2011; Cohn-Hokke et al. 2011
3. Gershon & Alliey-Rodriguez, 2013; Costain et al. 2013
4. Manning et al. 2010
5. Mefford et al. 2012
6. Miller et al., 2010
Amstutz, et al., 2014
8. Hicks et al., 2013 and
11. Green et al., 2009; Christensen et al., 2011, Francke et al., 2013