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Published in final edited form as: Can J Psychiatry. 2001 Mar;46(2):123–130. doi: 10.1177/070674370104600202

Genetic Counselling for Schizophrenia in the Era of Molecular Genetics

Kathleen A Hodgkinson 1,2, Jillian Murphy 2, Sheri O’Neill 2, Linda Brzustowicz 3, Anne S Bassett 4
PMCID: PMC3276586  CAMSID: CAMS2095  PMID: 11280080

Abstract

Objective

To review the role of genetic counselling for individuals with psychiatric illnesses.

Method

Using schizophrenia as an example and including updated information about a genetic subtype (22q deletion syndrome), we discuss the value of the genetic counselling process in psychiatry, with support from the literature and our clinical experience.

Results

Genetic counselling, the process through which knowledge about the genetics of illnesses is shared, provides information on the inheritance of illnesses and their recurrence risks; addresses the concerns of patients, their families, and their health care providers; and supports patients and their families dealing with these illnesses. For comprehensive medical management, this service should be available to all individuals with schizophrenia and their families.

Conclusions

New findings in the genetics of psychiatric illness may have important clinical implications for patients and their families.

Keywords: genetic counselling, schizophrenia, 22q deletion syndrome, psychiatric genetics

Burgeoning interest in the genetics of schizophrenia and other major psychiatric disorders in the 1970s and 1980s led to several papers addressing the issue of genetic counselling for these conditions (1–13). Since then, we have gained appreciable knowledge, both in the field of genetic counselling and in the field of psychiatric genetics, which has helped to shape how genetic information about these psychiatric illnesses is conveyed to patients and families in the 21st century. In this paper, we review the genetic counselling process and use schizophrenia as an example to outline current knowledge about its genetics and issues arising in genetic counselling, including those pertaining to a genetic subtype of schizophrenia.

What is Genetic Counselling?

The term genetic counselling was coined by Sheldon Reed in the 1950s (14); it is a well-defined process that should ideally occur for any disorder wherein a significant risk to relatives is present (15). A formal definition of genetic counselling was established at the beginning of the 1970s by the American Society of Human Genetics (15) (Figure 1). This definition describes genetic counselling as a communication process that provides genetic information in a nondirective manner, facilitates decision making, and supports the individual seeking counselling (consultand) and the individual’s family.

Figure 1.

Figure 1

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Definition of genetic counselling: American Society of Human Genetics: 1975 Ad Hoc Committee on Genetic Counselling

Genetic counselling is traditionally provided for 1) mendelian disorders with a straightforward inheritance pattern (for example, dominant and recessive) of both pediatric and adult onset; 2) nonmendelian disorders of complex genetic etiology (for example, multifactorial) of both pediatric and adult onset; 3) genetic syndromes; 4) prenatal diagnosis of genetic conditions; and 5) teratogen assessment in pregnancy (16). Genetic counselling is provided by health-care professionals trained in genetics—primarily, by genetic counsellors (who are typically graduates from Master’s programs or equivalently trained nurses) and medical geneticists.

The following 5 components are key aspects of the genetic counselling process: 1) gathering information (which includes determining the consultand’s needs and concerns, obtaining a detailed family history, and validating the diagnosis); 2) assessing risk; 3) conveying information (which includes providing details of the condition of interest, its inheritance, recurrence risks, and future options); 4) providing support and facilitating decision making; and 5) providing follow-up support and counselling (16). These are described below.

Gathering Information

The first step in the genetic counselling process is to determine the needs of the consultands. This ensures that their specific questions and concerns are addressed and emphasizes to consultands and their families that their needs are of the utmost importance. The questions that individuals have are usually related to their own circumstances and may include questions regarding the illness of concern, its management and treatment, and the risk that they or other family members may develop the illness. In some cases, the primary concern is the consultand’s unfounded belief that he or she may somehow have caused the illness. Consultands may express signs of anxiety, stress, or depression that are related to their concerns about genetic risk.

The next major step is to obtain a detailed family history documenting the state of mental and physical health of the consultand and all first-, second-, and third-degree relatives. Collection of family-history information is necessary for accurate risk assessment regarding the illness of concern; it may also provide other health information (for example, risk of hereditary cancer) important to the individual or family. Along with information about physical and psychiatric illnesses, a complete family history includes details of miscarriages, stillbirths, infant deaths, learning difficulties, childhood behaviour problems, birth defects, ethnicity, cultural group, and consanguinity. The psychiatric family history component includes information about vocational, occupational, and social functioning and any history of psychiatric illnesses, symptoms, treatments, completed suicides or suicide attempts, alcohol or drug abuse, and trouble with the law.

Sometimes family members may erroneously ascribe a disease to a family member, although underreporting of psychiatric disorders is more common (17). Either situation may artificially alter the risk assessment. For this reason, it is important to obtain the individual’s consent and to confirm diagnostic information with medical records.

Risk Assessment

For mendelian disorders the recurrence risks for specific conditions are well defined. However, diagnostic uncertainty and such genetic phenomena as reduced penetrance (no expression of the phenotype despite the presence of the genotype), variable expressivity (expression occurs at all times but varies in severity between individuals), and genetic heterogeneity (different genotype causing the same phenotype) can make risk assessment more complex. Empiric risk data are, however, available for many disorders without an obvious mendelian inheritance pattern, including psychiatric illnesses (3,8–27). Empiric risk data are derived from family studies of the condition of interest. Information about the consultand’s own family history will, however, usually also be needed to modify available empiric data and tailor risk assessment to the individual situation.

Conveying Information

The provision of recurrence-risk information may require several strategies to confer the ideas of probability and numerical risks. Also, the magnitude of the risk is likely to be perceived differently by different people. Thus, recurrence-risk information must be provided in an unbiased manner to minimize influencing individual perceptions of risk.

In addition to information on recurrence risks, information regarding the illness, its medical management, and available support services (for example, disease-specific support groups or agencies) is often provided during the genetic counselling process. This information, along with the risk assessment, can assist consultands in making informed decisions in their own or their family’s best interests, or both.

Support and Facilitation of Decision Making

In situations where consultands are faced with decisions (for example, whether to undergo genetic testing), genetic counsellors provide support during decision-making processes and assistance in adjusting to these decisions. Genetic counselling is nondirective in that it does not tell individuals what course of action to take.

In some cases, a session may focus on attempting to reconcile misconceptions and alleviate feelings of guilt, stress, anxiety, or depression. The genetic counsellor attempts to resolve these issues. Some individuals may need repeat appointments; for others, a single session may suffice. If psychological or psychiatric issues cannot be fully addressed during the genetic counselling process, referral to appropriate psychiatric specialists may be necessary.

Follow-up of Consultand

Providing written information (generally in the form of a follow-up letter) is another critical component of the genetic counselling process. This provides follow-up contact with the consultand and serves to reinforce the information covered during the counselling session. This letter records information discussed in the counselling session and may be shared with other family members or the consultand’s family physician, or both. The consultand is encouraged to recontact the genetic counsellor if new information is obtained or new questions arise.

The genetic counselling process has evolved over the years to provide a nondirective and supportive environment in which to educate consultands and families about genetic disease. With increasing knowledge in clinical and molecular genetics, genetic counselling is embracing more areas of clinical medicine, including such complex diseases as psychiatric disorders, cancer, and heart disease. We are now in a position to outline how genetic counselling may be helpful for schizophrenia and other psychiatric disorders, based on an improved understanding of the underlying genetics.

Genetics of Schizophrenia

Schizophrenia, a serious mental illness characterized by negative symptoms (social withdrawal and blunted affect), positive symptoms (hallucinations and delusions), and disordered thinking, has a lifetime prevalence of approximately 1%. This illness exerts a significant toll on health-care resources (28,29) and an equally significant emotional toll on families (30). Determining the etiology of this complex condition presents a major challenge in medicine, but research has consistently indicated a significant genetic component.

The evidence for genetic factors as the primary contributors to the etiology of schizophrenia is based on family, twin, and adoption studies. Family studies have consistently shown that first- and second-degree relatives of individuals with schizophrenia have higher risks of developing schizophrenia than do individuals in the general population (18,31). Twin studies have shown far greater concordance rates for monozygotic than for dizygotic twins: monozygotic twin concordance rates are 4 to 8 times higher than dizygotic twin concordance rates (32,33). Adoption studies indicate that biological children of parent(s) with schizophrenia who are adopted into families with no major psychotic illness have the same risk of developing schizophrenia as do biological first-degree relatives (34–36). Thus, the support for a genetic component to this disease is strong. Family and twin studies also indicate that other disorders occur more frequently than expected in the relatives of individuals with schizophrenia. Variable expression of a schizophrenia phenotype may include related disorders, such as schizoaffective disorder and other nonaffective psychoses (37), schizotypal and paranoid personality disorders (38–40), and mood disorders (41,42).

How is Schizophrenia Inherited?

The genetic etiology of schizophrenia has usually been considered to be multifactorial (43–45). Multifactorial inheritance as defined by Falconer (46) includes both genetic (multiple genes) and, possibly, nongenetic factors—now known to include epigenetic mechanisms (modifiers of gene expression), such as methylation. A model of multifactorial inheritance assumes that a number of genes (estimates suggest possibly 2 to 3 major interacting loci in schizophrenia [47]) act together in an additive or multiplicative fashion with or without nongenetic risk factors to increase susceptibility to develop the disorder. This model is often used to explain conditions with complex etiologies. It is likely, however, that many multifactorial conditions will be considered genetic as causative genes are identified and epigenetic mechanisms modifying their expression elucidated.

Multifactorial inheritance, therefore, may not explain all cases of schizophrenia. In some families, a single major gene may exist that increases an individual’s susceptibility to express schizophrenia (48). Pedigrees, or family trees, showing numerous individuals with schizophrenia should be evaluated closely to determine whether there is evidence that a single major gene may be present, resulting in a mendelian inheritance pattern that could indicate significantly increased risks to family members. The pattern of inheritance in schizophrenia is rarely so clear-cut, however. This may be due in some cases to incomplete penetrance or variable expressivity, making the determination of the inheritance pattern more challenging. The phenomenon of incomplete penetrance in schizophrenia is supported by studies of offspring of discordant monozygotic twins (49,50), that showed similar rates of schizophrenia in offspring of both affected and unaffected monozygotic co-twins. Clarification of genetic transmission patterns in schizophrenia awaits identification of genes involved in susceptibility for schizophrenia.

Locating Genes for Schizophrenia

Research is ongoing to localize major loci that contain genes for schizophrenia. Linkage findings achieving significance (51) have recently been reported for susceptibility loci on both chromosome 1 (52) and chromosome 13 (53). The chromosome 13 locus has also been found by independent research groups to be linked to schizophrenia (54) and bipolar disorder (BD) (55). Another paper reviews recent linkage and association studies of schizophrenia. (56). Research to identify the susceptibility genes in these regions is currently being actively pursued.

A Genetic Subtype of Schizophrenia: the 22q11 Deletion Syndrome

Another recent finding of note has been the identification of a genetic subtype of schizophrenia, known as 22q deletion syndrome (22qDS) (57–59). The 22q deletion syndrome, also known as velocardiofacial syndrome, DiGeorge syndrome, or conotruncal anomaly face syndrome, involves a microdeletion on chromosome 22q. The syndrome has a prevalence in the general population of approximately 1 per 4000 live births (60), although this is likely an underestimate. The syndrome is a highly variable genetic condition, even within families (61) and between monozygotic twins (62–65). The variable phenotype includes learning difficulties, characteristic facial features, palatal anomalies, and psychiatric illnesses—most commonly, schizophrenia (66,67). The prevalence of schizophrenia in 22qDS is approximately 25% (or 25 times the general population risk of schizophrenia) (67,68). Current estimates suggest that 22qDS may comprise 0.5 to 2.0% of all patients with schizophrenia (69,70). Other psychiatric illnesses reported in adults with 22qDS include major depression, bipolar disorder, obsessive–compulsive disorder, and alcoholism (67,68,71).

The deletion associated with 22qDS is too small for detection using routine karyotype analysis (61). A specialized cytogenetic technique—fluorescence in situ hybridization (FISH)—available in most clinical genetics laboratories is necessary for molecular diagnosis. Because the phenotype is often subtle, and relatively few clinicians are yet aware of 22qDS, the condition is underrecognized, especially in adults (72). A diagnosis of a 22qDS subtype of schizophrenia has important medical and genetic counselling implications (59).

Genetic Counselling for Schizophrenia

Who Requests or Should Be Offered Genetic Counselling?

Our experience with referrals for genetic counselling for schizophrenia is similar to that reported by Reveley (9). Referrals are related primarily to risks for offspring to develop schizophrenia. Consultands are mainly individuals with schizophrenia and their relatives, especially siblings. Some relatives of individuals with schizophrenia are also interested in learning of their own chance of developing the illness. Prospective adoptive parents, parents who have already adopted a child with a biological family history of schizophrenia, and coordinating agencies such as the Children’s Aid Society may also request genetic counselling. In addition to recurrence risks, issues relevant to consultands with schizophrenia may include pregnancy-associated risks, such as the use of psychiatric medications during pregnancy. The recent Canadian Clinical Practice Guidelines for the Treatment of Schizophrenia suggested that genetic counselling be offered to all patients with schizophrenia (73). Genetic counselling can assist patients to make informed decisions when embarking upon family planning.

Information Gathering for Risk Assessment

Detailed family history and medical history are necessary to determine whether the consultand’s history indicates 1) an isolated case of schizophrenia within a family; 2) a more complex family structure with schizophrenia or other psychiatric disorder(s), or both, in several members; or 3) a genetic subtype of schizophrenia, such as 22qDS. The genetic counsellor must also keep in mind the possibility of other genetic conditions associated with schizophrenia or schizophrenia-like psychoses, such as mosaic Turner syndrome (74), adult-onset Tay-Sachs disease (75,76), tuberous sclerosis (77), and Huntington’s disease (78). If 22qDS or another genetic syndrome is suspected, a referral to a genetics specialist would usually be appropriate.

Genetic Counselling for Recurrence Risks in 2 Common Situations and 1 Special Situation

“Isolated” Cases of Schizophrenia

In families with only 1 individual diagnosed with schizophrenia and no features suggestive of a genetic subtype of schizophrenia, information for risk assessment at this time continues to rely on empiric data. Empiric risks are based on the observed frequencies of the condition of interest in relatives of an individual who has the condition. Empiric data on recurrence risks for multifactorial disorders are available for simple pedigree situations (a single first-, second-, or third-degree relative with the condition) (Table 1). Risks for first-degree relatives range from 5% to 16% and for second-degree relatives, from 1% to 8%. The risk estimate for third-degree relatives is approximately 2%, but this figure is based on few studies. As in other genetic illnesses (79), one must also consider the age of the consultand seeking counselling, since it may be appropriate to modifiy risk information for individuals beyond the most common age range of presentation (in the case of schizophrenia, mid-to late adolescence to approximately age 40 years).

Table 1.

Empiric risks for schizophrenia for relatives of individuals with schizophrenia

Relationship of relative to individual with schizophrenia Life-long risk % (range)
First-degree relative
 Parent 6 (5–10)
 Sibling 10 (8–14)
 Offspring 13 (9–16)
 Offspring with 2 parents with schizophrenia 46
Second-degree relative
 Uncle or aunt 2
 Nephew or neice 3 (1–4)
 Grandchildren 4 (2–8)
 Half sibling 4
Third-degree relative
 First cousin 2 (2–6)
General population 1
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Adapted from Gottesman (1991) (31) and Vogel and Motulsky (1997) (99).

Complex Family Structures

For consultands with a more complex family history, it is more difficult to provide accurate recurrence risks. There is limited risk information available for cases of 2 affected relatives. For the offspring of 2 parents with schizophrenia, a 46% risk of developing schizophrenia is reported. Additional situations would include schizophrenia in other relatives on both sides of the family or in 2 or more relatives on the same side of the family. For such families, it may be appropriate to modify the recurrence risks provided by available empiric data for single affected relatives. Difficulties in providing accurate recurrence risks also arise when there are other psychiatric disorders in the same family (for example, BD, psychotic or nonpsychotic depression, and possible schizophrenia “spectrum” disorders). The presence of such disorders may alter risks, yet specific data for these situations are not currently available.

In all cases using empiric risks, the genetic counsellor discusses the nature of these risks as estimates of probabilities only and outlines how they are derived. In most cases, we have found that individuals are relieved after genetic counselling because they often perceive their risk to be higher than actual risks that are based on empiric data and their own family history.

Special Situation: 22qDS

This syndrome is caused by a microdeletion of 22q11.2 on 1 of the 2 copies of chromosome 22 in each cell of the body. For those with the syndrome, transmission of this deletion follows a mendelian autosomal dominant pattern. Thus, an individual with 22qDS has a 50% chance of having a child with 22qDS in each pregnancy. As with most mendelian conditions, however, the severity of the condition and any of its physical or mental manifestations cannot be predicted.

Parents of an individual with 22qDS are routinely tested for the deletion because in about 10% of cases the deletion may be inherited from a parent, who often has a mild presentation of the syndrome (80). A comprehensive family history can help to determine whether there are other individuals (for example, siblings) who may be eligible for genetic testing for the deletion. In most newly diagnosed cases of 22qDS, however, the deletion has occurred as a de novo mutation. Counselling regarding its chance nature and likely occurrence during gametogenesis may relieve parents of guilt or inappropriate blame for causing behavioural manifestations of the condition (81).

Genetic counselling regarding the syndrome, its variable expression, available testing, and future pregnancies is an essential component of the comprehensive medical management of patients with 22qDS. As with other genetic syndromes involving varying levels of learning disabilities, genetic counselling for these patients may require unique approaches to help convey the information (for example more concrete explanation of concepts, visual aids, and use of analogies from the person’s own experience).

Other Issues Within the Genetic Counselling Session for Schizophrenia

It is important to emphasize the value of a multidisciplinary approach for comprehensive management of individuals with schizophrenia. In 22qDS schizophrenia this will include recommendations for related investigations (for example, renal ultrasound and calcium and parathyroid hormone levels) and follow-up (59).

Family members who are concerned about the recurrence of schizophrenia in themselves or other family members, such as children, may benefit from a discussion of possible early signs and symptoms and from the encouragement to seek a psychiatric evaluation if they feel it necessary.

Because most genetic disorders are treatable, determining a genetic risk can allow for early and relevant treatment that may alter the disorder’s prognosis. For schizophrenia, early diagnosis and treatment is especially relevant for better prognosis (82–85). Also, an effective treatment for one family member may prove to be effective for other family members as well (86). Thus, history of treatment trials, future treatment options, and proneness to certain side effects may also be discussed in the genetic counselling session.

During the genetic counselling session, it is usual to identify incidental information regarding family history of other common illnesses such as cancer, heart disease, alcohol and drug abuse, or other genetic disorders (for example, cystic fibrosis or autosomal dominant polycystic kidney disease). In these situations, further family history pertaining to these other illnesses may also be gathered. Genetic counselling and appropriate referrals can then be provided for these illnesses. Similarly, a history of significant psychiatric symptoms in the consultand may lead to a referral for psychiatric assessment and treatment when necessary.

Future Considerations in Genetic Counselling for Schizophrenia

The Possibility of Genetic Testing for Susceptibility to Schizophrenia

Evidence for schizophrenia loci on chromosomes 1 and 13 (52,53) suggests that identifying schizophrenia susceptibility genotypes may become a reality sometime in the future. This will, hopefully, lead to an understanding of the pathophysiology of schizophrenia and, subsequently, to the development of more specific treatments. It may also be possible to assess at-risk individuals for susceptibility. Given the complex genetics of schizophrenia, however, identifying a schizophrenia susceptibility gene may not significantly alter risks already indicated by empiric risk data. It may continue to be difficult or impossible to account for the presence of other predisposing genes or nongenetic risk factors, or both, and assess their potential interaction (87). Also, given the likely genetic heterogeneity of schizophrenia, individual gene findings may only relate to a few families. A similar situation is seen in the case of Alzheimer’s disease (AD). AD is also genetically heterogenous: at least 4 distinct AD genes for early-onset AD have been described, likely acting through a common biochemical pathway (88). One of the AD genes is a susceptibility genotype in the form of the APOE 4 allele; it does not confer absolute risks, merely an increase in susceptibility or a modification in age at onset, or both (89). Although not recommended as a screening methodology (90), research is in progress to determine how at-risk individuals respond when an APOE 4 genotype is used as a risk modifier (91). As exemplified by 22qDS, however, the determination of identifiable etiologies for some forms of schizophrenia should aid understanding of at least those subgroups.

Potential Ethical Issues Regarding the Possibility of Pre-symptomatic Testing

If individual susceptibility genes are identified, will pre-symptomatic screening for schizophrenia ever become available? This would perhaps be possible for a rare subset of individuals from families in which a major susceptibility locus had been identified. One could theoretically perform such testing in children, a situation envisaged in the early 1970s (92) and available today for some forms of AD (93). However, as with the other genetic disorders for which presymptomatic testing is available (for example, familial adenomatous polyposis [94]), one would only perform such testing if the clinical benefits in terms of disease prevention clearly outweighed compromising the child’s autonomy and the risks of any interventions (95).

Testing children with syndromal features for 22qDS could be construed as presymptomatic testing for schizophrenia. The risk for later-onset conditions such as schizophrenia and other psychiatric disorders has not yet, however, become part of the standard information given to parents of infants or children diagnosed with 22qDS. We anticipate that this information will become incorporated into most genetic counselling sessions for this syndrome as practice using currently available data evolves.

In summary, the ethical issues surrounding molecular genetic testing of individuals for schizophrenia should be no different from those already encountered with several other genetic conditions (96,97). In all cases, individuals should be clearly informed of the benefits and disadvantages of testing and should be counselled regarding the potential insurance and employment discrimination issues (96).

Attitudes Toward the Possibility of Presymptomatic Testing

No studies of the attitudes toward genetic testing for schizophrenia are currently available, but findings from a study of BD (98) indicated that there is a keen interest in genetic testing. In this study, most adult patients and spouses who completed a survey reported that they would use genetic testing for BD if it were available. They also indicated that they would not use this information to terminate an affected fetus, nor would the information deter them from marriage or child-bearing. Although BD often differs from schizophrenia in terms of the burden of illness and ability to function with treatment, this study is an interesting examination of the predicted use of genetic testing for psychiatric disease.

Summary

Recent advances in genetic research have opened the door to potentially important advances in our understanding of schizophrenia and the elucidation of a genetic syndrome associated with schizophrenia. These advances, and future discoveries, may lead not only to further modifications of information currently available for genetic counselling but also to opportunities for genetic testing for this and other psychiatric illnesses. Unfortunately, it is still rare for families with a history of schizophrenia or other psychiatric illnesses to be referred for genetic services, although these families may wish to gain this knowledge. Because the burden and distress caused by major psychiatric illnesses rests with patients and their families, referrals for genetic counselling, together with supportive counselling or psychoeducation, or both, may be helpful and welcome services for patients and their families.

Clinical Implications

  • Access to genetic counselling should be available to all individuals with schizophrenia and is particularly important for family planning.

  • Information on empiric risks for schizophrenia is available, but it must be used in the context of the individual’s family history to tailor the risk assessment to the individual.

  • Genetic counselling issues, including medical management and recurrence risks, differ for individuals with a genetic subtype of schizophrenia, such as 22q11 deletion syndrome.

Limitations

  • Although individuals and families dealing with schizophrenia and other psychiatric disorders may benefit from genetic counselling, this service is not routinely offered.

  • Causal genes for schizophrenia have yet to be identified. Finding such genes will likely have an impact on our understanding of pathophysiology and may alter what information will be available to patients and families for genetic counselling.

  • Research of the ethical considerations related to genetic testing for schizophrenia is limited. This knowledge will be essential, once causal genes are identified, to determine the most appropriate implementation of services for genetic testing.

Acknowledgments

Funded in part by the Medical Research Council of Canada, Ontario Mental Health Foundation, and by an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (ASB).

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