More MS news articles for May 2002

Genetic testing for disease susceptibilities: consequences for genetic counseling

Trends in Molecular Medicine 2002, 8:306-307
Vol. 8, No. 6, June 2002
Roberta A. Pagon
University of Washington School of Medicine, GeneReviews, 9725 Third Ave NE, Suite 610, Seattle, WA 98115, USA


The role of genetic counseling in future testing for inherited susceptibilities for common diseases is debated. Currently, genetic testing, ideally supported by genetic counseling, is most often used to modify the assessment of genetic risk of Mendelian-inherited disease in high-risk individuals for the purpose of personal decision-making. By contrast, it is anticipated that genetic testing will be used to identify increased disease susceptibility in low-risk individuals for the purpose of instituting medical or lifestyle interventions to modify risk for future disease.

To explore the consequences of genetic testing for disease susceptibilities for genetic counseling, one first needs to clarify the current purposes and practice of genetic counseling for Mendelian disorders. Moreover, it should be noted that as genetic testing for disease susceptibilities is still in its infancy, the role of genetic counseling most certainly will evolve.

Genetic counseling, developed to address the medical and social consequences of Mendelian disorders, has become an integral part of genetic testing [1,2] . Genetic counseling as currently practiced is focused on the assessment of genetic risk; education of at-risk family members about disease manifestations and management; education about reproductive options; and provision of psychological and emotional support to develop coping strategies for largely untreatable diseases. Given that Mendelian disorders are often diseases of considerable medical impact with no definite treatment, genetic counseling as part of predictive testing focuses on providing information to patients and families about decisions of a personal, rather than medical, nature [3]. The purpose of genetic counseling is not to modify behaviour but to enhance informed decision-making, so it should come as no surprise that the roots of genetic counseling were in the social sciences. Although genetic counseling promotes appropriate and timely medical interventions when available, its mainstay is non-directive counseling to facilitate personal decision-making when interventions are supportive only.

Mendelian disorders

In Mendelian disorders, a disease-causing mutation in a single gene has high penetrance, producing an observable, often profound effect on phenotype. Commonly, the manifestations are not amenable to environmental manipulation and thus are untreatable. Affected individuals are ascertained because of overt symptoms or signs, or a family history. For a family, the social consequences of having a relative with a Mendelian disorder can be enormous: revelation of one member's genetic status can have profound implications for the health and/or reproductive risks of relatives.

With single-gene disorders genetic testing assumes four primary roles:
Diagnosis of symptomatic individuals. Often molecular genetic testing is the most sensitive and specific means of diagnosis (e.g. Huntington's disease) or the only way of confirming the diagnosis of a heritable disorder (e.g. primary pulmonary hypertension).

Risk assessment modification in relatives. Relatives have an a priori high risk that is clearly identifiable and quantitative (e.g. 50%, 25%, 12.5%). Genetic testing can, in many instances, clarify genetic status by determining, for example, if an individual at risk for an autosomal dominant disorder is affected or unaffected, or if an individual at risk by virtue of family history or ethnicity is a carrier or not for an autosomal recessive disorder.

Predictive testing. In predictive testing an individual at-risk is tested for the presence of a disease-causing mutation in his/her family; individuals with that genotype who live long enough will develop symptoms.

Prenatal diagnosis for fetuses at 25% risk or 50% risk. A couple who are carriers for an autosomal recessive disorder have a 25% risk of an affected child; the sons of a woman who is a carrier for an X-linked disease are at 50% risk to be affected.

The model for genetic counseling for a'traditional' Mendelian disorder in the USA is a team approach with genetic counselors, and/or nurses in genetics, working collaboratively under the supervision of an MD or PhD medical geneticist. Genetic counselors are trained in accredited masters' degree programs and are certified either by the American Board of Medical Genetics (ABMG) or by the American Board of Genetic Counseling (ABGC). Few training opportunities and limited certification exist for nursing genetics training (until recently, see footnote *). PhD or MD medical geneticists are certified by the American Board of Medical Genetics, a primary speciality board [4].

Common complex disease susceptibilities

Common complex disorders are presumed to result from the additive effect of mutations of low penetrance at multiple loci. Although when occurring individually these mutations may have no phenotypic effect, when acting in concert, and in the presence of environmental stimuli, these mutations may produce disease or increase the risk of disease. In this model mutations are regarded as 'predisposing' mutations because they are necessary to disease causation but not sufficient. Genetic testing for disease susceptibilities may rely upon the Mendelian model of genetic counseling when the risks conveyed by a single gene are high (e.g. the presence of a BRCA1 mutation can confer a lifetime risk for breast cancer of 70% or greater) [5]. However, when the risk associated with known gene mutations is low, it is anticipated that the medical issues and psychological and educational support issues that accompany genetic testing for these complex diseases will differ from the issues that accompany genetic testing for Mendelian disorders ( Table 1). Although a stimulus for lively conversation, genetic testing for complex disease susceptibilities is virtually absent from medical practice today. Furthermore, because common complex diseases are thought to result from the combined effects of genetic and environmental influences in unknown proportions, hypothesized interventions are medical, not psychological. In this model, the primary role of genetic testing is to allow healthcare providers to assign relative risks for common diseases to ostensibly healthy individuals to reduce the actual risk of developing the disease through medical interventions (including health screening and presymptomatic medication use) or through behavioural changes (including lifestyle and diet) [6]. The rationale for genetic testing in this model is decidedly medical. The counselors for these risk-modifying interventions may be part of a continuum of medical care provided by physicians, dietitians, health educators, and nurses. The psychological impact of risks that represent a small multiple of a small background risk is presumed to be low, and thus emotional support for psychological burden is not integral to the model. Extending the model of genetic testing for complex diseases further, one can assume that these asymptomatic at-risk persons will be identified through public health or screening measures applied broadly and based on ethnicity and other factors identified in population-based epidemiological studies.
Table 1. Mendelian disorders versus complex diseases
Aspects of the disorder Disorder type
Mendelian Complex
Population frequency Low High
Number of genes required to produce the phenotype One Many
Penetrance of individual genes High Low
Environmental influence on disease occurrence Low High
Method of patient ascertainment Family history and/or patient signs/ symptoms Medical screening
Benefit of early identification of at-risk individual Personal decision-making Risk modification through medical/behavioural intervention
Reproductive issues Many Few

Genetic counseling versus predispositional testing?

The fundamental difference between these two models is that the Mendelian disease model uses genetic testing to modify the assessment of disease risk in high-risk individuals most often for personal decision-making. By contrast, the complex disease model uses genetic testing to identify increased risk in low-risk individuals for the purpose of instituting interventions to modify risk for future disease.

Do the Mendelian model with predominance of genetic influences and the complex disease model with a predominance of environment influences contrast as sharply as Table 1 suggests? Absolutely not. In reality, the distinctions between these two models are not clear-cut. Table 1 serves to highlight fundamentals that in reality can be regarded as the extremes of a spectrum, in which most disorders occupy varying amounts of middle ground.

It is increasingly being recognized that Mendelian disorders are complex diseases in which environment plays a central role in disease causation [7,8] . Variability in some heritable disorders is unequivocally mediated by environment [e.g. dietary phenylalanine in classic phenylketonuria (PKU)]. Even in the absence of identifiable environmental influences, genotype often does not predict phenotype (e.g. in Huntington disease, the presence and/or size of a pathogenic CAG triplet repeat does not predict age of onset or disease severity). Thus, even the presence of a major disease-causing allele can be considered'predisposing' rather than predictive.

Conversely, according to Francis Collins, 'most of the successful efforts to identify genes associated with common diseases have focused on highly heritable subgroups' [9] in which single genes inherited in a Mendelian fashion have been identified as the cause of familial breast cancer, colon cancer, diabetes, Alzheimer disease, and Parkinson disease, to name a few. So, in the search for predisposing genes within families with complex common disorders, all the genetic counseling and social issues of the high-risk, high-hereditability single-gene disorders become relevant for the 510% of families with common diseases in which a Mendelian disorder is identified. Thus, as the determination of 'what is genetic' becomes murkier, so do the boundaries of 'inherited' disease versus 'acquired' disease.

Concluding remarks

Will genetic counseling vanish when predispositional testing becomes the norm in the primary practitioner's office, as risk modification becomes the primary reason to seek health care? Definitely not. Gene discovery, through which our understanding of common complex diseases will flourish, will also continue to expand our understanding of hundreds if not thousands of rare Mendelian disorders. Novel knowledge of disease causation will enable more accurate diagnosis and create more demand among high-risk relatives for genetic testing for risk assessment modification and reproductive decision-making in other words, genetic counseling.


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[2] Pagon R.A. (2001) Genetic diagnosis and counseling.
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[3] Broadstock M. et al. (2000) Psychological consequences of predictive genetic testing: a systematic review.
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[4] Walker A.P. (1998) The practice of genetic counseling.
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[8] Scriver C.R. et al. (1999) Monogenic traits are not simple: lessons from phenylketonuria.
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[*] The International Society of Nurses in Genetics (ISONG) awarded its first credentialing in October 2001 called the Advanced Practice Nurse in Genetics (APNG), and ISONG is currently developing a credential for Genetics Clinical Nurse.

© 2002 Elsevier Science Ltd