chapter 31 Genetic conditions

INTRODUCTION AND OVERVIEW

Genetic conditions are those that are directly or indirectly due to a pathogenic variation in a person’s genome that is present at birth. The variant may be inherited from a parent, or occur for the first time in the family in that person in the production of the egg or sperm or at conception (spontaneous mutation or chromosomal change).

Until recently, the focus has been on genetic conditions, usually rare, that are directly due to a genetic variation. There are many thousands of these conditions, and they include changes to chromosome number and structure, pathogenic variants in single genes. For example, around 2300 comparatively rare conditions are now known to be primarily due to an inherited mutation in a single gene.¹ As they follow a pattern of inheritance in families first defined by Mendel over 100 years ago, these conditions are often referred to as Mendelian. Still, the genes and mutations causing around 1600 or so Mendelian conditions remain to be identified.¹ Also, more than one gene can be involved in the causation of some Mendelian conditions.

For all these genetic conditions, treatment is limited and symptomatic. Gene therapy—treatment to correct the underlying genetic change—is still in its infancy and research is continuing, to ensure its safety and efficacy.² Currently the only preventive strategy is detection through genetic testing prenatally and termination of an affected pregnancy or pre-implantation. These strategies can only be used where pregnancies are identified as at-risk. This determination results from genetic counselling and genetic testing where appropriate, and may be available based on a positive family history or ethnicity.

An emerging area is the use of DNA genetic testing to guide prescribing and drug response (pharmacogenomics).³ This field epitomises the move to tailored medicine.

EPIGENETICS

For decades, our view of heredity has been rather fixed and one-dimensional. It was written in the language of DNA—and genetic mutations and recombinations have driven most descriptions of how phenotypic traits are handed down from one generation to another. However, recent discoveries in the field of epigenetics—the study of heritable changes in gene function that occur without a change in the DNA sequence—have blurred this picture, and are changing the way we think about heredity.

Increasingly there is recognition of the significant contribution to many common conditions of the interaction between the person’s inherited genome and factors in their fetal, childhood and/or adult environment. Despite the presence of the predisposing mutation since birth, a person will remain asymptomatic unless further acquired genetic variations or other interactions occur during the person’s lifetime that lead to disease onset. Identification of the factors that lead to the variants or interactions is crucial for prevention.

In practical terms it means that non-genetic factors such as drugs, diet, exercise, stress responses and environmental factors can cause an organism’s genes to behave (or ‘express themselves’) differently and even pass that expression on to the next generation. In other words, Nurture can alter Nature.

Epigenetic mechanisms, and their effects in gene activation and inactivation, are increasingly being found to play a critical role in phenotype transmission and development. The study of epigenetics is therefore telling us much about the mechanisms whereby lifestyle, environmental and psychosocial factors can influence the activation and progression of chronic illnesses, including cancer,⁴ dementia⁵ and ageing.⁶ But, more optimistically, it also tells us much about the potential for lifestyle and environmental modification to alter disease progression.

LIFESTYLE FACTORS AND GENETICS

Our genes are programmed not just by the DNA but also by the ‘epigenome’, which is the chemicals and proteins laid down over the genes and which alter their expression. Epigenetic patterns are sculpted during fetal development, and are affected by maternal nutrition and exposure to environmental toxins as well as psychological stress.⁷ It is now also known that extensive lifestyle changes, such as those undertaken in the Ornish program, are associated with alterations of cancer gene expression⁸ and improved telomerase-based genetic repair.⁹ Thus, alterations in genetic function and repair probably explain a significant amount of the benefit of lifestyle-based interventions.

Some further examples and implications are explored below.

Mind–body and DNA modulation

An important but possibly under-recognised factor in determining the development, expression and repair of genes is our mental and emotional state.

Psychological stress increases DNA damage ¹⁰ in animal studies^11,¹² and studies on humans. There is an increase in DNA damage in humans under stress—in students taking examinations, for example—and stress increases the number of genetic mutations and probably impairs the body’s ability to repair them¹³ (due to the effect of the mediators of the stress response¹⁴), increases oxidation and affects DNA repair enzymes.

DNA damage stimulates the body’s DNA repair mechanisms in order to compensate for the damage.¹⁵ A study of healthy medical students showed that during the exam period, compared with low-stress periods after vacations, there was an increase in DNA repair capacity (DRC) in nearly all the study participants.¹⁶ Students who had higher and more consistent levels of stress and mood disturbance during exam periods had a reduction in DRC, or no change when they needed it most, suggesting that the response had been impaired in some way due to emotional stress. The implications of DRC are important. A study comparing DRC in women with breast cancer and in cancer-free women found significant differences.¹⁷ Women with breast cancer have a lower DRC (5.6% DRC) than women without breast cancer (8.7% DRC). Younger breast cancer patients had a more significant reduction in DRC. A low DRC increased susceptibility to breast cancer, with a 1% decrease in DRC corresponding to a 22% increase in breast cancer risk.

Not only is DNA function, damage and repair affected by psychological states, but the mind also affects genetic ageing. Telomeres are segments of DNA at the ends of the DNA strands that help the DNA to not ‘unravel’, which would cause the cell to die. A study of healthy premenopausal women who were carers for someone with a major disability found that psychological stress, in terms of both perception and duration, was significantly associated with markers of cell death and longevity. The women who were coping least well with the demands showed higher oxidative stress, lower telomerase activity (the enzyme that repairs telomeres) and shorter telomere length. Women with the highest levels of perceived stress, compared with those with the lowest, had telomeres shorter on average by the equivalent of 9–17 years of additional ageing.¹⁸ A similar finding has been demonstrated for people with depression.¹⁹ Low telomerase activity is associated with high allostatic load and also with other risk factors for cardiovascular disease, such as smoking, lipids, high blood pressure, high fasting glucose, and metabolic syndrome.²⁰

Much work is now going into investigating whether practices such as mindfulness training, which have been found to reduce stress and improve mental health, can also slow the ageing process, measured by markers such as telomere length and telomerase activity. Interestingly, the research is suggesting that ageing may be able to be slowed, or even reversed to an extent, through the use of these practices. ‘We review data linking telomere length to cognitive stress and stress arousal and present new data linking cognitive appraisal to telomere length. Given the pattern of associations revealed so far, we propose that some forms of meditation may have salutary effects on telomere length by reducing cognitive stress and stress arousal and increasing positive states of mind and hormonal factors that may promote telomere maintenance. Aspects of this model are currently being tested in ongoing trials of mindfulness meditation.’²¹

Psychological states also affect genetic expression in conditions as varied as addictive behaviours,²² cardiovascular disease,²³ mental health problems such as depression²⁴ and schizophrenia,^25,²⁶ and asthma,²⁷ which goes some way to explaining why stress is such a common trigger for many diseases. For example, chronic pain is associated with depression, but it is the emotional reactivity to chronic pain that can sensitise the brain to pain messages, increase the likelihood of a genetic disposition to depression activating itself, and impair the ability of the brain to make new neurons (neurogenesis).²⁸

Spirituality and religion may have important effects on lifestyle, including assisting in lowering rates of substance abuse in those genetically at risk.²⁹ For example, this may be mediated by the reduced risk of expressing a genetic disposition to smoking and other addictive behaviours in those with a high level of self-rated religiosity.³⁰

Exercise

Physical activity levels have been linked with genetic function, expression and repair.³¹ How exercise does this is coming to be understood, but it is not necessary to understand how it works in order to enjoy the benefits. Regular moderate exercise helps to reduce oxidative damage and is associated with improved DNA repair, which may be one of the reasons that exercise is associated with slower ageing and cell death.³² Extreme training, on the other hand, is associated with more oxidative damage,³³ although it does stimulate DNA repair.³⁴ These effects can be seen for a week after extreme exertion, such as after a marathon.³⁵ Part of the protective effect of exercise may relate to it producing a similar effect to calorie restriction—that is, it helps to change the balance of calories and exceeding calories out.³⁶ The anti-inflammatory effect of exercise may also be a factor. Exercise also has beneficial effects on mental health which, bearing in mind the preceding section on stress management and genetics, may be an important factor in protecting our genes. All in all, healthy genes are just another reason to exercise regularly.

Nutrition

Nutrition has an important role in the function, repair, expression and ageing of DNA.³⁷^–³⁹ Various micronutrients, vitamins and minerals are required for DNA synthesis, prevention of oxidative damage and DNA maintenance. For example, low levels of folate are associated with increased risk for a baby with a neural tube defect, whereas increasing folate is associated with better DNA repair.⁴⁰ Also, the minerals selenium, manganese and zinc minerals are cofactors for DNA repair enzymes.⁴¹ The Mediterranean diet, rich in olive oil and vegetables, is associated with a reduced incidence of cancer, which is postulated to be partly because of effects on DNA damage and repair.⁴²

GENETIC COUNSELLING AND GENETICS SERVICES

Genetic counselling is provided as part of a comprehensive genetics service ^43,⁴⁴ whose elements include clinical, laboratory and education. Genetic counselling provides information, supportive counselling regarding the diagnosis and risk for a genetic condition in the family, genetic testing where appropriate and management of rare conditions in some cases. The healthcare professional team providing genetic counselling may consist of clinical geneticists or other medical specialists, genetic counsellors and social workers. Internationally, genetic counselling is increasingly provided by genetic counsellors working as part of mainstream medicine.

Taking and verifying the family history is at the core of genetic counselling and the provision of appropriate genetic testing. The history is, optimally, collected by the general practitioner at the first visit and updated regularly as it can provide information for preventive strategies. The family history changes with time, and ideally the patient should maintain their own copy of their family health history, update it opportunistically and be able to answer the question: ‘Do you have a family history of XX condition?’. For example, the family health record can be downloaded from the NSW Health (New South Wales government) Centre for Genetics Education website.⁴⁵

While it may not always be possible, the record of the family history will optimally be three-generational, including primary relatives (children, siblings, parents) and secondary relatives (aunts, uncles and grandparents) on both sides of the family, and noting in particular: ethnic background (ancestry and culture); adoption; age at diagnosis; age and cause of death; birth defects, stillbirths and miscarriages. It is not always possible to assume ethnicity from country of birth or surname. More information can be obtained by asking patients where their parents, grandparents or great-grandparents were born.⁴⁶ There are no privacy implications in taking a family history.

GENETIC TESTING

Genetic testing for changes in chromosome number and structure traditionally used cytogenetic karyotyping, but increasingly will rely on molecular cytogenetic testing, which can reveal very small changes not identifiable under the light microscope.⁴⁷ DNA genetic testing also is changing rapidly, with increased use of sequencing of parts, or the whole, of a patient’s genome.

FIGURE 31.1 Karyotype of a normal individual

Genetic screening is done for a particular condition in individuals, groups or populations without family history of the condition (e.g. genetic carrier screening for genetic conditions common in the Ashkenazi Jewish population ⁴⁸). Usually, a panel of mutations that are common to the population group will be tested for, so rarer mutations will not be detected.

Genetic testing is done for a particular condition where an individual is suspected of being at increased risk due to their family history or as the result of a genetic screening test. Direct DNA gene testing looks at the presence or absence of a known mutation in the gene. The mutation may be family-specific. The test is very accurate and is used for diagnosis and screening, including prenatal, genetic carrier testing, cascade testing, and presymptomatic and predictive testing (Table 31.1). Limitations of direct DNA genetic testing include the following:

• Interpretation of the test result—for example, finding that a person has a mutated gene does not always relate to how a person is, or will be, affected by that condition.

• The testing may be time-consuming and expensive—for the health service, if not for the patient.

• For some complex conditions (e.g. cancer), the testing may have to be done on a family member with the condition, to identify a family-specific mutation in the gene (mutation searching) before unaffected family members can be offered predictive testing.

TABLE 31.1 Uses of genetic testing

Type of test	Use
Genetic carrier testing	Testing an individual to determine whether they are a carrier of a faulty, or mutated, gene for a particular condition
Cascade testing	Testing of blood relatives when a mutation has been identified in a family member
Pre-implantation testing	Testing an at-risk embryo for a genetic condition, prior to implantation, thereby obviating the need to terminate an affected pregnancy
Prenatal testing	Testing to detect fetal abnormalities
Diagnostic testing	Specific testing in an individual who has symptoms suggestive of a genetic condition
Presymptomatic testing	Testing to determine, prior to any sign of the condition, whether an individual will, without appropriate intervention, develop the condition in the future
Predictive testing	Testing prior to any sign of the presence of the condition, to determine whether an individual is at risk for developing the condition in the future

ORDERING GENETIC TESTS

Costs to the patient of genetic testing vary according to how pathology testing is funded in each country—that is, whether there is a national health system or private health insurance. With developments in technology, such as sequencing the patient’s whole DNA, rather than just looking at specific genes using direct gene testing, costs are expected to decrease in the next few years.⁴⁹

Before obtaining consent, the patient should be informed about the purpose and personal/family implications of a genetic test. Patients who have had a predictive or presymptomatic genetic test have a duty to inform life insurers of the test result when applying for a new, or altering an existing, policy.⁵⁰

The patient should be encouraged to share the information with their relatives, and supported in doing so.⁴⁶ Changes to the Australian National Privacy Act in 2006 allow, in appropriate exceptional circumstances, for a healthcare professional working in the private sector to release information to genetic relatives without the consent of the person being tested.⁵¹ However, this should only be seen as the last resort after counselling patients to inform their relatives where there is a serious risk to their life, health or safety. When such action is considered, guidelines are available.⁵² A general practitioner has no duty to inform a patient’s relatives about a positive genetic test result.⁵³

A number of ethical issues arise from genetic testing that are relevant not only for individuals and families but for society in general as well.⁵⁴ These issues have been addressed internationally⁵⁵^–⁵⁷ and include:

• predictive and presymptomatic genetic testing for disorders for which there are currently no treatments, especially in children and adolescents

• privacy and confidentiality, especially when the privacy of the individual is to be balanced against the needs of other family members

• the necessity to ensure that all decision-making regarding genetic testing is made, as far as possible, on an informed basis

• the implications of genetic testing for those wishing to take out superannuation, or life or disability insurance

• the effect that genetic information will have on the concept of ‘disability’.

Increasingly, genetic tests are being marketed directly to consumers through the internet (direct to consumer (DTC) genetic testing). Laboratories conducting DTC genetic testing are largely based in the United States ^58,⁵⁹ as regulation in countries such as Australia allows laboratories to conduct tests for health conditions only when referred from a medical practitioner.⁶⁰ DNA samples are collected at home using kits provided (a cheek swab or saliva sample) and sent to the laboratory through the mail. Payment is made via the internet. Support may or may not be available for explanation of the results, again via the internet. Concern has been raised about the marketing and scientific credibility of these DTC genetic tests internationally.^61,⁶² Further, for genetic tests that purport to provide evidence for lifestyle and dietary modification, caution should be exercised in interpreting the results and recommendations provided, on the basis that analysis of the person’s DNA is in a non-holistic context.⁶³