Genetic conditions

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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

CHROMOSOMAL CONDITIONS

While chromosomal conditions due to a change in the number of chromosomes in the cells are rare overall, some are encountered more commonly. These include trisomy 21 (Down syndrome), XXY syndrome (Klinefelter syndrome) and 45,X syndrome (Turner syndrome.

TRISOMY 21, DOWN SYNDROME ⁶⁴^–⁶⁶

Incidence: 1 in 660 births.

Aetiology

• Extra copy of chromosome 21 (trisomy 21) in all cells of the body (about 95% of cases)

• Extra copy of chromosome 21 in some cells of the body (mosaic trisomy 21; about 1%) and clinical features may be less severe

• Or chromosomal translocation involving chromosome 21 (about 4%).

History

Associated with increased maternal age (Fig 31.2). A family history may indicate the translocation type of trisomy 21.

FIGURE 31.2 Chance of having a live-born baby with Down syndrome (trisomy 21) according to the mother’s age at the time of delivery of the baby

(source: Morris et al,⁶⁷ adapted from Barlow-Stewart 2007⁶⁸)

Investigations

For the neonate/infant: cytogenetics.

For the parents:

• personal/family history of recurrent miscarriage, infertility or developmental delay

• consider cytogenetics pre-conception or in the prenatal period as appropriate.

Management

47,XXY KLINEFELTER SYNDROME ⁶⁹

Incidence: 1 in 500 total births (1 in 1000 male births).

Aetiology

Boys who have:

• two copies of the X chromosome instead of the usual one copy (47,XXY) in all cells of their body—about 80% of cases

• three or four extra X chromosome copies in all cells (48,XXXY or 49,XXXXY)—very rare, but the clinical features may be more exaggerated

• two or more copies of the X chromosome in some of the cells of the body (mosaic XXY syndrome)—about 6% of cases, and the clinical features may be less severe.

Investigations

Diagnosis by cytogenetics may first be made when the development of secondary sexual characteristics is delayed and incomplete.

Management

Prevention

Recurrence risk is low. If detected prenatally, genetic counselling is important, to discuss options and the condition.

Self-help

Refer to Klinefelter syndrome support group.

Medical referral

Refer to paediatric endocrinologist for treatment with testosterone to promote virilisation, including growth of the testes. Hormone therapy usually starts at around 11 or 12 years of age. Gynaecomastia may require surgery.

Complementary therapies

The use of testosterone therapy has secondary benefits in helping to improve self-image and self-esteem. This in turn will affect a boy’s performance at school and his ability to form friendships. Learning problems and language deficits can be helped with expert intervention following a thorough assessment. The personality and language delay may lead to the learning difficulties experienced at school. Intervention services (including physiotherapy, occupational and speech and reading therapies) can be helpful.

Important pitfalls

Sexuality is normal, although men with the syndrome may be infertile. Not all features may be present.

Prognosis

Testosterone treatment (available using patches) does not restore the function of the testes, and infertility will persist. Testicular sperm aspiration and intracytoplasmic sperm injection of the egg at IVF have resulted in some pregnancies.

45,X TURNER SYNDROME ⁷⁰

Incidence: 1 in 2000 total births.

Aetiology

Girls are missing:

• one (or part of one) of their two X chromosome copies (45,X) in all cells of their body—about 50% of cases

• the X chromosome in some cells of the body (mosaic Turner syndrome)—about 20% of cases.

Or: two copies of the X chromosome are present but with a number of possible rearrangements of the second X chromosome—about 30% of cases.

History

Does not appear to be related to maternal or paternal age.

Investigations

Diagnosis by cytogenetics may be made in the neonatal or infancy period, or when the development of secondary sexual characteristics is delayed and incomplete. Elevated circulating follicle-stimulating hormone (FSH) levels in girls in infancy or adolescence indicates gonadal failure.

Management

Prevention

Recurrence risk is low. If detected prenatally, genetic counselling is important, to discuss options and the condition.

Self-help

Referral to Turner syndrome support group.

Medical referral

Refer to paediatric endocrinologist for oestrogen and growth hormone treatments. Frequent otitis media can cause deafness and predispose to cholesteatoma. Close monitoring and treatment are required. Hypertension requires treatment.

Complementary therapies

Feeding difficulties sometimes require specific intervention due to physical problems such as the high-arched palate, requiring special teats, or Rosti (cleft palate) feeding bottles, and advice from an infant feeding consultant or speech therapist. Assistance in addressing the associated sleeping problems and specific learning difficulties is warranted.

Important pitfalls

Most girls with Turner syndrome do not have all the features. Most will be mosaic for 45,X. Intellectual disability is not part of the syndrome.

Prognosis

About 5% of girls of will menstruate but the period of fertility will be short and pregnancy is very rare. Women with other arrangements of the X chromosome can occasionally be fertile. However, the rate of miscarriage and birth abnormalities in the children of women with Turner syndrome is likely to be higher than average. Referral for IVF (GIFT) may be considered.

SINGLE GENE CONDITIONS

Of the 20,000 or so human genes identified, pathogenic variants in about 12,000 of these result in a genetic condition that follows a clear pattern of inheritance in families.¹ Again, each one is individually rare but several are more commonly found in particular population groups—these include cystic fibrosis and haemoglobinopathies such as alpha and beta forms of thalassaemia and sickle cell anaemia.

CYSTIC FIBROSIS ⁷¹^–⁷⁴

Incidence: 1 in 2500 births. Of the population with Northern European ancestry, 1 in 25 carry a cystic fibrosis mutation. It is less frequent in southern European and Middle-Eastern populations, and is rare or absent in Asians.

Aetiology

Cystic fibrosis (CF) is caused by mutations in the CFTR (cystic fibrosis transmembrane regulator) gene. It follows an autosomal recessive pattern of inheritance (Fig 31.6), so both parents must carry the mutated gene. There is often no family history of the condition, because the mutation has previously only been present in healthy carriers on each side of the family. CFTR regulates the transport of chloride and sodium ions in the epithelial surfaces of the airway, pancreatic and biliary ducts, gastrointestinal tract, sweat ducts and vas deferens. Pathogenic mutations either remove or reduce the function of the CFTR gene. There are more than 1500 known CFTR mutations, but not all are associated with classic CF (see below).⁷⁵ A genetic carrier for CF—that is, a person carrying only one mutated copy of the CFTR gene—will still produce sufficient amounts of the salt-transport protein for normal body function.

FIGURE 31.6 Autosomal-recessive inheritance when both parents are unaffected genetic carriers for the condition. The mutated copy of the gene containing a recessive mutation is represented by ‘r’, the working copy of the gene by ‘R’

(adapted from Barlow-Stewart 2007⁷⁶)

History

Ninety-five per cent of new cases will be detected by newborn screening.

Investigations

Refer to a paediatrician/respiratory physician for a sweat test where there is clinical suspicion of CF, regardless of the newborn screening result. Diagnosis may be made on the presentation of male infertility due to CABVD. All primary relatives of an affected family member should be referred to genetics services for cascade testing. Carrier testing is accurate if the CFTR gene mutation in the family is known.

Management

Prevention

Pre-conceptional cascade genetic carrier testing and screening in appropriate population groups to identify mutation carriers enables prenatal testing and reproductive choice. The most common mutation in the CFTR gene is known as p.Phe508del (traditionally known as ΔF508 or dF508), which accounts for approximately 70% of all CF gene mutations in those of northern European ancestry. Laboratories test for varying numbers of the common mutations. Testing for 12 or more mutations covers at least 80% of possible mutations in Australians of northern European ancestry.⁷⁷ The rest of the mutations are extremely rare. Mutations that are common in populations other than those whose ancestry is northern European may not be included in the panel of mutations that are routinely tested for by laboratories.

Self-help

Referral to cystic fibrosis association.

Medical

Under-treated bacterial infection is responsible for destruction of the airways in CF patients. Antibiotics are usually started early and continued until symptoms improve. Prolonged therapy might be required in some patients. Sputum culture is important in guiding antibiotic therapy. Pancreatic enzyme replacement is necessary in most people with CF prior to all meals and snacks. A DEXA scan should be performed during puberty, to determine bone mineral density.

Lifestyle

Daily chest physiotherapy is usually performed. Salt replacement is necessary during periods when there is a risk of salt depletion. Patients with CF have an increased basal metabolic rate requiring 120–150% of the recommended daily calorie intake. This requirement increases if there are additional persistent lung infections. A diet high in fat and protein is required.

Complementary therapies

Most patients require fat-soluble vitamin supplements (principally vitamins A and E, and some will require vitamin D). Serum levels should be measured annually.

Important pitfalls

In the absence of a family history of CF, a negative screen for CFTR gene mutations is reassuring, but cannot absolutely rule out the possibility of being a carrier, as not all mutations can be tested. Therefore if a couple choose screening for CF there is still a small risk of having a baby with CF if their carrier test is negative. The major selection criterion for lung transplantation is a life expectancy predicted to be 50% or less at 2 years. This can be indicated by increasing decline in respiratory function, quality of life and weight, and more frequent need for IV therapy.

Prognosis

Life expectancy is improving and is now up to the third or fourth decade. Lung transplantation is currently the only available efficient treatment of life-threatening CF, and it can improve quality of life and long-term survival. Regardless of the form of transplant (single lung, double lung, or heart and double lung), the majority of patients (approximately 90%) will live for at least a year or more following their transplant, and 80% will live for four or more years. Quality of life, measured by ability to exercise and attend educational courses, is significantly improved.

HAEMOGLOBINOPATHIES (including alpha- and beta-thalassaemia and sickle cell disease)⁷⁸^–⁸⁰

Incidence

Incidence varies depending on ancestry. Globally, at least 5% of adults are carriers for a haemoglobin condition: approximately 2.9% for thalassaemia and 2.3% for sickle cell disease. Carriers of a haemoglobinopathy mutation are most common in those with any of the following ethnic backgrounds: southern European, Middle Eastern, African, Chinese, South-East Asian, Indian sub-continent, Pacific Islander, New Zealand Māori, South American and some northern Australian Indigenous communities.

Aetiology

Haemoglobinopathies are caused by mutations in the genes of the ‘alpha-globin chain’ and/or the ‘beta-globin chain’ of haemoglobin. They follow an autosomal-recessive pattern of inheritance (Fig 31.6), so both parents must carry the mutated gene.

• Alpha-thalassaemia major (also known as Hb Barts hydrops fetalis) is caused by absence of production of the alpha-globin chains in the haemoglobin protein, due to deletion of or a change in the alpha-globin chain genes. This condition is fatal at or around the time of birth.

• Beta-thalassaemia major is caused by reduced or absent production of the beta-globin chain of the haemoglobin, due to deletion or change in both copies of the beta-globin chain gene. The main symptom is severe anaemia requiring lifelong blood transfusions.

• Sickle cell disease is caused by changes in the structure of the beta-globin chains of haemoglobin, resulting in red blood cells that form an irreversible sickle shape and leading to severe anaemia and other problems.

History

Carriers are often detected following routine blood screening. Carriers for a thalassaemia have the minor form of the disease and can have mild anaemia. Carriers for sickle cell disease are healthy and are not affected by anaemia; rarely (e.g. under anaesthesia), the red blood cells of a carrier can undergo sickling. Anaesthetists should be informed when a patient is a carrier for sickle cell disease.

Examination

• Alpha-thalassaemia major—fatal at or around the time of birth.

• Beta-thalassaemia major—severe anaemia, pallor, lethargy, poor appetite, developmental delay, failure to thrive, irritability, splenomegaly, growth failure with bone changes and fractures.

• Sickle cell disease—anaemia, failure to thrive, repeated infections, painful swelling of the hands or feet, infarction, asplenia, abdominal and chest pain.

Investigations

• Undertake full blood evaluation (FBE), iron studies (ferritin) and haemoglobin electrophoresis, especially in women of reproductive age.

• Indications for DNA testing:

• possible carrier for alpha-thalassaemia (low-borderline MCV or MCH, normal ferritin and normal haemoglobin electrophoresis)

• proven carrier for beta-thalassaemia and partner is also a carrier for thalassaemia or other haemoglobinopathy

• confirmation of carrier status for a haemoglobin variant.

Management

Prevention

Screening pre-conception to identify mutation carriers enables prenatal testing and reproductive choice. Those most likely to be carriers are those:

• with a family history of anaemia/thalassaemia/abnormal haemoglobin variant

• from the ethnic groups listed above

• whose partners are known or identified haemoglobinopathy carriers, and when their mean corpuscular volume (MCV) < 80 fL or mean cell haemoglobin (MCH) < 27 pg. If both partners of a couple are carriers, refer to a genetics service and/or haematology clinic for genetic counselling and testing. This is particularly urgent for pregnant couples.

Self-help

Refer to a thalassaemia association (see Resources list).

Medical

• Beta-thalassaemia major—require lifelong blood transfusions every 3–4 weeks with iron chelation.

• Sickle cell disease—usually have chronic anaemia due to increased destruction of red blood cells and may also experience sickle cell crises due to blockage of blood vessels by these cells, causing bone and chest pain and damage to other organs. These crises require immediate treatment in the emergency department of a hospital for administration of IV fluids, pain relief and other treatment if indicated, which may include regular blood transfusions. Usually autosplenectomise within the first 10 years of life.

A haematologist or thalassaemia service should be consulted for assistance in interpreting haemoglobinopathy testing results, as interpretation is influenced by the clinical picture (Table 31.2). Prenatal diagnosis is available to couples where there is a risk of having a child affected by a haemoglobinopathy and the causative globin mutations carried by the parents are known. Because of the time-consuming nature of DNA testing to identify causative gene mutations, it is important that, wherever possible, DNA studies are carried out pre-pregnancy.

TABLE 31.2 Interpretation of haemoglobinopathy carrier testing results ⁷⁷

Prognosis

The life expectancy of well-treated, compliant patients for both Beta-thalassaemia major and sickle cell disease is likely to be normal or near normal. Bone marrow transplantation may cure Beta-thalassaemia major but has a significant risk of complications and mortality.

INHERITED GENETIC SUSCEPTIBILITY

Many of the more common adult-onset conditions seen in general practice may be indirectly due to an inherited mutation. These conditions, such as some forms of cancer, cardiac and haematological conditions, involve inherited predisposition and are usually associated with a positive family history. Where the family history is suggestive of an inherited predisposition, genetic counselling and, where appropriate and available, genetic testing may identify the causative predisposing inherited mutation. National guidelines have been produced for healthcare professionals to triage on the basis of the family history into those who are at potentially high risk for the condition running in the family due to an inherited predisposition. For example, those whose family history suggests they are at potentially high risk for breast, ovarian or colorectal cancer could be referred to a family cancer service.⁴³ If appropriate, genetic testing may then be used to identify the family-specific mutation and enable predictive genetic testing for other blood relatives.

BREAST AND OVARIAN CANCER INHERITED SUSCEPTIBILITY ⁸¹

Incidence: About 5% of all breast and ovarian cancers.

Aetiology

A mutation in either the BRCA1 or the BRCA2 gene is identified in a blood relative who has or had breast and/or ovarian cancer and who was identified at potentially high risk on the basis of her family history. Inheritance of the mutated gene follows a pattern of autosomal-dominant inheritance (Fig 31.7). The BRCA1 or BRCA2 genes are tumour suppressor genes that normally function in both breast and ovarian tissues as ‘cancer protection’ genes in the cell, contributing to the maintenance of controlled cell growth. The woman’s breast and/or ovarian cancer is due to her having inherited a mutation in one copy of her BRCA1 or BRCA2 gene in her cells. For breast and/or ovarian cancer to develop, other mutations must build up over time in other ‘cancer protection’ genes in the cells of the breast and/or ovary. The mutation is family-specific, and now predictive genetic testing for the mutation can be offered to unaffected blood relatives.