Genetics: Aetiology, Distribution and Control of Disease in Relatives
AETIOLOGY, DISTRIBUTION AND CONTROL OF DISEASE IN RELATIVES
Familial clustering of disease
Single-gene 'Mendelian' diseases were first recognised because of their patterns of inheritance through families. Relatives of affected individuals may be at high risk of disease; the actual level of risk depends on a variety of factors including the biological relationship with the affected individual, the mode of inheritance of the condition and its penetrance. Many common diseases such as coronary heart disease, Alzheimer's dementia and type II diabetes also have a tendency to cluster in families, suggesting a genetic contribution to their aetiology, though the shared environment experienced by most families contributes to familial clustering of disease.
The degree of familial clustering of disease can be expressed as the familial relative risk (FRR). This is the ratio of disease risk in biological relatives of an affected individual compared with disease risk in the general population. Separate values can be calculated for each type of relative, for example the familial relative risk for siblings. In general, the higher the familial relative risk the stronger the genetic effect. The FRR for first-degree relatives of a dominant Mendelian trait such as Huntington disease is approximately 5000. The sibling FRR for the Mendelian recessive disorder, cystic fibrosis, is about 500.
Familial risks for more common disorders tend to be considerably lower but may still be significant (see table 3).
As a general rule, an individual's risk of a disease increases with increasing numbers of affected relatives. For adult-onset conditions, an early age of onset in affected relatives increases risk still further. Multiple relatives affected at an early age is often an indication that a single-gene Mendelian subset of a common disease is segregating in the family. For example, the criteria for suspecting that an individual may be at risk of hereditary non-polyposis colorectal cancer, a familial form of bowel cancer, include assessment of the number of affected relatives and the age of onset of the condition (box 3).
Genetic diagnosis in affected individuals
If genetic disease is suspected in an individual, for example a newborn child, the clinical geneticist will attempt to assess whether the condition has a genetic aetiology and, if it does, to make a diagnosis. Sometimes the condition can be identified on the basis of physical features such as facial or other dysmorphologies that are diagnostic for a well-characterised syndrome. In other cases, one or more medical tests may be needed to confirm or exclude a diagnosis. A family history may reveal whether any relatives have been affected by the same condition and, if so, whether a diagnosis was made.
Diagnostic tests for Mendelian diseases may be carried out at any stage of life: antenatally, in newborn infants or children, or during adult life. Many congenital diseases are diagnosed in infancy or early childhood but if symptoms are unrecognised, non-specific or relatively mild, then diagnosis may be delayed. Adult-onset conditions such as hereditary breast cancer due to BRCA gene mutations, or hereditary non-polyposis colorectal cancer, may not be diagnosed until mid-life or even later, if at all.
Tests for Mendelian conditions do not necessarily involve direct examination of DNA or chromosomes. For example, biochemical tests are routinely used to diagnose many diseases including sickle cell disease, phenylketonuria and familial hypercholesterolaemia. Autosomal dominant polycystic kidney disease is diagnosed by renal ultrasound. Neurological and radiological tests are used in diagnosis of some other Mendelian conditions.
Population screening programmes have been implemented for some genetic conditions in the UK. These include newborn screening for phenylketonuria, congenital hypothyroidism, cystic fibrosis and sickle cell disease. A pilot programme has been introduced for medium chain acyl coenzyme A dehydrogenase deficiency (MCADD). The aim of newborn screening programmes is to improve early detection of the condition so that treatment can be initiated as early as possible and disease progression prevented as far as possible. For example, early introduction of a phenylalanine-free diet prevents severe brain damage in newborn babies affected by phenylketonuria. A national antenatal screening programme is in place to diagnose unborn babies affected by Down syndrome, the most common chromosomal disorder. In this case, the aim is to enable reproductive choice by parents, discussed further in a later section.
Tests on the genetic material itself are generally classified as cytogenetic tests or DNA tests. Cytogenetic tests involve using microscopic techniques to look for changes in the number and/or structure of the chromosomes, such as the extra copy of chromosome 21 that is the cause of Down syndrome. Traditional cytogenetic analysis does not depend on knowing which chromosome is likely to be affected but it is quite low in resolution: the smallest changes that can be detected are many thousands of base pairs in size. Greater resolution has been achieved by the incorporation of molecular technologies such as fluorescent in situ hybridisation (FISH) into cytogenetic analysis. Molecular cytogenetic techniques can improve resolution down to the level of single genes or partial gene sequences but they can generally only be used to test for one or a few specific genetic lesions that are suspected to be causing the condition.
Molecular DNA tests are also specific: that is, they are generally applied to look for a mutation in a specific gene that is suspected to be involved in the aetiology of the condition. The causal genes are now known for about 1800 Mendelian conditions and an increasing number of DNA tests are available.
DNA testing may be a straightforward procedure if the nature of the suspected mutation is known. This is the case for conditions such as Huntington disease where there is no genetic heterogeneity: all affected individuals have the same type of mutation in the same region of the same gene.
However, as we have seen, genetic heterogeneity is very common in Mendelian disease. In this situation, DNA testing in the index case or proband (the first affected family member to come to the attention of the clinical geneticist) may be more complex. Various strategies are possible. For example, testing may be carried out for a panel of mutations that are known to be those most commonly encountered in the population to which the affected individual belongs. For example, most genetics centres in the UK are currently using a diagnostic test for cystic fibrosis that tests for a panel of 30 mutations accounting for about 90% of CF mutations found in people of northern European origin. If no mutations are found using this test, a further test may be carried out for a set of rarer mutations.
For conditions where there is substantial allelic heterogeneity and no particular mutations are known to be predominant, mutation scanning techniques may be used to try to find a mutation within the gene in question in an affected individual. Many general mutation scanning techniques rely on detecting subtle physicochemical differences in the behaviour of DNA molecules with slightly different sequences. Complete sequencing of the entire gene can also be used as a mutation scanning technique but at present this is generally too expensive for routine service use.
A major difficulty in interpreting the results from mutation scanning is that it is not always easy to say whether a sequence difference that is detected is a disease-associated mutation or a normal polymorphism. Sequence changes are assumed to be pathogenic if they would be predicted to lead to a grossly altered protein but more subtle differences may be less readily categorised.
Genetic testing in relatives of affected or carrier individuals
Diagnosis of a Mendelian condition in an affected individual, or of carrier status for a recessive condition, can have important consequences for that person's biological relatives. In some cases, options are available for prevention or control of the disease in relatives. Genetic testing of relatives is generally available for one of two purposes: in the context of reproductive choice, or to enable presymptomatic identification of individuals who are at high risk, ideally so that preventive interventions may be offered.
Genetic testing and reproductive choice
If a couple know, on the basis of their family history or because they have had a previous affected child, that they are at risk of having a child affected by a specific Mendelian disease or a chromosomal disorder, diagnostic testing may be possible in the antenatal period. If testing shows that the baby is affected, the couple has the option of preparing for the birth of an affected child or, if they wish, of terminating the pregnancy. In some cases, pre-implantation genetic diagnosis (PGD) may be an option. This procedure involves the creation of embryos by in vitro fertilisation (IVF). At a very early stage, 1-2 cells are removed from each embryo and tested genetically for the disease-causing genotype. An embryo can compensate for the loss of these cells and develop to term. Only embryos that are unaffected by the genetic disease are used to establish a pregnancy.
If an individual's family history suggests that they may be a carrier of an autosomal or X-linked genetic disease, then they may be offered carrier testing if they wish to know whether they are at risk of passing on the disease-causing mutation to their children. Carrier testing may be carried out before conception, or in the antenatal period to establish whether there is a risk that the fetus may be affected. A typical situation might be an individual with a sibling affected by cystic fibrosis, or a woman with a brother or nephew affected by haemophilia or Duchenne muscular dystrophy. The risk to the individual's children will depend on the mode of inheritance of the condition (see figures 12 and 13) and its penetrance. In the case of an autosomal recessive disease such as cystic fibrosis, if testing revealed that the individual was a carrier of the condition, his or her partner would also be offered carrier testing; only if both parents were carriers would their children be at risk. For an X-linked condition, any male children of a carrier mother would be at 50% risk of the condition.
In some populations (see table 2 for examples), carrier frequencies for certain recessive genetic diseases may be sufficiently high to warrant community or population carrier screening programmes. For example, carrier frequencies for Tay Sachs disease are significantly elevated in Ashkenazi Jewish communities: approximately 1 in 25 individuals is a carrier compared with 1 in 250 in the general population. A community-based carrier testing programme for Tay Sachs disease has been available to the Ashkenazi Jewish community in the UK for over 30 years and has strong community support.
A national antenatal carrier screening programme is being implemented in England and Wales for sickle cell disease and the thalassaemias. The aim is to allow informed reproductive choice by identifying couples at risk of an affected pregnancy. The programme offers antenatal carrier screening to all pregnant women (with the proviso that, in areas where the prevalence of sickle cell disease is low, full laboratory screening for carrier status for this condition is dependent on assessment of risk by means of a questionnaire on ethnic origin). If the mother tests positive, her partner is also offered testing. If both parents are carriers, they are offered antenatal diagnostic testing to determine if the fetus is affected.
It is essential that genetic testing to enable reproductive choice is preceded and followed by skilled genetic counselling of the individuals concerned. The consultant geneticist and/or genetic counsellor must be able to describe the condition, its inheritance and the risk to the couple's children in a way that is clear and comprehensible but does not confront people with highly medicalised or shocking images or descriptions. In explaining the couple's options, the genetic counsellor tries as far as possible to be non-directive: the aim of the process is to enable informed choice and not to influence the couple's decision one way or the other.
Population screening programmes must also avoid the pitfall of eugenics. Eugenic programmes, widespread in America and parts of Europe in the late nineteenth century and first half of the twentieth century, were state-mandated or supported programmes that aimed systematically to increase the 'genetic fitness' of the population by selective breeding and, sometimes, sterilisation or even murder of those considered genetically inferior. As well as being scientifically misguided, these programmes were clearly immoral and in some countries have left a legacy of suspicion about genetics that has had serious implications for the development of clinical genetics services. It must be clearly understood that the aim of any population screening programme is not to reduce the population prevalence of a genetic condition. Although this outcome may be a consequence of such a programme, the programme's aim is to enable autonomous reproductive choice by individuals and couples, who must feel that an informed choice to carry on with an affected pregnancy is no less valued and supported by society than a choice to terminate the pregnancy.
Predictive genetic testing in at-risk relatives
For certain high-penetrance adult-onset conditions such as BRCA-related breast cancer, at-risk but asymptomatic relatives of an affected individual may be offered genetic testing to find out if they are carrying the mutation associated with the disease in the affected family member. Testing may sometimes be requested in the context of reproductive choice, as discussed in the previous section. For example, a person with a parent affected by Huntington disease may wish to know whether they have inherited the mutation so that they can take steps to avoid having an affected child themselves.
More frequently, however, testing is offered or requested to enable an individual who is found to be at high genetic risk to take some risk-reducing action. For example, a woman who knows she is at risk of BRCA1-related breast or ovarian cancer may opt for mammographic surveillance or perhaps for prophylactic mastectomy and/or oophorectomy to reduce her risk of disease. If genetic testing reveals that she does not carry the disease-causing mutation that is present in her affected relative, she can be reassured that her risk is likely to be no higher than the population average.
Predictive genetic testing is also available for some other conditions including familial adenomatous polyposis coli and hereditary non-polyposis colorectal cancer (where affected individuals can be offered bowel surveillance by colonoscopy), and hypertrophic cardiomyopathy (where drug treatments and/or lifestyle advice may be effective in reducing risk in some individuals).
Predictive genetic testing by DNA analysis is generally only available clinically when family history indicates that an individual is at high genetic risk of a condition, and when the disease-causing mutation in that family is known.
Family tracing or 'cascade' testing
Some adult-onset Mendelian diseases are significantly under-diagnosed in the population, perhaps because of reduced penetrance or because symptoms are not recognised. This may be the case, in particular, for people with Mendelian forms of common diseases. It has been estimated, for example, that at least 75% of people affected by familial hypercholesterolaemia in the UK are undiagnosed.
For such diseases, a systematic approach of case-finding in affected families (also known as family tracing or cascade testing) may be warranted if an effective risk-reducing intervention is available.
Promising candidates for a family tracing approach include familial hypercholesterolaemia (where elevated cholesterol in affected family members can be successfully controlled by statin treatment, dramatically reducing the risk of early coronary heart disease) and hereditary haemochromatosis (a disease of iron metabolism that can be effectively controlled by frequent phlebotomy, reducing the risk of liver cirrhosis). Family tracing for familial hypercholesterolaemia is currently being trialled in selected lipid clinics in the UK.
Family history as a tool in prevention of common disease
Family history information may provide a useful - and currently under-used - tool to identify individuals who are likely to be at increased risk of common disease.
As we have already seen, family history is currently used as a form of triage in clinical practice to identify those at high risk of Mendelian forms of common cancers, particularly familial breast/ovarian cancer and familial bowel cancer (see box 3).At present this is not undertaken in a systematic or proactive way in the health service. Rather, a GP will respond to an individual who is concerned about their familial risk by taking a family history and assessing whether it suggests a risk that is high enough to warrant referral for specialist genetic advice. The National Institute for Health and Clinical Excellence (NICE) has published a protocol for managing women at increased familial risk of breast cancer. It specifies criteria for dividing women into high, moderate and low genetic risk groups on the basis of their family history and outlines the recommended management strategy for each group.
Some have suggested that family history should be used more proactively as a tool for risk assessment and prevention of common disease. Enthusiasts for this approach suggest that family doctors should prospectively elicit family history information from their patients and encourage those with family histories suggesting significant risk to adopt preventive measures such as dietary or lifestyle change. Caution is needed, however, as this approach is effectively a population screening strategy and has not yet been systematically evaluated. More research is needed to establish the accuracy of family history as a risk predictor, identify interventions that are effective for individuals with a family history of a particular disease, and determine whether screening on the basis of family history leads to improved health outcomes.
© Public Health Genetics Unit 2006