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Ætiology, distribution and control of disease in relatives


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Genetic testing is used to identify if an individual is carrying a particular genetic mutation and can help to:

  • Diagnose a genetic disorder;
  • Predict the likelihood of future disease occurrence;
  • Facilitate disease management through personalised treatment;
  • Assist with primary and secondary disease prevention.

Routine population screening programmes have been implemented for some genetic conditions in the UK. For example, the newborn bloodspot screening programme is offered to all babies in England to test for nine rare but serious conditions, including cystic fibrosis and inherited metabolic diseases such as phenylketonuria.

For a single gene disorder, testing and subsequent diagnosis can be made at any point during a person's life. Although there is often no cure, follow up counselling can assist with treatment and management decisions, or at a minimum help people know what to expect and identify useful support and advocacy resources. It can also suggest whether other family members can be at risk of developing an inherited condition through the use of pedigree charts.

For multifactorial diseases, testing can be used for risk stratification or targeted interventions. However, the predictive utility of a genetic test based on a single risk allele is poor in this context as it may only result in a slight increase or decrease in risk.

Testing in an individual
Prior to carrying out a genetic test, the following approaches can be carried out to ensure they are used appropriately, i.e. there is an indication of a genetic disorder:

  • Physical examination and investigation
    A thorough physical examination and measurements may identify distinctive features which may be suggestive of a genetic disorder. For example, ultrasound of the uterus and fetoscopy (inserting a camera into the uterus) can check for development of the foetus.
  • Personal medical history
    Results of any prior tests or health issues may indicate a genetic disorder.
  • Family medical history
    Reviewing medical histories of family members can be a critical tool in identification of genetic disorders due to the inheritance patterns.

Family history
Generally, an individual's risk of disease increases with an average younger age of onset of the condition and an increasing number of affected relatives. Getting information on the family history of a specific disease may help to identify individuals likely to be at increased risk of the disease. It is already done for common cancers resulting from single gene variants such as familial breast, ovarian and bowel cancer, though it is not currently done in a systematic or proactive way across all health care systems.

The degree of familial clustering of disease can vary according to a range of factors, including the mode of inheritance and its penetrance. It can be quantified with the familial relative risk - the ratio of the risk of disease in the biological relatives of an affected individual compared with the risk of disease in the general population. Values can be stratified by each type of relative. The familial relative risk for first-degree relatives of a dominant Mendelian trait such as Huntington’s disease is approximately 5,000. Familial risks for more common disorders such as multiple sclerosis tend to be considerably lower, approximately seven, but may still be significant.

More research is required before considering if family history should be considered as a population screening strategy for identifying increased risk for certain diseases. In line with screening criteria, there should be an effective intervention for individuals with a family history of a specific disease which, following identification from screening based on family history, leads to improved health outcomes.

Genetic laboratory tests
Genetic testing typically involves taking a blood or tissue sample and analysing the DNA for any abnormalities. During pregnancy, genetic testing can also be used to find out whether a foetus is likely to be born with a genetic condition, through extracting and testing a sample of cells from the womb. Samples can be obtained via amniocentesis (where amniotic fluid is removed) or chorionic villus sampling.

The following tests can be carried out dependent upon the suspected genetic condition:

  • Molecular genetic tests are used to assess large changes by looking at single genes or short lengths of DNA taken from a bodily fluid. This is possible when it is known that a specific mutation results in a certain genetic condition (e.g. cystic fibrosis).
  • Features of a person's set of chromosomes can also be assessed. The number and structure can be identified from karyotyping (e.g. Down syndrome). More sophisticated technology such as fluorescent in-situ hybridisation analysis can detect small changes in the chromosome structure (e.g. Duchenne muscular dystrophy). Biochemical tests analyse the amounts or activities of key proteins, e.g. metabolic conditions such as phenylketonuria.
  • Non-invasive prenatal diagnosis (NIPD) or testing (NIPT) is a new method of testing free foetal DNA from the maternal blood sample. This is known as cell-free DNA - fragments of DNA present in the maternal plasma during pregnancy. Testing will soon become part of the neonatal screening pathway and is used to detect Down syndrome, Edward syndrome, Patau syndrome and Turner syndrome.

DNA testing is not as straightforward when there is genetic heterogeneity/polymorphisms present, which is common in Mendelian diseases. In these cases, testing the index or proband case (the first affected family member identified) may be more complex to identify the mutation. For example, testing may be carried out for a panel of mutations known to be those most commonly encountered in the patient's population. For conditions where there is substantial allelic heterogeneity and no specific mutations are known to be predominant, mutation scanning techniques may be used to try and find a mutation within the gene in question. Complete sequencing of the gene can also be used as a scanning technique, but this is generally expensive for routine service use. It is then still difficult to say if a sequence difference detected is a disease-associated mutation or a normal polymorphism.

Genetic testing for polygene disorders is not yet part of routine clinical or public health practice. It could be used for risk stratification and to target preventative interventions (e.g. screening, chemoprevention, behavioural modification) to the high-risk groups. However, predictive genetic testing gives probabilities not certainties and some susceptibility variants are poor discriminators between individuals who will or will not develop the disease. There is, therefore, a risk of an incorrect outcome from the test.

Testing in relatives

Reproductive choice
If a couple know, based on their family history or a previously 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. Carrier testing may be offered if the family history suggests an individual may be a carrier of an autosomal or X-linked recessive disease and the couple wishes to know their risk of passing on the mutation prior to conception or during the antenatal period.

In some populations, carrier frequencies for certain recessive genetic diseases may be sufficiently high to warrant community or population carrier screening programmes, such as for Tay Sachs disease in Ashkenazi Jewish communities. In England all pregnant women are offered screening tests for the following:

  • Sickle cell disease and thalassaemia (inherited blood disorders). If the mother is found to be a carrier then screening is offered to the father, and if both parents are carriers, antenatal testing is made available. If this shows the foetus is affected, the couple may choose to continue with the pregnancy in the knowledge that their child will be affected or terminate the pregnancy.
  • Down, Edward and Patau syndromes. If the screening test indicates the woman is at a higher chance of having a baby with Down, Edward or Patau syndromes, diagnostic tests will be offered to find out for certain if the baby has the condition.

For some genetic disorders, pre-implantation genetic diagnosis may be an option. This involves in-vitro fertilisation, testing the resulting embryos for a specific mutation and transferring only unaffected embryos to the uterus. While avoiding termination of foetuses, there is a modest success rate, with significant financial and emotional costs.

Predictive genetic testing in at risk relatives
For certain adult onset genetic conditions with high penetrance, such as BRCA-related breast cancer, relatives of an affected individual who are at risk but asymptomatic may be offered genetic testing to find out if they are carrying the mutation associated with the disease. These tests are generally only available when there is a family history indicating the individual is at high genetic risk of a condition and when the mutation in the family is known. Testing can be done in the context of reproductive choice, however more frequently it is to enable an individual who is found to be at high genetic risk to take action to reduce their risk. Examples include taking tamoxifen to decrease the risk of developing breast cancer and prophylactic oophorectomy to decrease the risk of ovarian cancer. If the relevant mutation is not present, the individual’s risk is then likely to be no higher than the population average.

Family tracing
Some adult-onset Mendelian diseases are significantly under-diagnosed in the population, for example because the symptoms are not recognised. For such diseases, such as familial hypercholesterolemia, a systematic approach of case finding in affected families may be warranted if an effective risk reduction intervention is available. This is termed family tracing or cascade testing.

Genetic counselling
Whenever genetic testing is being considered, it is essential that skilled genetic counselling is available prior to and following testing. The service aims to provide support, information and advice about genetic conditions and is conducted by trained healthcare professionals. In explaining options, the role of the counsellor is to enable informed choice and not to influence the individual/couple's decision. The exact process will depend on the reason for referral but may involve drawing a family tree, assessment of risk and learning about a health condition.

Ethics with genetic testing
There are significant ethical considerations with genetic testing. It can result in the potential for harm to individuals such as psychological harm and social consequences such as stigmatising of the family. There can also be economic consequences, for example insurance companies may decline coverage if an individual’s genetic test results are known. There are further issues with testing of children, because they may too young to provide informed consent to testing. Also important is the wider impact on the family. If a person is identified as being at risk of developing or being a carrier for a genetic disorder, this has implications for relatives.

Population screening programmes must be distinguished from eugenics. Such screening programmes aim to enable autonomous reproductive choice by individuals and couples, not to reduce the population prevalence of a genetic condition – though this may follow. The programmes must value equally an informed choice to carry on with an affected pregnancy and a decision to terminate the pregnancy.


© Public Health Genetics Unit 2006, H Green 2017