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Genetic screening and testing

Genetics is the study of the way genes influence our individual characteristics including our health. In medicine, the field of genetics was once confined to a few rare, heritable diseases where there was little chance for treatment or prevention. There has been rapid change over the past few decades as new techniques have been developed for detecting a wide range of diseases and health problems with a genetic cause (genetic conditions). These advances have often been accompanied by increasing options for prevention and treatment. Such scientific breakthroughs are regularly reported in the media, and the increasing availability of genetic screening and testing in pregnancy and at birth has also widened public experience in this area. As a consequence, there is an increasing demand for information about genetic testing to support decisions about taking these tests.

This section provides a brief overview of genetics and genetic testing, and outlines the reasons for developing DISCERN Genetics. We have written it for any interested readers as a very general introduction to genetic conditions and to the key issues surrounding genetic testing. You may find it a useful guide to some of the concepts and terms from the field which are used throughout the DISCERN Genetics tool and Handbook. However, you do not need to read this section in order to use DISCERN Genetics effectively.

This overview is highly simplified. If you would like more detailed technical information, please refer to the books by Rose and Lucassen (1999) and Robinson (2005) which have been used as sources for this section, and to other resources listed here. The Glossary provides a simple guide to many of the terms and definitions that are introduced here.

Basic Genetics

Genes are the basic units of heredity. They contain sequences of DNA (deoxyribonucleic acid) which produce proteins that control cells and enable our body to develop and function. Genes are located at specific positions on chromosomes inside each cell nucleus.

Humans have 46 chromosomes organised into a set of 23 pairs – one in each pair inherited from each parent. Each pair carries numerous genes responsible for different physical characteristics. These characteristics are known as traits or phenotypes, and a single trait can be controlled by a number of genes located on different sections of different chromosomes. 22 pairs of chromosomes are responsible for non-sex characteristics and are called autosomes. The remaining pair are sex chromosomes and they determine gender. Males (XY) inherit a Y chromosome from their father and an X from their mother. Females (XX) inherit an X from each parent. The X chromosome is particularly important for normal development and function.

Our genome is all the genetic information contained in the DNA of a set of chromosomes from a cell nucleus. Our unique, individual genetic makeup is called a genotype which we inherit from our parents through sexual reproduction. Our phenotype is the physical expression of our genotype. Phenotype can also be influenced by environment and random genetic changes.

Genetic Mutations

A genetic mutation is a change in DNA and is often random. Many are not necessarily harmful and are responsible for a wide range of genetic variations in humans. Some mutations can be passed down the generations and underlie the process of evolution. When a genetic mutation alters the function of some cells, it can cause disease and physical defects. A person is said to be affected by a genetic condition if they express the phenotype for a faulty genotype - i.e. they have a disease or condition arising from a genetic abnormality.

A simple overview of genetic mutations and the conditions they may cause is given below. Fuller details are provided by the references and resources.

Types of Mutations and Genetic Conditions

All cells are the product of the division of pre-existing cells (through the processes of mitosis and meiosis). The division and replication of genetic material during cell division are crucial factors for producing normal offspring. Somatic mutations (sometimes called sporadic or acquired mutations) occur in non-sex cells during a person’s lifetime and can lead to conditions which are not usually hereditary. In contrast, germline mutations occur in the sex cells that lead to embryo formation and can be passed on to subsequent offspring. Studying patterns of inheritance of a condition or disease in a family, by examining a family tree or pedigree, can identify the mode of transmission and tell us who else in a family may be at risk.

Mutations lead to genetic conditions in the following ways:

a) Inherited disorders

Some inherited genetic diseases and conditions are single gene disorders (often described as classical inheritance disorders). They are caused by a mutation in a single gene or DNA sequence that is present in the germline and can therefore be passed from one generation to the next. The effect of the gene mutation dominates over other influences (such as environmental factors). The inheritance patterns are described as autosomal if they are due to mutations in genes situated on one of the 22 autosomes, and sex linked if they occur on one of the sex chromosomes. Details of different types of single gene disorder are outlined below. For all these conditions, the mutation will be present from birth but disease onset may be later in life. Not all offspring will inherit the mutation, and examination of the family tree or pedigree may hint at the chance or likelihood of inheriting or being affected by a faulty gene. The same mutation (genotype) may be associated with different phenotypes - such as varying age at onset, symptoms, and disease severity or even no disease at all (processes known as anticipation, expressivity and penetrance describe these variations – please refer to the Glossary and resources for more information).

Autosomal dominant disorders are caused by a mutation on one of the genes in a pair. The single mutated gene dominates. As only one copy of the faulty gene is needed to produce the disorder, an affected parent has a 50% chance of passing the mutation on to a child. The mutation occurs on non-sex chromosomes, so males and females are usually affected in equal numbers. Examples used in the Handbook are Huntington’s Disease and a form of Haemochromatosis.

Autosomal recessive disorders are caused by a mutation on both genes in a pair. The condition only arises when each parent passes on a copy of the faulty gene. For most recessive conditions, people who only have one copy of the faulty gene are not affected but they are carriers. When both parents are carriers, each pregnancy carries a 25% chance that the child will be affected and a 50% chance that the child will be a carrier. Children sharing common ancestry are more likely to be affected due to higher rates of carriers in their background than those whose parents are from different backgrounds. These disorders usually affect males and females equally. Examples used in the handbook are Tay Sach’s disease, cystic fibrosis and sickle cell disease.

Sex linked disorders are caused by mutations on the sex chromosomes (X-linked and Y-linked disorders). The most common sex-linked conditions are X-linked recessive disorders carried in genes on the X chromosome, where females are carriers and half their male offspring are affected. This is because females have 2 copies of the X chromosome, so problems arising from a faulty X are usually “compensated” for by a normal X. Males only have one X chromosome inherited from their mother so if the X is faulty, the disease will be expressed. These conditions are never passed from an affected father to a son, but daughters can become carriers through inheritance of a faulty X from either an affected father or a carrier mother. Examples used in the handbook are Fragile X Syndrome and some forms of Muscular Dystrophy. Details of other forms of sex-linked disorders are provided by the references and resources

Some conditions arise from more complex patterns of inheritance (e.g. combinations of dominant and recessive genotypes, non-classical inheritance patterns such as mitochondrial disorders). Details are provided by the references and resources.

b) Chromosomal disorders

Chromosomal disorders are caused by errors in the number or structure of the chromosomes during the formation of sex cells but they are not necessarily passed through generations. These genetic abnormalities are common causes of mental retardation and physical defects in humans. Examples used in the Handbook are Down’s Syndrome (also known as Down Syndrome) which is most commonly caused by an extra copy (trisomy) of chromosome 21, and Turner’s Syndrome, which involves only one copy (a monosomy) of the sex chromosomes - a single X.

c) Multi-factorial conditions

Many common health conditions may be caused by a combination of inherited genetic mutations and other risk factors, and are known as multi-factorial conditions. Examples include chronic adult diseases such as diabetes and rheumatoid arthritis and congenital conditions such as cleft palate.

At present, identifying all the different causes and components of multi-factorial diseases is not possible. Throughout the DISCERN Genetics Tool and Handbook, we have therefore limited ourselves to disorders with a strong inherited component – the examples we use are inherited cancers.

Inherited cancers: All cancers are caused initially by genetic abnormalities within a cell. These genetic abnormalities may be inherited or acquired. Most are sporadic diseases caused by somatic mutations in the tumour cells which cannot be passed to offspring. However, if a germline mutation in a particular gene that plays a part in cell growth and reproduction is inherited, then fewer somatic changes to that cell are required before a cancer is initiated. Inheriting the mutation is not enough to cause cancer, but a person with the mutation is more likely to develop cancer and at a younger age than people who have not inherited such a faulty gene. This explains why not everyone who has inherited the gene fault will develop cancer - other factors are still required to produce the somatic changes. Examples included in the Handbook are some types of inherited breast cancer and colon cancer. They are included because a lot is known about the underlying mutation and inheritance patterns, and reliable genetic testing, effective management and treatment options are available.

Misconceptions about genetic conditions and inheritance

Rose & Lucassen (1999) identified some common misconceptions about genetic conditions. Misconceptions can impede informed choice about genetic testing, so we have provided some simple clarifications as follows:

Any condition present at birth is genetic: No. A congenital condition is not necessarily a genetic condition. Many conditions present at birth arise spontaneously during conception and pregnancy or are due to factors other than genetic mutations, including maternal factors such as diet and medical conditions with a non-genetic cause.

A family history of a condition means it must be hereditary: No. Many conditions that run in families may be hereditary but the genetic mutations have not yet been identified. However, these conditions may also be caused by non-genetic factors that family members have in common, such as diet and environment.

The absence of a family history of a condition means it cannot be hereditary: No. Some hereditary conditions may be expressed for the first time in the current generation (e.g. a recessive condition). It is also possible that an inherited genetic mutation (genotype) is only expressed as a genetic condition (phenotype) when other unique factors are present (e.g. environmental risks or other medical conditions). A further possibility is that your family history is unreliable or incomplete.

Cancer is a single disease, so a family history of cancer must mean it is inherited. No. Cancers have many different origins and causes. Many people observe that ‘cancer runs in their family’ but this does not mean it has an inherited cause. In the western world, as medicine treats or cures conditions that previously killed people in early middle age or before, cancer as an acquired disease of older age is increasingly common. Approximately one third of such populations are diagnosed with cancer in their lifetime, so families often have a history of cancer because of chance or shared lifestyles. For example, lung cancer is not an inherited cancer, but if a family includes lots of smokers, more than one family member may get lung cancer because of the smoking. However, a tendency to certain cancers may be inherited. If a family has several cases of breast cancer or ovarian cancer, or bowel and womb cancer, particularly if diagnosed at a young age (before 50) then a strongly inherited susceptibility may be present in the family. Health professionals look for clusters of these related cancers to get an idea of whether a family might have an inherited susceptibility to cancer.

What is a genetic test?

Understanding and diagnosing a genetic condition involves combining information from a range of sources, including your personal and family history and current health status. For most genetic conditions, a key part of this process will be a genetic test.
There is no standard definition of a genetic test, but it is commonly understood to refer primarily to tests to detect the presence or absence of disease through analysis of genetic material or gene products (UK Human Genetics Commission, 2003).

A number of laboratory techniques are available to examine genetic material in cells taken from a blood or tissue sample:
- Cytogenetics is used to detect chromosomal abnormalities. The number and shape of chromosomes within a cell are examined using a process called karyotyping.
- Molecular genetics is used to detect changes at the level of a single gene or DNA sequence within cells (e.g. DNA sequencing, PCR or polymerase chain reaction, linkage analysis).
- Biochemical techniques are used to detect markers of changes in genetic function (e.g. enzyme and protein analyses).

The materials we have used to develop DISCERN Genetics and the Handbook have focused on these methods of genetic testing, as they distil the key issues for patients and are at the forefront of current scientific and ethical debates. However, there are numerous conditions with a genetic cause that are not currently detectable using laboratory analysis of genetic material - either because the genetic mutation has not yet been identified or a gene test has not yet been developed. In these cases, other methods (such as scans and clinical examination) may provide reliable indicators of genetic mutations and genetic conditions. The implications for patients if a genetic condition is detected are largely the same.

Patient information about testing for a genetic condition should therefore conform to the same standards regardless of the type of test used. DISCERN Genetics is appropriate for use with information about all types of screening and testing for genetic conditions. For DISCERN Genetics, we therefore use a broad definition of genetic testing to mean any test for a disease or condition with a genetic cause.

The nature of a genetic test.

You may be offered a genetic test for a number of different reasons:

Screening test: genetic tests are called screening tests when they are offered routinely to large groups of people to assess their chance of having genetic mutations that could lead to disease. For example, members of ethnic groups known to be at increased risk of a genetic condition may be offered screening tests. In many countries, routine antenatal and neonatal screening tests are also offered to all pregnant women to assess the likelihood that their baby has a genetic condition. Screening test results indicating the baby might be affected are confirmed by a diagnostic test (see below).

Diagnostic test: a genetic test is called a diagnostic test when it is used to confirm (or reject) the diagnosis of a genetic condition in an individual who has symptoms of the condition or a positive result from a genetic screening test.

Predictive or pre-symptomatic test: a genetic test is called a predictive or pre-symptomatic test when it is used to detect the presence of a genetic mutation in individuals who are currently well but who may be at risk of developing a genetic condition.

Carrier test: a genetic test can be used to find out if an unaffected individual is carrying a mutation which could be passed on to their offspring. Routine carrier screening is offered to certain groups at higher risk of inheriting a genetic condition (e.g. in the UK, screening for Tay Sachs disease amongst the Ashkenazi Jewish community; screening for sickle cell disease amongst Afro-Caribbean and Mediterranean communities).

The need for DISCERN Genetics

Most medical tests detect simple symptoms and conditions which only affect you and which are usually transient and treatable. In contrast, a genetic test can reveal detailed information about your physical make-up which has much broader consequences for your long-term health and that of your family. Genetic testing therefore has many important ethical, psychosocial and practical implications. (See special issues of the British Medical Journal 2001 and New England Journal of Medicine 2003 for reviews and discussion).

Making a decision about genetic testing is clearly an area where patients and professionals need good quality information. It is also an area where controversy and debate are commonplace. There is currently a lot of publicly available information on genetic testing from a variety of sources. Unfortunately, not all of this information is good quality. For many people, the primary sources of information provide unbalanced and emotive coverage of the major issues, or inaccurate or confusing advice. It may be difficult to know which information to use and which to discard.

Various initiatives are underway to improve the quality of health information about genetic testing. These include databases of evidence-based literature (e.g. NELH; OMIM; NiH), standards for test accuracy and reporting test performance (UK Human Genetics Commission, 2003), and consultations about direct to public testing (GeneWatch UK, 2003). However, there is currently no clear guidance for users and producers of publicly available information on genetic screening and testing (British Medical Journal special issue 2001).

Experience arising from the development of the DISCERN Treatment tool

DISCERN Treatment (Charnock et al., 1999) is a set of criteria for judging the quality of written health information on treatment choices. The tool has good levels of inter-rater agreement and validity and consumers were involved at every stage of development. Detailed user support is provided by the questions and hints in the tool and by the DISCERN treatment handbook (Charnock, 1998) and training programme. (Clisby and Charnock, 2000; Charnock & Shepperd 2004). Training has demonstrated that DISCERN is appropriate for use with both print and online information, and has provided anecdotal evidence that it is also being applied to verbal consultations and audio-visual aides. A 5-star rating scheme has also been developed (Shepperd et al., 2002).

Since its publication in 1999, the DISCERN Treatment tool has had a significant impact on the quality of information on treatment choices available to the public. Independent studies have confirmed its reliability and validity (Rees et al. 2002; Ademiluyi et al. 2003). Research has also demonstrated a strong correlation between DISCERN quality scores and measures of the scientific quality and evidence base of the information (Griffiths & Christensen 2002), as well as confirming that DISCERN addresses a broader range of information needs for patients than evidence-based medical information alone (Griffiths & Christensen 2002).

DISCERN has been translated into German (, Italian, Japanese, Danish, Turkish and French and is now used internationally for producing and selecting print and online health information (e.g. The German Clearing House for Patient Information - Sanger et al. 2002; Macmillan Cancer Relief Directory 2004/5). It is also an important tool in global surveys of information quality, particularly on the internet (Godolphin et al., 2001; Bartels et al., 2003; Bessell et al. 2003; Hargrave et al., 2003; Ilic et al. 2003; Ilic et al., 2004; Molassiotis & Xu, 2004; Maloney et al. 2005).Our own research with workshop participants has demonstrated that DISCERN is a valuable educational tool and equips users with simple and flexible skills for dealing with a broad range of information in a systematic and critical way (Charnock & Clisby 2000; Charnock & Shepperd 2004). Many health care providers and researchers have suggested wider use of DISCERN amongst professional and patient groups to raise standards and to support patients as they achieve greater autonomy and enter more equitable partnerships with health care professionals (Molassiotis & Xu, 2004; Bessell et al.2003; Griffiths & Christensen 2002; Rees et al. 2002; Sanger et al. 2002; Godolphin et al., 2001).