Clinical genetic testing refers to the laboratory analysis of DNA or RNA to aid in the diagnosis of disease. Genetic testing can provide definitive diagnosis as well as help predict the likelihood of developing a particular disease before symptoms even appear. It can tell if a person is carrying a specific gene that could be passed on to his or her children and sometimes it can give information as to whether some treatments will work before a patient starts therapy. These are definite advantages. However, there are also some issues in genetic testing that should be carefully thought out and discussed with a genetic counsellor or clinical geneticist before undergoing any testing. These aspects are reviewed in the section titled Pros and cons of genetic testing. In an era of patient responsibility, it is important that both health professionals and patients are educated in these matters to fully appreciate the value as well as the drawbacks of genetic testing.
Testing genetic material

Testing of genetic material is performed on a variety of specimens including blood, urine, saliva, body tissues, bone, or hair. Cells in these samples are isolated and the DNA within them is extracted and examined for possible mutations or alterations. Looking at small portions of the DNA within a gene requires specialised and specific laboratory testing. This is done to pinpoint the exact location of genetic errors (mutations). This section will focus on the examination of a person’s genes to look for the gene mutation responsible for a particular disease.

There are four basic reasons that genetic material is tested for clinical reasons.

  1. Presymptomatic testing and predictive testing identifies the presence of a faulty gene (a gene that has a mutation) that may cause disease, even if the symptoms and signs associated with the disease are not yet present in an individual.
  2. Diagnostic genetic testing is performed on a symptomatic individual with symptoms sufficiently suggestive of a genetic disorder. This assists the individual’s physician in making a specific diagnosis.
  3. Carrier screening is where testing of genetic material is performed as a screening tool to assess whether two individuals who wish to become parents have an autosomal or X-linked recessive gene mutation that, when combined in a child, will produce a serious disorder in that child.
  4. Prenatal testing refers to genetic testing of the fetus to determine if there is a particular genetic condition present. It is done especially in the context of an abnormality seen on prenatal ultrasound scans.

To test DNA for medical reasons, some type of cellular material is required. This material can come from blood, urine, saliva, body tissues, bone marrow, hair, etc. The material can be submitted in a tube, on a swab, in a container, or frozen. If the test requires RNA, the same materials can be used. Once received in the laboratory, the cells are removed from the substance they are in, broken apart, and the DNA in the nuclei is isolated and extracted.

The laboratory professionals who perform and interpret these tests are specially trained pathologists and scientists. The extracted DNA is manipulated in different ways in order for the molecular pathologist or molecular geneticist to see what might be missing or mutated in such a way as to cause disease. Examples of common manipulations of the DNA include amplification, sequencing, or a special procedure called hybridisation. Another more traditional manipulation involves ‘cutting’ the DNA into small pieces using special enzymes. These small pieces are much easier to test than the long strands of uncut DNA, and they contain the genes of interest.

When the results of these different tests are examined and compared with results from a normal person, it is possible to see differences in the genes that might cause a disease.

Specific genetic diseases
There are many diseases that are now thought to be caused by alterations in DNA. These alterations can either be inherited or can occur spontaneously. Some diseases that have a genetic component to them include:
Alzheimer's disease Bone marrow disorders Breast cancer
Colon cancer Cystic fibrosis Down syndrome
Haemochromatosis Leukaemia Lupus
Lymphoma Osteoarthritis Ovarian cancer
Sickle cell anaemia Suxamethonium apnoea Thalassaemia
Thrombotic disorders Thyroid cancer Wilson's disease
Fragile X syndrome    

Note that only some of the diseases in the table above are strongly genetic and can be tested for in nearly all cases e.g. Wilson’s disease, Down syndrome, Cystic fibrosis and Thalassaemia. Others including most of the cancers, Alzheimer’s disease, Osteoarthritis and Lupus may have a genetic component but many factors including multiple genes and environmental factors are involved in causation and thus genetic testing is usually not useful. However, in some cancers genetic testing may be useful to guide treatment. For more information see our video on Targeted Therapies and Cell Signalling

Some of the related tests include:

Apo E genotyping B-cell immunoglobulin gene rearrangements BCR-ABL1
BRCA1 and BRCA2 CF gene mutation testing Chromosome analysis
EGFR mutation testing Factor V Leiden & PT 20210 FMR1 mutations
Genome-wide microarray testing HER2/neu HFE mutations
HIV genotypic resistance HLA testing JAK2 mutation
Microsatellite instability MTHFR mutation NIPT
Pharmacogenomic tests PSEN1 T-cell receptor gene rearrangements
TPMT ALK Mutation  

Several things can go wrong with the genes that make up the DNA, resulting in these and other diseases. The section below discusses what can happen to DNA, and specifically to genes, that might lead to a disease.
Genetic variation and mutation

All genetic variations or polymorphisms originate from the process of mutation. Genetic variations occur sometimes during the process of normal body or somatic cell division. If this type of mutation occurs very early in development so that it is passed on to all the cells that develop from that mutated cell, it can cause disease. These types of mutations may also cause or contribute to the development of cancer, especially when they occur in bone marrow cells that give rise to the cells that make up the blood. Other genetic variations can occur during the cycle of cell divisions that give rise to eggs and sperm. These mutations will be passed on to that person’s children and so if the gene mutation is harmful in some way, the child will be affected. If the mutation is recessive then the child will not be affected but they will pass the mutation on to half of their own children. Some mutations lead to disease, while some mutations have no noticeable effect. Genetic variations can be classified into different categories: stable genetic variations, unstable genetic variations, silent genetic variations, and other types.

Stable genetic variations are caused by specific changes in single nucleotides. 

  • Substitutions, in which one nucleotide is replaced by another are called single nucleotide polymorphisms or SNPs
  • deletions, in which a single nucleotide is lost, and
  • insertions, in which one or more nucleotides are inserted into a gene.

If the SNP causes a new amino acid to be made, it is called a “missense mutation.” An example of this is in sickle cell anaemia, in which one nucleotide is substituted for another. The genetic variation in the gene causes a different amino acid to be added to a protein, resulting in a protein that doesn’t do its job properly and causes cells to form sickle shapes and not carry oxygen to the body as effectively as normal blood cells.

Unstable genetic variations occur when a nucleotide sequence repeats itself over and over. These are commonly called "triplet repeats"; a triplet group of nucleotides repeats over and over and is usually present within a normal range, such as in groups of 5-35 repeats. However, if the number of repeats increases too greatly, it is called an "expanded repeat" and has been found to be the cause of many genetic disorders; most of which affect the central nervous system. An example of a disease caused by an expanded triplet repeat is Huntington disease, a severe late onset progressive neurodegenerative disorder which leads to dementia, psychological changes and involuntary movements.

Silent genetic variations are those mutations or changes in a gene that do not change the protein product of the gene. These mutations rarely result in a disease.

Other types of variations occur when an entire gene is duplicated somewhere in a person’s genome. When this occurs, extra copies of the gene are present and makes extra protein product. An example is a disorder that affects peripheral nerves called Charcot-Marie-Tooth disease type 1. In other cases a gene or many genes in the same area may be deleted. If the same gene that causes Charcot-Marie-Tooth type 1 when duplicated is instead deleted from the person’s genome, this results in a different disease called Hereditary Neuropathy with Pressure Palsies.

Some variations occur in special parts of the DNA that control when DNA is copied to RNA. When the timing or regulation of protein production is thrown off, it results in decreased or increased protein production. Other variations include defects in genes that make proteins that serve to repair broken DNA in our cells. This type of variation can result in many types of diseases, including colorectal cancer and a skin disease called xeroderma pigmentosum.

Testing for products of genetic expression

Many inherited disorders are identified indirectly by examining abnormalities in the genetic end products (proteins or metabolites) that are present in abnormal forms or quantities. So, rather than detecting the problem in the gene, many other types of laboratory testing look for abnormalities in the pertinent proteins, such as their absence or the presence of unusual amounts of other substances due to the defect in the protein.

An example of testing for genetic products includes those widely used to screen newborns for a variety of disorders. For example, newborns are tested for phenylketonuria (PKU), an inherited autosomal recessive metabolic disorder caused by a mutation in a gene that makes a special enzyme that breaks down phenylalanine, an amino acid. When too much of phenylalanine builds up in blood, it can lead to intellectual disability if not treated early in life with a special, restricted diet. The newborn screening test uses a blood sample from a baby’s heel to look for the presence of extra phenylalanine, rather than looking for the mutated gene itself. Other examples include blood tests for congenital hypothyroidism, diagnosed by low blood levels or absence of thyroid hormone, and cystic fibrosis where high levels of trypsin are found in the newborn’s blood.  Frequently, abnormal blood screening tests in the newborn may be augmented by genetic testing when appropriate. This is the case in cystic fibrosis where high blood trypsin levels are followed up by genetic testing looking for all the common mutations known to cause cystic fibrosis.