The Universe of Genetic Testing

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Clinical genetic testing refers to the laboratory analysis of DNA, RNA or chromosomes to aid in the diagnosis, management and prevention of genetic disease. Clinical Genetic testing can:

1. Provide or rule out a particular diagnosis suspected in an individual or family.

2. Predict the likelihood of developing a particular disease before symptoms appear.

3. Tell if a person is carrying a specific genetic change that could be passed on to his or her children.

4. Determine whether some treatments are more or less likely to work before a patient starts therapy.

These are definite advantages but there are also some qualities of genetic testing that should be carefully thought through and discussed with a medical professional or genetic counsellor before undergoing any test. These aspects are reviewed in the section entitled  Pros and Cons of Genetic Testing. In an era of patient responsibility, it is important that you can obtain information to fully appreciate the value as well as the drawbacks of genetic testing.

Testing Genetic Material
Testing of genetic material can be performed on a variety of cellular specimens. DNA can be extracted from these tissues and examined for possible genetic changes or cells can be cultured for chromosome analysis. Looking at small portions of the DNA within a gene, or copy number changes across the genome, requires specialised techniques and specific laboratory testing. This is done to pinpoint the exact location of genetic errors or copy number changes. This section will focus on the examination of a person’s genes and chromosomes to look for the changes responsible for a particular disease.

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

1. Diagnostic genetic testing is performed on a symptomatic individual with a phenotype sufficiently suggestive of a genetic disorder. This assists the individual’s physician in making a clear diagnosis and preventing a recurrence of the same disorder by prenatal diagnosis (see below).

2. Carrier testing of genetic material to see whether predisposing factors can be identified in the parents of an affected child that confer a risk of having further children with a genetic condition. Analysis of parental DNA or chromosomes may also be necessary to decide on the significance of some genetic changes.

3. Presymptomatic testing identifies the presence of a variant or mutant gene that can cause disease even if the physical abnormalities associated with the disease are not yet present in an individual.

4. Prenatal testing can be used to determine the genetic status of the unborn child because of parental risk factors, physical abnormalities detected in the child using ultrasound or a risk of a serious condition identified by biochemical screening.

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 or hair, etc. The material can be submitted in a tube, on a swab or in a container but it is important to follow the guidelines for the taking and transport of material appropriate to each specific test. These are usually available from the laboratories to which genetic tests are sent. If the test requires RNA, the same materials can be used but may need rapid handling and despatch. Once received in the laboratory, the cells are used for the extraction of DNA (or RNA) from the nuclei or cell culture for chromosome analysis.

The lab professionals who perform and interpret these tests are specially trained physicians and scientists usually working in accredited laboratories. The extracted DNA is manipulated in different ways in order for the scientist or technologist to see what might be missing, mutated or extra in such a way as to cause disease. The results can be broadly divided into:

1. Changes in the number of copies or the structure of a chromosome or chromosomal segment.

2. Changes in the sequence of DNA bases or the copy number of a gene, part of a gene or a factor that controls its expression.

These changes may be present in an individual from the beginning of their life (termed “constitutional”) or take place during the development of the body or a cancer (called “acquired”).

Specific Genetic Diseases
There are many diseases that are now thought to be caused by alterations in DNA or chromosomes. 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
Ovarian Cancer Bowel Cancer Cystic Fibrosis
Down Syndrome Haemochromotosis Leukaemia
Lupus erythematosis Lymphoma Osteoarthritis
Pre-senilin Mutation
Sickle Cell Anaemia Thalassaemia

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

Genetic Variation and Mutation
All genetic variations or polymorphisms originate from the process of mutation. The constitutional genetic variation you are born with arises during meiosis, the specialised cell division that that leads to the formation of each sperm or egg. Acquired genetic variation arises after conception during mitosis, the normal somatic cell division that all cells undergo in growing tissues, or as a result of exposure to environmental factors. Some variations are passed down through the generations while others appear in a particular individual for the first time (termed “de novo”). It is important to realise that copy number variation and mutation are natural processes and that only certain changes lead to disease whereas others may have no detectable effect. Genetic variations can be classified into different categories including:

1. Unbalanced chromosome abnormalities or copy number variations: a whole extra chromosome 21 can cause Down syndrome while a whole missing X chromosome can cause Turner syndrome. An extra copy of part of chromosome 17 causes Charcot-Marie-Tooth disease while a missing part of chromosome 22 leads to DiGeorge syndrome. Copy number variation of the defensin genes on chromosome 8 can increase the risk of the common skin complaint, psoriasis, but many other copy number variations are phenotypically neutral.

2. Balanced rearrangements: chromosomes may exchange segments with each other such that the “carrier” of the translocation is phenotypically normal but may have a risk of producing children that are not.

3. Mutations: these come in a bewildering variety of forms that include:

a. Deletions, in which one or more nucleotides are lost such as the delta 508 mutation in cystic fibrosis.

b. Insertions, in which one or more nucleotides are inserted into a gene.

c. Indels in which both insertion and deletion occur.

d. Substitutions, in which one nucleotide is replaced by another.

e. Triplet variations which have a range of variation in normal individuals but may expand to cause diseases such as Fragile X syndrome or Huntington disease.

4. Splice site variations that result in one or more different messenger RNAs and proteins being produced by a single gene.

5. Single nucleotide polymorphisms: these are often phenotypically neutral but are useful to track changes in copy number or the pattern of inheritance of a linked gene.

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.

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. As a reminder, genes code for the production of thousands of proteins and, if there is an error in the code, changes can occur in the production of those proteins. So, rather than detecting the problem in the gene, some types of testing look for abnormalities in the amount or structure of the proteins themselves or their precursors.

An example of testing for genetic products includes those widely used to screen newborns for a variety of disorders. For instance, instead of looking for the gene mutations in the autosomal recessive condition, Phenylketonuria(PKU), a biochemical test can be used on a tiny blood sample from a baby’s heel to look for the presence of the extra phenylalanine that is characteristic of this disease. Too much phenylalanine up in the blood can lead to mental retardation but, once detected, this can be avoided by treatment with a special restricted diet.

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