Genetic testing, through interrogation of DNA, RNA, chromosomes, or proteins, can provide critical information for the detection of heritable disease genotypes for a number of different applications (Table 3) (15). Many procedures can be used in either a direct or indirect mutation analysis. Most types
Applications of Molecular Genetic Testing
Diagnostic testing: Testing for a gene mutation in symptomatic individuals as a diagnostic aid.
Newborn screening: Testing is used to screen populations to identify prevalent genetic mutations in asymptomatic infants. The purpose of the screening is to identify affected babies early in life to allow for appropriate intervention before irreversible damage occurs.
Presymptomatic testing: Testing for a gene mutation in asymptomatic individuals in order to predict or assess the risk of disease in the future. These applications include testing for diseases in which lifestyle changes, increased medical surveillance, or medical intervention might be beneficial if the mutation is known. Testing requires extensive pretest and posttest counseling.
Carrier screening: Testing for a gene mutation in an autosomal recessive disorder in asymptomatic individuals for the purpose of family planning and genetic counseling to determine probability of disease in children. Requires extensive pretest and posttest counseling. Carrier screening might be recommended in various situations including (1) if one or both partners have a family history of the disease, (2) if one or both partners are members of a population or ethnic group with a higher incidence of the disease, (3) if partners are seeking preconception or prenatal testing, and (4) general population screening.
Prenatal diagnosis: Testing fetal cells/tissues for mutations to determine if a fetus is affected with a disease early in the pregnancy so that termination of the pregnancy can be an option. Testing can be done at 8- to12 wk gestation by chorionic villus sampling (CVS) or at 14-16 wk by amniocentesis.
of genetic testing rely on some form of in vitro amplification before proceeding with the actual analysis. Direct analysis refers to those procedures that detect the specific disease-causing mutations or foreign DNA sequence. These assays require that the mutation and/or the gene sequence of interest is known. Allele-specific oligonucleotide probes, DNA sequencing, and a wide array of polymerase chain reaction (PCR) mediated procedures are examples of direct analysis methods.
Indirect detection methods, on the other hand, are utilized when the sequence of a disease-associated gene or disease-causing mutation is not known. Polymorphic markers or gene sequences closely associated with the disease-causing gene are used to assess whether an individual has inherited the gene responsible for the disease phenotype. This type of testing is commonly referred to as linkage analysis. Linkage analysis is based on tracking the inheritance of polymorphic markers in a family with a genetic disease. If the markers and the disease-associated gene are in proximity, then the likelihood of a recombination event occurring between them is minimal. Thus, coinheritance of the markers and the disease-associated gene is likely. The advantage of linkage analysis is that the gene of interest need only be mapped to a chromosomal location. Limitations to this technology include significant labor and turnaround-times, the need to analyze samples from many family members, and the possibility of having to use numerous markers to obtain informative data. Despite technological capabilities for both direct and indirect testing, several considerations must be taken into account when interpreting these types of results (Table 4).
Penetrance: The percentage of individuals with the mutation who express the disease; not all individuals with a disease mutation will express the disease.
Heterogeneity: When a genetic disease is caused by more than one mutation. Molecular heterogeneity of a genetic disease might include mutations in a number of different genes or a large number of different mutations within the same gene. They might also result in differences in disease severity.
Expressivity: The variation in symptoms that can occur in individuals with the same genetic mutation.
Anticipation: A progressive increase in severity of a disease in future generations.
Burden of disease: The effect of a disease on the quality of life of an individual. Genetic diseases vary from those in which affected individuals can live a normal life to those that are severely disabling and ultimately fatal.
Uniparental disomy: An autosomal recessive disorder occurs when a child inherits two copies of an abnormal gene from one parent and no copies from the other parent.
Imprinting: Results in a different expression of a gene dependent on whether it was inherited from the mother or father.
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