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Clinical Uses of Genetics

By David N. Finegold, MD, Professor of Human Genetics, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh

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(See also Overview of Genetics.)

Disease Understanding

Genetics has advanced understanding of many disorders, sometimes allowing them to be reclassified. For example, classification of many spinocerebellar ataxias has been changed from one based on clinical criteria to one based on genetic criteria. The Online Mendelian Inheritance in Man (OMIM) database is a searchable catalog of human genes and genetic disorders.


Genetic testing is used to diagnose many disorders (eg, Turner syndrome, Klinefelter syndrome, hemochromatosis). Diagnosis of a genetic disorder often indicates that relatives of the affected person should be screened for the genetic defect or for carrier status. A catalog of genetic tests and reviews of many genetic diseases with diagnostic strategies and recommendations for risk counseling are available from the Genetic Testing Registry.

Genetic Screening

Genetic screening may be indicated in populations at risk of a particular genetic disorder. The usual criteria for genetic screening are

  • Genetic inheritance patterns are known.

  • Effective therapy is available.

  • Screening tests are sufficiently valid, reliable, sensitive and specific, noninvasive, and safe.

Prevalence in a defined population must be high enough to justify the cost of screening.

One aim of prenatal genetic screening is to identify asymptomatic parental heterozygotes carrying a gene for a recessive disorder. For example, Ashkenazi Jews are screened for Tay-Sachs disease, blacks are screened for sickle cell anemia, and several ethnic groups are screened for thalassemia (see Table: Genetic Screening for Some Ethnic Groups). If a heterozygote’s mate is also a heterozygote, the couple is at risk of having an affected child. If the risk is high enough, prenatal diagnosis can be pursued (eg, with amniocentesis, chorionic villus sampling, umbilical cord blood sampling, maternal blood sampling, or fetal imaging). In some cases, genetic disorders diagnosed prenatally can be treated, preventing complications. For instance, special diet or replacement therapy can minimize or eliminate the effects of phenylketonuria, galactosemia, and hypothyroidism. Corticosteroids given to the mother before birth may decrease the severity of congenital virilizing adrenal hypoplasia.

Screening may be appropriate for people with a family history of a dominantly inherited disorder that manifests later in life, such as Huntington disease or cancers associated with abnormalities of the BRCA1 and BRCA2 genes. Screening clarifies the risk of developing the condition for that person, who can then make appropriate plans, such as for more frequent screening or preventive therapy.

Screening may also be indicated when a family member is diagnosed with a genetic disorder. A person who is identified as a carrier can make informed decisions about reproduction.


Understanding the genetic and molecular basis of disorders may help guide therapy. For example, dietary restriction can eliminate compounds toxic to patients with certain genetic defects, such as phenylketonuria or homocystinuria. Vitamins or other agents can modify a biochemical pathway and thus reduce toxic levels of a compound; eg, folate (folic acid) reduces homocysteine levels in people with 5,10-methylene tetrahydrofolate reductase polymorphism. Therapy may involve replacing a deficient compound or blocking an overactive pathway.


Pharmacogenomics is the science of how genetic characteristics affect the response to drugs. One aspect of pharmacogenomics is how genes affect pharmacokinetics. Genetic characteristics of a person may help predict response to treatments. For example, metabolism of warfarin is determined partly by variants in genes for the CYP2C9 enzyme and for the vitamin K epoxide reductase complex protein 1. Genetic variations (eg, in production of UDP [uridine diphosphate]-glucoronosyltransferase 1A1) also help predict whether the anticancer drug irinotecan will have intolerable adverse effects.

Another aspect of pharmacogenomics is pharmacodynamics (how drugs interact with cell receptors). Genetic and thus receptor characteristics of disordered tissue can help provide more precise targets when developing drugs (eg, anticancer drugs). For example, trastuzumab can target specific cancer cell receptors in metastatic breast cancers that amplify the HER2/neu gene. Presence of the Philadelphia chromosome in patients with chronic myelogenous leukemia (CML) helps guide chemotherapy.

Gene therapy

Gene therapy can broadly be considered any treatment that changes gene function. However, gene therapy is often considered specifically the insertion of normal genes into the cells of a person who lacks such normal genes because of a specific genetic disorder. The normal genes can be manufactured, using PCR, from normal DNA donated by another person. Because most genetic disorders are recessive, usually a dominant normal gene is inserted. Currently, such insertion gene therapy is most likely to be effective in the prevention or cure of single-gene defects, such as cystic fibrosis.

Viral transfection is one way to transfer DNA into host cells. The normal DNA is inserted into a virus, which then transfects the host cells, thereby transmitting the DNA into the cell nucleus. Some important concerns about insertion using a virus include reactions to the virus, rapid loss of (failure to propagate) the new normal DNA, and damage to the virus by antibodies developed against the transfected protein, which the immune system recognizes as foreign. Another way to transfer DNA uses liposomes, which are absorbed by the host cells and thereby deliver their DNA to the cell nucleus. Potential problems with liposome insertion methods include failure to absorb the liposomes into the cells, rapid degradation of the new normal DNA, and rapid loss of integration of the DNA.

With antisense technology, rather than inserting normal genes, gene expression can be altered; eg, drugs can combine with specific parts of the DNA, preventing or decreasing gene expression. Antisense technology is currently being tried for cancer therapy but is still very experimental. However, it seems to hold more promise than gene insertion therapy because the success rates may be higher and complications may be fewer.

Another approach to gene therapy is to modify gene expression chemically (eg, by modifying DNA methylation). Such methods have been tried experimentally in treating cancer. Chemical modification may also affect genomic imprinting, although this effect is not clear.

Gene therapy is also being studied experimentally in transplantation surgery. Altering the genes of the transplanted organs to make them more compatible with the recipient’s genes makes rejection (and thus the need for immunosuppressive drugs) less likely. However, this process works only rarely.

Key Points

  • Genetic screening is justified only if disease prevalence is high enough, treatment is feasible, and tests are accurate enough.

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