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.
(See also Overview of Genetics.)
Diagnosis
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, people with African ancestry are screened for sickle cell disease, and several ethnic groups are screened for thalassemia. 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, amniocentesis, chorionic villus sampling, umbilical cord blood sampling, maternal blood sampling, fetal imaging). In some cases, genetic disorders diagnosed prenatally can subsequently 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.
Treatment
Pharmacogenomics
Pharmacogenomics is the science of how genetic characteristics affect the response to drugs. One aspect of pharmacogenomics is how genes affect pharmacokinetics
Another aspect of pharmacogenomics is pharmacodynamicsHER2/neu gene. Presence of the Philadelphia chromosome in patients with chronic myeloid 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 polymerase chain reaction (PCR) methodology, 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 virus, viral vector, or 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. Modified RNA can be used to target specific parts of the DNA or RNA to prevent or decrease gene expression. Antisense technology is currently being tried for cancer therapy and some neurologic disorders 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. Antisense oligonucleotides are available for clinical use for the treatment of spinal muscular atrophies and Duchenne muscular dystrophy.
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, thus far this process works only rarely.
CRISPR-CAS9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9) uses a versatile RNA guided DNA gene editing platform adapted from bacterial biology to manipulate and modify an organism's genetic make-up. While still experimental, CRISPR-CAS9 is rapidly moving toward human therapeutics.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
The Online Mendelian Inheritance in Man (OMIM) database: A continuously updated catalog of human genes and genetic disorders and traits, with particular focus on the molecular relationship between genetic variation and phenotypic expression
Genetic Testing Registry: Provides a central location for voluntary submission of genetic test information by providers
Key Points
Genetic screening is justified only if disease prevalence is high enough, treatment is feasible, and tests are accurate enough.
