Genetics has advanced understanding of many disorders, sometimes allowing them to be reclassified. For example, classification of many spinocerebellar ataxias Hereditary 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 Diagnosis In Turner syndrome, girls are born with one of their two X chromosomes partly or completely missing. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis. Treatment... read more , Klinefelter syndrome Diagnosis Klinefelter syndrome is the presence of two or more X chromosomes plus one Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis... read more , hemochromatosis Diagnosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more ). 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 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 Prenatal Genetic Testing of Parents Genetic testing is part of routine prenatal care and is ideally done before conception. The extent of genetic testing is related to how the woman and her partner weigh factors such as The probability... read more is to identify asymptomatic parental heterozygotes carrying a gene for a recessive disorder. For example, Ashkenazi Jews are screened for Tay-Sachs disease, Black people are screened for sickle cell anemia, and several ethnic groups are screened for thalassemia ( Professional.see Table # on p. # Genetic Screening for Some Ethnic Groups 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, amniocentesis Amniocentesis All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more , chorionic villus sampling Chorionic Villus Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more , umbilical cord blood sampling Percutaneous Umbilical Blood Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more , maternal blood sampling Noninvasive Prenatal Screening Strategies Noninvasive maternal screening, unlike invasive testing, has no risk of test-related complications. By more precisely assessing the risk of fetal abnormalities, noninvasive maternal screening... read more , fetal imaging Prenatal Ultrasonography All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more ). 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.
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 Overview of Pharmacokinetics Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution... read more . 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]-glucuronosyltransferase 1A1) also help predict whether the anticancer drug irinotecan will have intolerable adverse effects.
Another aspect of pharmacogenomics is pharmacodynamics Overview of Pharmacodynamics Pharmacodynamics (sometimes described as what a drug does to the body) is the study of the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding... read more (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 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 Single-Gene Defects Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , 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; 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, 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.
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
Genetic screening is justified only if disease prevalence is high enough, treatment is feasible, and tests are accurate enough.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Folacin , Folicet, Q-TABS|
|Herceptin, Herzuma, KANJINTI, Ogivri, Ontruzant , Trazimera|