Definitions of Terms

Genetics

Definition:
It is common knowledge that a person's appearance -- height, hair color, skin color, and eye color -- are determined by genes. Mental abilities and natural talents are also affected by heredity, as is the susceptibility to acquire certain diseases.

An inherited, abnormal trait or "anomaly" may:

• Have no consequence to a person's health or well being (for example, a white patch of hair or an extended ear lobe).
• Be of minor consequence (for example, color blindness).
• Have dramatic effect on the quality or length of life.

For most genetic disorders, genetic counseling is advised. Many people may also want to seek prenatal diagnosis.

The terms anomaly, abnormality, disorder, defect, disease, and syndrome are not used consistently, and do not have precise definitions.
 
Alternative Names:
Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers
 
Information:
Human beings have cells with 46 chromosomes --2 sex chromosomes and 22 pairs of autosomal (non-sex) chromosomes. Males are "46, XY" and females are "46, XX". These chromosomes are made up of extremely long DNA molecules in combination with chromosomal proteins.
Genes are defined by intervals along one of the DNA molecules. The location of the gene is called the locus. Most genes carry information which is necessary to synthesize a protein.
The pairs of autosomal chromosomes (one from the mother and one from the father) carry basically the same information. That is, each has the same genes, but there are slight variations in the DNA sequence of nucleotide bases in each gene.
These slight variations occur in less than 1% of the DNA sequence and produce different variants of a particular gene that are called alleles.

The information contained in the nucleotide sequence of a gene is transcribed to mRNA (messenger RNA) by enzymes in the cell's nucleus and then translated to a protein in the cytoplasm. This protein may be a structural constituent of a given tissue. It may be an enzyme which catalyzes a chemical reaction, or it may be a hormone. There are also many other potential functions for proteins.

If a gene is abnormal, it may code for an abnormal protein or for an abnormal amount of a normal protein. Since the autosomal chromosomes are paired, there are 2 copies of each gene. If one of these genes is defective, the other may code for sufficient protein, so that no disease is clinically apparent. This is called a recessive disease, and the gene is said to be inherited in a recessive pattern.
In the case of a recessive disease, if one abnormal gene is inherited, the child will not show clinical disease, but they will pass the abnormal gene to 50% (on average) of their offspring. If one abnormal gene produces disease, this is called a dominant hereditary disorder. In the case of a dominant disorder, if one abnormal gene is inherited from mom or dad, the child will likely show the disease.
A person with one abnormal gene is termed HETEROZYGOUS for that gene. If a child receives an abnormal recessive disease gene from both parents, the child will show the disease and will be HOMOZYGOUS for that gene.

If two parents are each heterozygous for a particular recessive disease gene, then each child has a 25% chance of being homozygous for that gene and therefore, of showing the disease. If one parent is homozygous and the other heterozygous, then each child has a 50% chance of being homozygous.

GENETIC DISORDERS
Almost all diseases have a genetic component, but the importance of that component varies. Disorders where genetics play an important role, so-called genetic diseases, can be classified as single gene defects, chromosomal disorders, or multifactorial.

A single gene disorder (also called Mendelian disorder) is one that is determined by a single genetic locus and the specific allele on one or both members of a chromosome pair. Single gene defects are rare, with a frequency of less than 1 in 200 births. But since there are about 6,000 known single gene disorders, their combined impact is significant.
The incidence of serious single gene disorders is estimated to be about 1 in 200 births.

Single-gene disorders are characterized by the pattern of transmission in families -- this is called a pedigree. The term "kindred" includes the relatives outside of the immediate nuclear family. The affected individual that initially comes to light (or is of immediate interest) is called the proband. The brothers and sisters of the proband are called siblings.

There are only 5 basic patterns of single gene inheritance:

• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive
• Maternal (mitochondrial) inheritance

The observed effect of an abnormal gene (the appearance of a disorder) is called the abnormal phenotype. A phenotype expressed in the same way (in both homozygotes and heterozygotes) is dominant. A phenotype expressed only in homozygotes (or, for X-linked traits, expressed in males but not females) is recessive.
Heterozygotes for a recessive gene are called carriers. They usually don't express the phenotype clinically, but it can frequently be identified by sensitive laboratory methods.

In AUTOSOMAL DOMINANT INHERITANCE, the abnormality or abnormalities usually appear in every generation. Every affected child has an affected parent and each child of an affected parent has a 50% chance of inheriting the disease.
Normal members of the family do not transmit the disease. Males and females are equally likely to have the disease and to transmit the disease. Male-to-male transmission can occur (unlike with X-linked inheritance), and males can have unaffected daughters (unlike with X-linked dominant inheritance).

In AUTOSOMAL RECESSIVE INHERITANCE, the parents of an affected individual may not express the disease. On average, the chance of an affected child's brothers or sisters having the disease are 1 in 4. Males and females are equally likely to be affected. For a child to have symptoms of an autosomal recessive disorder, the child must receive the defective gene from BOTH parents.
Because most recessive disorders are rare, a child is at increased risk of a recessive disease if the parents are related. Related individuals are more likely to have inherited the same rare gene from a common ancestor.

In X-LINKED RECESSIVE INHERITANCE, the incidence of the disease is much higher in males than females. Since the abnormal gene is carried on the X chromosome, males do not transmit it to their sons -- they do transmit it to their daughters.
The presence of one normal X chromosome masks the effects of the X chromosome with the abnormal gene. So, almost all of the daughters of an affected man appear normal, but they are all carriers of the abnormal gene. The sons of these daughters then have a 50% chance of receiving the defective gene.

In X-LINKED DOMINANT INHERITANCE, the presence of the defective gene appears in females even if there is also a normal X chromosome present. Since males pass the Y chromosome to their sons, affected males will not have affected sons, but all of their daughters will be affected. Sons or daughters of affected females will have a 50% chance of getting the disease.

EXAMPLES OF SINGLE GENE DISORDERS
Autosomal recessive:

• Cystic fibrosis (CF) is a very common hereditary disorder (1 out of 2,000 Caucasian births). The normal function of a particular protein is to transport chloride ions into certain cells. Deficiency of this protein somehow results in the accumulation of thick mucus in the lungs and other parts of the body. This situation compromises respiration and greatly increases the chance of pulmonary infections. Affected individuals rarely survive to the age of 40.
• Phenylketonuria (PKU) is a common genetic disorder (1 out of 12,000 births) which results from a deficient enzyme required for the metabolism of the amino acid phenylalanine. Failure to recognize the disorder early in life results in mental retardation. Many states require all newborns to be screened for this disease.
• Alpha-1-antitrypsin (AAT) deficiency is a disorder seen in about 1 out of 10,000 births. The normal function of the protein is to inhibit enzymes which escape from white blood cells in the process of destroying invading bacteria. Affected individuals are much more likely to develop emphysema than usual.
• Sickle cell anemia is a disorder common in individuals with an African ethnic background. The high frequency of the gene probably relates to the fact that the heterozygotes are resistant to malaria. The homozygotes have a predominance of an abnormal hemoglobin in their red blood cells. This abnormal protein causes the red blood cells to assume abnormal shapes and to lyse (a process of disintegration or dissolution) in small blood vessels under conditions of reduced oxygen pressure.
• ADA deficiency is a rare immunodeficiency disorder, sometimes called the "boy in a bubble" disease, which results from the deficiency of an enzyme called adenosine deaminase. This enzyme is important for the normal function of lymphocytes which are the primary components of the immune system. This disease has the distinction of being the first to be treated effectively by genetic engineering. Some of the patient's cells are removed from the body, injected with a normal gene, then reintroduced to the body.

X-linked recessive:

• Duchenne muscular dystrophy is a very common (1 out of 3,500 male births) disorder which results from the presence of an abnormal muscle protein. Muscles of young boys gradually deteriorate until even the muscles required for normal respiration become ineffective. These boys usually die of pulmonary infections before the age of 20.
• Hemophilia A is seen in 1 out of 10,000 male births. The defective protein (coagulation factor VIII) is required for normal blood clotting. Affected individuals require injections of the protein or transfusion of blood products to prevent internal bleeding. Until recently, when the genetically engineered protein became available, many of these individuals contracted viral hepatitis or AIDS as a result of their many transfusions.
• Tay-Sachs disease is a disorder which is seen almost solely in Ashkenazi Jew populations. The incidence in this population has been substantially reduced (from about 1 out of 900) as a result of massive screening programs. The affected protein is an enzyme necessary to breakdown lipids in the membranes of cells. Abnormal membrane fragments accumulate and cause a deterioration of the nervous system. Individuals affected with the severe form of the disease die before the age of 3.

Autosomal dominant:

• Familial hypercholesterolemia (FHC) is a fairly common disorder (1 out of 500 individuals are heterozygous). The affected gene codes for a protein which is found on the external surface of most of the body's cells. This so-called receptor protein mediates the uptake of cholesterol into the cells. This cholesterol is transported in the blood by a lipoprotein called LDL. When LDL can't get into cells, it increases to high levels in the blood. High levels of LDL (with its associated cholesterol) increases the risk of developing arteriosclerosis and coronary artery disease. Homozygous individuals (about 1 out of 1,000,000 births) have extremely high levels of LDL and develop coronary heart disease in childhood.
• Huntington's disease is a neurodegenerative disease which doesn't appear until approximately age 30. It has recently become possible to test for the presence of the abnormal gene at any age. This information may be of great interest to individuals who know they will develop the disease later in life since they may wish to modify their plans in regards to marriage and childbearing. Other individuals prefer not to know as the prognosis is grim and there is no effective treatment.

X-linked dominant:
Only a few, very rare, disorders are classified as X-linked dominant. One of these is hypophosphatemic rickets (also called Vitamin D resistant rickets). In this case a protein in the kidneys is defective. This protein normally transports phosphate from the urinary filtrate back into the blood. Since the amount of phosphate in the blood is much lower than normal, the bones are chronically stimulated to release calcium and phosphate by hormones such as parathormone. This results in fragile and abnormally structured bones.

CHROMOSOMAL DISORDERS
In chromosomal disorders, the defect is due not to a single gene, but to an excess or deficiency of the genes contained in a whole chromosome or chromosome segment.

Down syndrome is the most common chromosomal disorder (1 out of 800). Affected individuals have an extra copy of chromosome 21. This unbalanced set of genes results in mild to moderate mental retardation and numerous physical changes. Other common examples are Klinefelter syndrome (1 out of 1,000 males) and Turner syndrome (1 out of 5,000 females).
MULTIFACTORIAL DISORDERS
Many of the most common diseases which affect humans undoubtedly involve interactions of numerous genes, including coronary heart disease, hypertension, stroke, and various kinds of cancer. These are currently active areas of research.
MITOCHONDRIAL DNA-LINKED DISORDERS
Mitochondria are small organelles present in most of the body's cells which function in the conversion of certain chemicals in our food, in the presence of oxygen, to the common currency of energy inside cells (ATP).
Mitochondria contain their own private DNA. In recent years, more than 20 hereditary disorders have been shown to result from mutations in mitochondrial DNA. Because mitochondria come only from the egg, they are inherited exclusively from the mother.
A person with a mitochondrial disorder may exhibit maternal inheritance (only individuals related by a maternal relative are at risk). Fathers do not pass on the disease.

Review Date: 8/19/2003 Reviewed By: Douglas R. Stewart, M.D., Division of Medical Genetics, Hospital of the University of Pennsylvania, Philadelphia, PA. Review provided by VeriMed Healthcare Network.
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