Genetic Diseases

Abnormalities in an individual's genetic makeup cause genetic disease.

A genetic disease is any disease caused by an abnormality in the genetic makeup of an individual. The genetic abnormality can range from minuscule to major -- from a discrete mutation in a single base in the DNA of a single gene to a gross chromosomal abnormality involving the addition or subtraction of an entire chromosome or set of chromosomes. Some people inherit genetic disorders from their parents, while other changes are acquired changes or mutations in a preexisting gene or group of genes cause other genetic diseases. Genetic mutations can occur either randomly or due to some environmental exposure.

The environmental influence on genetics is currently one of the rapidly evolving areas of research (epigenetics).

There are four different types of genetic disorders (inherited diseases and disorders) and include:

1. Single gene inheritance
2. Multifactorial inheritance
3. Chromosome abnormalities
4. Mitochondrial inheritance diseases

Single gene inheritance is also called Mendelian or monogenetic inheritance. Changes or mutations that occur in the DNA sequence of a single gene cause this type of inheritance. There are thousands of known single-gene disorders. These disorders are known as monogenetic disorders (disorders of a single gene).

Single-gene disorders have different patterns of genetic inheritance, including

• autosomal dominant inheritance, in which only one copy of a defective gene (from either parent) is necessary to cause the condition;
• autosomal recessive inheritance, in which two copies of a defective gene (one from each parent) are necessary to cause the condition; and
• X-linked inheritance, in which the defective gene is present on the female, or X-chromosome. X-linked inheritance may be dominant or recessive.

Some examples of single-gene disorders include

1. cystic fibrosis,
2. alpha- and beta-thalassemias,
3. sickle cell anemia (sickle cell disease),
4. Marfan syndrome,
5. fragile X syndrome,
6. Huntington's disease, and
7. hemochromatosis.

Multifactorial inheritance is also called complex or polygenic inheritance. Multifactorial inheritance disorders are caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Some common chronic diseases are multifactorial disorders.

Examples of multifactorial inheritance include

1. heart disease,
2. high blood pressure,
3. Alzheimer's disease,
4. arthritis,
5. diabetes,
6. cancer, and
7. obesity.

Multifactorial inheritance also is associated with heritable traits such as fingerprint patterns, height, eye color, and skin color.

Chromosomes, distinct structures made up of DNA and protein, are located in the nucleus of each cell. Because chromosomes are the carriers of the genetic material, abnormalities in chromosome number or structure can result in disease. Chromosomal abnormalities typically occur due to a problem with cell division.

For example, Down syndrome (sometimes referred to as "Down's syndrome") or trisomy 21 is a common genetic disorder that occurs when a person has three copies of chromosome 21. There are many other chromosomal disorders including:

1. Turner syndrome (45, X0),
2. Klinefelter syndrome (47, XXY), and
3. Cri du chat syndrome, or the "cry of the cat" syndrome (46, XX or XY, 5p-).

Diseases may also occur because of chromosomal translocation, a type of genetic variation in which portions of two chromosomes are exchanged.

There are various types of genetic mutations based on where they develop. These include germline mutations and somatic mutations.

Germline mutations

• They occur in reproductive cells, such as sperm and eggs. These mutations are significant because they are heritable. This means they can be passed on to offspring, and every cell in the offspring will carry the mutation.
• Germline mutations are inherited from parents and can be passed to future generations.
• These mutations can lead to genetic disorders or contribute to the risk of developing certain diseases, such as hereditary cancers.
• Examples of germline mutations include mutations in the BRCA1 and BRCA2 genes, which increase the risk of breast and ovarian cancers.

Somatic mutations

• Somatic mutations occur in nonreproductive cells and are not inherited. These mutations happen after conception and can occur in any cell of the body except sperm and egg cells.
• Somatic mutations are not passed on to offspring.
• These mutations can lead to diseases such as cancer. For example, if a somatic mutation occurs in a gene that controls cell growth, it can lead to uncontrolled cell division and tumor formation.
• Examples of somatic mutation include mutations in the TP53 gene, which is involved in many cancers.

Both types of mutations can have important implications for human health and disease.

The human genome is the entire "treasury of human inheritance." The sequence of the human genome obtained by the Human Genome Project, completed in April 2003, provides the first holistic view of our genetic heritage. The 46 human chromosomes (22 pairs of autosomal chromosomes and 2 sex chromosomes) between them house almost 3 billion base pairs of DNA that contain about 20,500 protein-coding genes. The coding regions make up less than 5% of the genome (the function of all the remaining DNA is not clear) and some chromosomes have a higher density of genes than others.

• Most genetic diseases are the direct result of a mutation in one gene.
• However, one of the most difficult problems ahead is to further elucidate how genes contribute to diseases that have a complex pattern of inheritance, such as in the cases of diabetes, asthma, cancer, and mental illness.
• In all these cases, no one gene has the yes/no power to say whether a person will develop the disease or not.
• It is likely that more than one mutation is required before the disease is manifest, and a number of genes may each make a subtle contribution to a person's susceptibility to disease;
• Genes may also affect how a person reacts to environmental factors.

• Can genetic disorders skip generations? Yes, genetic disorders can skip generations, especially when they are recessive. Such disorders can manifest only if an individual inherits two copies of the defective gene (one from each parent). If individuals in a generation carry only one copy of the defective gene, they will be carriers but typically won’t show symptoms.
• What are examples of single-gene disorders? Common examples of single-gene disorders include cystic fibrosis (CF), sickle cell disease, Huntington’s disease, familial hypercholesterolemia, Duchenne muscular dystrophy, phenylketonuria, and hereditary hemochromatosis.
• What role do mutations play in genetic disorders? Mutations play a central role in genetic disorders by altering the DNA sequence of genes. These alterations can disrupt normal gene function, leading to the production of malfunctioning proteins or the loss of protein production altogether. Depending on the mutation's nature and location, the resulting genetic disorder can vary in severity and type. Some mutations are inherited, while others occur spontaneously which makes it impossible to predict the changes. Common types of mutations involved in genetic disorders include point mutations, insertions, deletions, and chromosomal rearrangements.
• Can mitochondrial diseases cause developmental delays? Yes, mitochondrial diseases can cause developmental delays. These genetic conditions affect the mitochondria’s ability to produce energy, which can impact the functioning of organs, including the brain and muscles, leading to developmental issues.
• Can mitochondrial diseases be detected before birth? Yes, mitochondrial diseases can be detected before birth through prenatal diagnosis techniques such as preimplantation genetic diagnosis (PGD), chorionic villus sampling (CVS), and amniocentesis.
• Are there prenatal tests for chromosomal disorders? Yes, there are some prenatal tests that can check for chromosomal disorders. The tests include noninvasive prenatal testing (NIPT), combined first trimester screening (CFTS), cell-free DNA testing, amniocentesis, and chorionic villus sampling (CVS).
• Are chromosomal disorders more common in older parents? Yes, chromosomal disorders are more common in children born to older parents. Specifically, older maternal age is associated with a higher risk of chromosomal abnormalities such as Down syndrome. Advanced parental age, typically over 35 years old, increases the risk of birth complications such as low birth weight and seizures.
• Can genetic abnormalities be inherited from one parent? Yes, genetic abnormalities can be inherited from just one parent. This can occur in several ways, such as through single-gene mutations, chromosomal disorders, or complex (multifactorial) disorders. Some disorders may show symptoms at birth, while others may develop over time. Patterns of inheritance can be autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, or mitochondrial.
• What is the role of gene therapy in genetic abnormalities? Gene therapy plays a crucial role in correcting genetic abnormalities by introducing functional copies of defective genes into cells to produce missing or malfunctioning proteins. This approach is particularly effective for treating rare genetic diseases, but it is also being studied for the treatment of common diseases such as cancer and degenerative diseases.