Inherited Diseases | Research & Encyclopedia Articles

Inherited Diseases

The human genome is composed of roughly three billion DNA base pairs. Each somatic cell of the body contains two copies of the entire genome, one inherited from the mother through the egg, and the other inherited from the father through the sperm. The DNA encodes a library of biochemical messages called genes, perhaps 60,000 in all. All of the genetic messages, no doubt, are important to the health of the organism, and it is likely true that every disease state in the human involves some compromise or redistribution of the biochemical agents produced by the genes. In other words, genes are involved at some level in virtually every human disease. Even so, most diseases are not inherited.

The genes are packaged into chromosomes. Each somatic cell contains 46 chromosomes; two copies of each of the 22 autosomes (numbered 1 through 22), and a pair of sex chromosomes (X and Y). Males and females share the same genetic makeup for all of the autosomal genes, but they differ in the distribution of genes found on the sex chromosomes. The X chromosome is a gene-rich medium length chromosome. The Y chromosome is a short chromosome with only a handful of genes. Females have two copies of the X chromosome, one inherited from the mother in the egg, and the second inherited from the father through the sperm. In contrast, males inherit one copy of the X chromosome from the egg. In place of the second X chromosome, males receive a Y chromosome through the sperm.

Inherited diseases are those conditions which result primarily or exclusively from genetic mutations or genetic imbalance passed on from parent to child at conception. These include Mendelian genetic conditions as well as chromosomal abnormalities. A third group of disorders exists wherein genetic factors interacting with environmental factors combine to produce a disease state. These conditions are often referred to as having multifactorial or complex inheritance patterns.

The first group, Mendelian diseases, also called single gene disorders, is defined by the property that mutation of just a single gene suffices to alter the overall physiology of the organism producing a recognizable disease state. Mendelian diseases are usually recognized by their distinctive patterns of inheritance in families. They can be broken into four major categories: autosomal dominant, autosomal recessive, X-linked dominant and X-linked recessive.

Autosomal dominant diseases result from mutations of genes found on any of the 22 pairs of autosomes, and the mutation need come from only one parent. Usually, the second copy of the gene received from the other parent is completely normal. A parent with an autosomal dominant genetic trait will pass the trait on to half of their sons and half of their daughters, and children who do not get the trait are not generally at risk for passing the trait on to their own children. Achondroplasia, a common cause of dwarfism, is an example of an autosomal dominant genetic disease.

Autosomal recessive diseases also involve genes found on the autosomes, but in contrast to autosomal dominant genes, both parents must pass a mutation to the child in order for the autosomal recessive disease to be expressed. The typical pattern of inheritance for autosomal recessive traits is that healthy carrier parents pass the disease on to one fourth of their children with an equal number of sons and daughters being affected. Cystic fibrosis is an example of an autosomal recessive genetic disease.

X-linked traits are the result of mutations of genes found on the X chromosome. The vast majority of the disease genes on the X chromosome behave as recessives in females. That is, both X chromosomes must have the mutation for the disease to arise. Since males have only one X chromosome, they will express the disease mutations whether they are dominant or recessive. The characteristic pattern of inheritance in X-linked recessive traits is that males having the disease are related to one another through healthy carrier females. Half of the sons of carrier females are affected. While none of the daughters of a carrier female parent is affected, half will themselves be mutation carriers. Affected males will pass the mutation on to all of their daughters, none of whom will have the disease. Father to son transmission is never seen in X-linked traits (recessive or dominant) because the father's X chromosome is passed on only to daughters. Duchenne muscular dystrophy is an example of an X-linked recessive disease.

X-linked dominant traits are far more rare. There are roughly twice as many females as males affected, although severity is frequently worse in males than in females. Affected females pass the disease on to half of their sons and half of their daughters. Affected males pass the trait on to all of their daughters and none of their sons. Fragile-X mental retardation syndrome is an example of an X-linked dominant disease.

The second group of inherited diseases is chromosomal. Chromosomes are long strands of DNA complexed with proteins and RNA that condense and allow for equal distribution of the genes when cells divide. Each chromosome contains hundreds or thousands of genes, and every cell needs to have two copies of each chromosome in order to maintain genetic balance. At the time of conception, an extra copy or missing copy of a chromosome or even a part of a chromosome disrupts normal development. Most chromosomal abnormalities result from simple accidents of chromosome segregation, and as such, they tend not to recur in families at nearly the rate as Mendelian genetic diseases. One example of genetic disease that results from chromosomal imbalance is Down syndrome. This condition is caused by the presence of an extra copy of chromosome 21, the smallest human autosome.

Diseases with complex or multifactorial inheritance are by far the most common, and their patterns of inheritance are indistinct and largely unpredictable. These diseases tend to cluster in families particularly when the contribution from genetic factors is relatively strong. The great majority of diseases that occur in humans can indeed be thought of as exhibiting complex inheritance. Chronic adult onset diseases such as hypertension, type II diabetes, obesity, heart disease, and strokes are examples.

Cancer is a genetic disease but is only rarely inherited. Most cancers are sporadic and arise in a particular tissue such as the colon, breast, lung or skin, following exposure of the normal tissue to carcinogens that cause somatic mutations in one or more oncogenes or tumor suppressor genes. Familial cancer syndromes, which in total account for less than one percent of all cancer, occur in individuals who have inherited a germline mutation in a tumor suppressor gene. Most familial cancers have autosomal dominant inheritance and are characterized by the development of cancer at a young age.

Inheriting a mutant tumor suppressor gene effectively knocks out one allele of the gene (i.e., the "first hit") in every cell in the body. This leaves the individual vulnerable to a "second hit" on the remaining normal gene allele. Some tissues or body organs such as the eye, the breast and colon, and soft tissues, are more susceptible to a "second hit" mutation which leads to complete loss of the tumor suppressor gene and the development of cancer in that particular tissue. This "two hit" hypothesis for the development of inherited cancers was described by Alfred Knudson in 1971.

Li-Fraumeni syndrome, first described by Li and Fraumeni in 1969, is one of the best-known familial cancer syndromes. This autosomal dominant disorder is caused by the inheritance of germline mutations in the p53 tumor suppressor gene (chromosome 17p13.1). Affected family members are prone to develop leukemia, melanoma, soft tissue sarcomas, bone tumors, and cancer of the colon, breast, prostate, brain, and lung, often before the unusually early age of thirty. Many different cancers can develop within the same family and some affected individuals may develop multiple different primary tumors.

Retinoblastoma, a rare eye tumor in children, is another autosomal dominant cancer syndrome. Children with familial retinoblastoma inherit a mutant allele of the RB1 tumor suppressor gene (chromosome 13q14.1) and are prone to develop multiple tumors in both eyes within months of birth. Sporadic retinoblastoma does occur but it usually develops later, and is confined to one eye.

Inherited breast cancer accounts for approximately 5% of all cases of breast cancer. Two different tumor suppressor genes, BRCA1 (chromosome 17q21), and BRCA2 (chromosome 13q12.3) cause an autosomal dominant pattern of inheritance. Individuals in families with BRCA1 mutations are prone to develop either breast or ovarian cancer at an early age, while families with BRCA2 mutations only develop breast cancer but have a higher frequency of males developing cancer of the breast.

A rare form of inherited stomach cancer has been described in the native New Zealand Maori population. Individuals who inherit mutations in the E-cadherin gene (chromosome 16q22.1) develop at an early age a rapidly fatal form stomach cancer. Presymptomatic gene testing of at risk individuals allows for early surgical treatment.

Some conditions do not directly cause cancer but are premalignant and predispose at risk individuals to the development of cancer. The most common premalignant syndrome is Neurofibromatosis, an autosomal dominant neurologic disease caused by mutations in one of the neurofibromin genes (NF1 or NF2). In NF1 (Von Recklinghausen disease chromosome 17q11.2) multiple benign neurofibromas develop in the peripheral nerves. The neurofibromas may become malignant nerve sheath tumors, and malignant tumors can develop in the brain.

Another premalignant condition is the Beckwith-Wiedemann syndrome. This congenital overgrowth disorder is associated with neonatal hypoglycemia (low blood sugar), macroglossia (large tongue), and a large birth weight and is caused by abnormal expression of the insulin-like growth factor 2 gene (IGF2 chromosome 11p). Some of these children later develop malignant tumors of the kidney (Wilms tumor), liver (hepatoblastoma), or adrenal gland (adrenocortical carcinoma).

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