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Genetic Diseases

By: , Posted on: September 11, 2016

NEW Biomedical Sciences Reference Modules LogoThe following is taken from the article Genetic Diseases by O. Shapiro and G. Bratslavsky included in both Brenner’s Encyclopedia of Genetics (Second Edition) and the Reference Module in Biomedical Sciences.

Genetic diseases are disorders that are inherited via DNA and thus can be passed down generation to generation. Whether the offspring of affected individual exhibits signs of disease depends on the mode of inheritance and the penetrance of the gene. Twenty-first century has seen an incredible advancement of our knowledge about genetics and disorders associated with faulty genes. Gene therapy is on the forefront of current medical research. Hopefully, in the near future, we will be able to prevent and cure many genetic diseases.

Unlike most disorders, which are acquired adventitiously during an individual’s lifetime as a result of invasion by a foreign organism in the case of an infection, a genetic disease results from a genetic code (DNA) defect (mutation) which in turn causes detectable malfunction of certain proteins and subsequently tissues and organs. Most disorders are fairly rare and affect one in thousands or millions of people.

The first molecular genetic change responsible for an inherited genetic disease was identified in 1957 by Ingram. He showed that a single amino acid substitution allowed the sickle-cell hemoglobin to differ from normal hemoglobin. Since the advancement of laboratory techniques and an introduction of recombinant DNA technology in the 1970s, the alterations of genes responsible for numerous disorders have been identified and recorded. The precise molecular lesions due to these mutations have also been established.

There are two main modes of inheritance: recessive and dominant. For a genetic disease caused by a recessive mutation, two unaffected parents must be heterozygous for the mutation (one mutated gene and one normal gene) and there will be 25% chance (1 in 4) of producing a homozygous affected child. Interestingly, heterozygous individuals (carriers) are often asymptomatic and can be completely unaware of their carrier status, and thus unprepared for the birth of a genetically compromised child. Examples of autosomal recessive disorders include cystic fibrosis, sickle-cell disease, and spinal muscular atrophy. Some recessive genetic diseases, such as Tay–Sachs disease, show dramatically increased prevalence in certain ethnic groups such as Ashkenazi Jews. Considerable effort has been devoted to identifying and counseling potential carriers within these groups. In contrast to autosomal recessive inheritance, autosomal dominant disorders are usually characterized by one nonaffected parent and one affected parent with a mutation in the causal gene. Examples include Huntington’s disease, Marfan syndrome, and neurofibromatosis type I. Sometimes, autosomal dominant diseases have reduced penetrance, allowing for individuals who carry the gene mutation to not develop the actual disease. Nevertheless, the penetrance of autosomal dominant disorders is usually high.

In addition to classic autosomal inheritance, some diseases are linked to specific sex chromosomes. X-linked recessive diseases such as hemophilia, for example, are characterized by half the male offsprings (on average) of heterozygous mothers being affected. Similar to autosomal dominant inheritance, individuals with X-linked genetic disorders are usually aware of their genetic and disease status, and thus able to make informed choices about parenthood. Unfortunately, some disorders caused by dominant mutations, such as Huntington’s disease, do not usually manifest until after the reproductive years, thus, not allowing an individual to consider alternatives to natural parentage. In such cases, genetic testing may be of great help, but such testing remains a controversial and ethical issue with numerous medical, psychological, and legal implications.


Nevertheless, two main approaches to the eradication of genetic disorders rely on identification of the affected gene. One approach is preventative and involves genetic testing of asymptomatic potential carriers or potentially affected individuals in high-risk groups (i.e., Ashkenazi Jews for Tay–Sachs disease or African-Americans for sickle-cell disease) to allow for identification of a carrier, so appropriate parenting decisions could be made early. Alternatively, in vitro fertilization allows for genetic testing of embryos and selection for those not carrying a mutant gene. This approach can permit carriers to produce their own children while simultaneously eradicating the disease mutation from their family lineage. Some in the medical community advocate neonatal genetic testing of all individuals for all possible genetic diseases. Such an approach may be favored in densely populated ethnic communities susceptible to certain genetic disorders.

The second approach is therapeutic and involves gene therapy. It is defined as an insertion, manipulation, or removal of genes within an individual to treat the genetic disease. In the 1970s, Friedmann and Roblin suggested using ‘good DNA’ to replace defective (mutated) DNA to treat a disease. The first gene therapy took place in 1990 at the National Institute of Health (NIH) to treat a girl afflicted with immune system deficiency. The effects were successful albeit temporary. Several other gene therapies and trials have been conducted throughout the 1990s. Unfortunately, the death of a patient in 1999 halted the gene therapy research in the United States. The Food and Drug Administration (FDA) questioned the ethics and procedures in the field effectively shutting down several clinical trials. The first decade of the twenty-first century saw many advances in gene therapy. UCLA (University of California, Los Angeles) scientists inserted genes into the brain using liposomes in 2003. This has potential benefits in treating Parkinson’s disease. NIH researchers treated metastatic melanoma using killer T cells genetically manipulated to attack cancer cells. In 2006, an Italian team developed a way to prevent the immune system from rejecting newly introduced genes. Also in 2006, University of Pennsylvania doctors treated HIV with gene-based immunotherapy. In 2009, the journal Nature reported on squirrel monkeys developing color vision after being treated with gene therapy. Currently, harmless, modified versions of viruses are proving to be the best vectors for introducing genes into somatic tissues of individuals with genetic diseases. Some of the problems with gene therapy include instability of therapeutic DNA and subsequent unsustainable effects of intervention. Also, viruses themselves are a potential source of problems for the patient. Many disorders including Alzheimer’s disease, arthritis, diabetes, and heart disease are multigene disorders. These are very difficult to treat effectively with gene therapy which is best suited for a single-gene disease.

In 1971, Knudson recognized the role of genes in carcinogenesis. All forms of cancer involve mutations to genes within an individual. For example, inactivation of the VHLgene, which causes a rare inherited cancer, was recently implicated in the most common type of renal cell carcinoma. Dissection of the VHL gene pathway has resulted in better understanding of renal carcinogenesis and creation of several new therapies for metastatic cancer of the kidney.

Read more about Genetics and Genomics here.

This excerpt is taken from the article Genetic Diseases by O. Shapiro and G. Bratslavsky included in both Brenner’s Encyclopedia of Genetics (Second Edition) and the Reference Module in Biomedical Sciences.

Hosted on ScienceDirect, the Reference Module combines thousands of comprehensive and encyclopedic articles into one interdisciplinary database. Every Month the content is reviewed, updated and new articles are commissioned where needed to ensure the latest developments and discoveries are included. Achieve more with this empowering resource, learn more here.

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