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Molecular Basis of Heredity: Part 3. Genetic Variation

Author(s): Raye L. Alford, PhD

Mendelian Disorders (I)

Mendelian disorders follow Mendel's rules of inheritance. They can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner. Autosomal dominant inheritance is typically characterized by the appearance of a disorder in every generation of a family, passed down from parent to child for several generations. Autosomal dominant inheritance was sometimes described as vertical inheritance although this term is not commonly used today. The word trait is typically used by geneticists to describe genetically inherited physical characteristics or features that are not considered to be diseases or disorders. Autosomal dominant traits are inherited in a manner similar to that of autosomal dominant disorders.

Humans typically carry two copies of each autosomal chromosome (chromosomes 1-22) and two copies of each autosomal gene. Most individuals affected by autosomal dominant disorders carry one affected and one normal copy of the gene associated with the disorder. These individuals are said to be heterozygous for the disease gene. Homozygous affected individuals carrying two affected copies of a gene associated with a disorder can occur, especially if the disorder is common. For some autosomal dominant disorders, homozygotes (persons with two copies of an affected gene) are more severely affected than heterozygotes (persons with one affected and one normal copy of the gene). Achondroplasia, the most common form of short-limb dwarfism, is an example of this phenomenon.

In general, males and females affected by autosomal dominant disorders will be affected with equal frequency and severity, but there may be exceptions in cases where a particular disorder affects the genders differently. Male to male transmission of the disorder can occur in families with affected males. The children of affected heterozygous individuals typically have a 50% chance of inheriting the disease associated gene and being affected, unless the disorder demonstrates reduced penetrance. Reduced penetrance is a phenomenon in which some gene carriers remain unaffected despite the fact that they carry a gene associated with a disorder. One explanation for this phenomenon is that the gene is necessary but not sufficient to cause the disease. In these cases, the child has a 50% risk of inheriting the gene from an affected parent but may not show the disorder. Some autosomal dominant disorders show reduced penetrance. Others do not. The degree of reduced penetrance associated with a particular disorder depends upon the disorder in question.

Persons not affected by autosomal dominant disorders generally do not have affected children. However, there are exceptions, such as when a new mutation in a gene occurs at some point during transmission of the gene from parent to child. The child could be affected by the disorder while the parent remains unaffected. The percentage of cases of a particular disease that arise from new mutations varies from disorder to disorder.

Autosomal dominant disorders also frequently show a high degree of variability. Variability means that individuals who are affected by the disorder can display a variety of symptoms and a range of severity of the symptoms. A heterozygous affected parent has a 50% chance of passing the gene associated with the disease to each of his or her children, but if the disorder is highly variable it may be difficult to predict the severity to which a child will be affected. In most cases, variability is thought to represent the influence of other genetic and/or environmental factors on the expression of the disorder.

Examples of autosomal dominant disorders include: Marfan syndrome, neurofibromatosis, and Waardenburg syndrome. In pedigree drawings, boxes are males, circles are females. Shaded shapes are affected individuals, open shapes are unaffected individuals. The drawing on this slide illustrates an autosomal dominant disorder. In this family, the disease is passed from a man to his son, and then from the son to his daughter.