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Molecular Basis of Heredity: Part 3. Genetic Variation

Author(s): Raye L. Alford, PhD

Mendelian Disorders (II)

Mendelian disorders, which follow Mendel's rules of inheritance, can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner. Humans typically carry two copies of each autosomal chromosome (chromosomes 1-22) and two copies of each autosomal gene. Individuals affected by autosomal recessive disorders carry two copies of the gene associated with the trait or disorder. 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 recessive traits are inherited in a manner similar to that of autosomal recessive disorders.

Autosomal recessive inheritance is frequently observed as the appearance of a disorder in only one generation of a family as isolated cases or affected siblings and/or cousins. Autosomal recessive inheritance is sometimes described as horizontal inheritance although this term is not commonly used today. In the case of common recessive disorders or disorders that lead to non-random mating, such as deafness, which is common and frequently leads to deaf by deaf matings, a pseudo-dominant pattern of inheritance may be observed. For genetic counseling and risk assessment, it is important to recognize the possibility that pseudo-dominant inheritance might be occurring in a family.

In general, males and females affected by autosomal recessive disorders will be affected with the same frequency and severity, but there may be exceptions in cases where a disorder affects the genders differently. In general, autosomal recessive disorders do not show reduced penetrance or the considerable variability that can be associated with autosomal dominant disorders. However, there are some autosomal recessive disorders for which variability in the severity of symptoms among affected individuals is observed. Reduced penetrance is a phenomenon in which some gene carriers remain unaffected despite the fact that they carry a gene associated with a trait or disorder. One explanation for this phenomenon is that the gene is necessary but not sufficient to cause disease.

Most often, children affected by autosomal recessive disorders are born to unaffected parents. However, for certain autosomal recessive disorders, there may be very mild or atypical manifestations of the disease in a carrier parent. Frequently in autosomal recessive disorders, there is no family history of the disease and no reason to suspect an affected child could be born. Carrier couples (in which both partners are carriers of the same autosomal genetic disorder) have a 25% risk of an affected child with each pregnancy. Examples of autosomal recessive disorders include cystic fibrosis (CF), Tay-Sachs disease, and sickle cell disease.

Under what conditions widespread screening should be undertaken for the identification of unaffected carriers of autosomal recessive disorders is a topic of much debate. At present, most carrier screening programs focus on high risk groups such as screening for cystic fibrosis (CF) carriers among Caucasians and screening for CF, Tay Sachs and other genetic disease carriers among Ashkenazi Jews.

In pedigree drawings, boxes are males and circles are females. Shaded shapes are affected individuals and open shapes are unaffected individuals. The drawing in this slide illustrates an autosomal recessive disorder. In this case, the affected child is born to unaffected parents with no family history of the disease.