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Molecular Basis of Heredity: Part 3. Genetic Variation

Author(s): Raye L. Alford, PhD

Mendelian Disorders (III)

Mendelian disorders, which follow Mendel's rules of inheritance, can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner. X-linked dominant disorders are characterized by the appearance of a disease in both males and females in several generations of a family. True X-linked dominant disorders are few in number. There are many more X-linked recessive disorders. 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. X-linked traits are inherited in a manner similar to that of X-linked disorders.

X-linked recessive disorders are typically observed as affected males born to unaffected parents. However, it may be more accurate to describe X-linked disorders simply as X-linked and not as recessive or dominant because with many disorders historically described as X-linked recessive, carrier females can demonstrate variable degrees of signs or symptoms of the disease. For X-linked disorders, there can be a family history of the disorder in the form of affected uncle-nephew pairs, affected brothers, or affected male cousins, depending upon the carrier status of the females in the family. For common conditions, a pseudo-dominant pattern of inheritance observed as an affected male with an affected father can also be seen. However in such cases, the affected son actually would have had to inherit the trait from his mother because males inherit their father's Y chromosome, not their father's X chromosome. It is important to understand the pattern of inheritance and genetic location of the associated gene, so that accurate risk analysis and genetic counseling can be performed for families.

In the case of X-linked disorders, father to son transmission is never seen because fathers give sons their Y chromosome. Each son of a female carrier of an X-linked disorder has a 50% chance of being affected; daughters have a 50% chance of being a carrier. All daughters of an affected male will be carriers because fathers have just one X chromosome to contribute to a daughter. Examples of X-linked disorders include Duchenne muscular dystrophy and hemophilia A and B.

In addition, the classic red-green colorblindness trait is inherited in an X-linked recessive manner. Because it is so common, colorblind females who carry a copy of the gene associated with colorblindness on both of their X chromosomes are sometimes seen, as are colorblind father-son pairs. However, because we know the inheritance pattern of the trait, we know that a son inherits the trait from his mother, not his father. Roughly 8% of US Caucasian males are colorblind, while less than 1% of females are colorblind.

In pedigree drawings, boxes are males and circles are females. Shaded shapes are affected individuals and open shapes are unaffected individuals. In the drawing in this slide, an uncle-nephew pair affected by an X-linked disorder is shown. In this case, the women in the pedigree with dots in the center of the circles representing them are obligate carriers of the disorder. The sister of the affected boy in the third generation of the pedigree has a 50% chance of being a carrier.