In X-linked diseases, the affected gene is located on the X chromosome. Because males only have one X chromo-some, they will manifest disease if their X chromosome carries the affected gene. The male carrier status is con-sidered hemizygous, while the female is almost always heterozygous.
X-linked recessive diseases are much more common than X-linked dominant diseases (Box 7.2). Some examples of X-linked recessive diseases are hemophilia and color blindness. Hypophosphatemia is an example of an X-linked dominant disease.
Fragile X syndrome is an X-linked disorder that causesmental retardation. It is caused by a repeat in the cytosine-guanine-guanine sequence in a specific gene located on the X chromosome. Transmission of the disease-producing genetic mutation to a fetus depends on the sex of the parent and the number of repeats in the parental gene. If the num-ber of repeats is between 61 and 200, the individual is said to have a “premutation.” These individuals are phenotypically normal, although women carrying the premutation are at increased risk for premature ovarian failure. A full mutation is characterized by more than 200 repeats. These individu-als display the signs and symptoms of the disorder.
More common in males than in females
An affected male will not pass the disease to his son, but all the daughters will be carriers
The disease is transmitted from carrier females to affected males.
The disease is usually twice as likely in females than in males.
An affected male will transmit the disease to all of his daughters, but not to any of his sons.
Heterozygous females will transmit the gene to 50% of their offspring, whereas homozy-gous females will transmit the gene to all of their offspring.
A male may transmit the unexpanded premutation gene to his offspring, but expansion to the full mutation is rare in a male with the premutation gene. A female with a premutation gene may also transmit the gene to her off-spring; however, the premutation gene may expand during meiosis and result in a full mutation. Women with a family history of boys with developmental delay, extreme hyper-activity, and speech and language problems should be offered fragile X carrier testing. Women with ovarian fail-ure or an elevated follicle-stimulating hormone level before 40 years of age without a known cause should be screened to determine whether they have the fragile X premutation.
Mitochondrial inheritance is different from other pat-terns of inheritance. Mitochondria contain unique DNA (called mitochondrial DNA) that differs from the DNA carried in the cell nucleus. Any mutations in this DNA are only transmitted from the mother to all of her offspring and, if a male fetus is affected, he will not pass it on to any of his offspring.
Multifactorial disorders are caused by a combination offactors, some genetic and some nongenetic (i.e., environ-mental). Multifactorial disorders recur in families, but are not transmitted in any distinctive pattern. Many congeni-tal, single-organ system structural abnormalities are multi-factorial, having an incidence in the general population of approximately 1 per 1000. Examples of multifactorial traits are cleft lip, with or without cleft palate; congenital cardiac defects; neural tube defects; and hydrocephalus.