Chicago Center for Jewish Genetics Disorders - About Jewish Genetic Disorders?

X-linked Recessive Inheritance
(Sex-Linked Inheritance)

Humans contain 22 pairs of chromosomes, called autosomes, and one pair of sex chromosomes: X and Y for men and X and X for women. A gene that is "X-linked" is physically located on the X-chromosome. For recessive inheritance, a person will be unaffected by a disorder as long as they have one functional copy of a gene present even if the other copy is not functioning. With X-linked disorders, when there is a mutated gene on the X-chromosome, men will be affected because they have only one copy of the X chromosome, or are Hemizygous, and have no "back-up" copy (to make the protein product required by the body). Women who have one mutated copy of the gene are unaffected carriers because their one functional copy acts as a "back-up" to the non-functional one, and produces the necessary protein product.

Males receive their Y chromosome from their father (which makes them male) and their X chromosome from their mother. Females receive an X chromosome from both parents. Depending upon which parent transmits the defective gene, very different possibilities can result for affected children (unlike autosomal dominant or autosomal recessive inheritance).

If a man is affected with an X-linked recessive disorder, he will give his mutated copy of the gene to all of his daughters and none of his sons. This is because his daughters receive his X-chromosome (which has the mutated gene) and his sons receive his Y-chromosome. Therefore, all of his daughters will be carriers and none of his sons will be affected. His daughters may have affected sons, but his sons will not have any affected descendents because they do not have a mutated copy to transmit.

If a woman carries a gene for an X-linked recessive disorder (ie. One of her copies of the gene is mutated and the other copy is normal), she will pass the mutated copy of the gene onto half of her sons and half of her daughters. On average, half of her sons would be affected and half of her daughters would be carriers.

It is possible (but highly unlikely that a woman) would be homozygous recessive for an X-linked disorder (and thus be affected by it). In this case, all of her sons would be affected and all of her daughters would be carriers.

Examples of X-linked recessive traits are color-blindness, hemophilia, and G6PD deficiency.

Manifesting Female Carriers

Woman occasionally are manifesting carriers of a X-linked recessive disorder, which means that they are affected although they have only one mutated copy of the gene. This is also called "skewed Lyonization" or "skewed X-inactivation."

In order to understand this, it is important to remember that women have two X chromosomes and men have only one. There are close to a thousand genes on the X chromosome that encode proteins necessary for the functioning of the body. These genes are important to both men and women. Both men and women normally make the same amount of protein product from these genes. In order for women, who have two X-chromosomes, to produce the same amount of protein as men who only have one X-chromosome, a process, called X-inactivation, occurs in the female body during early embryonic development. This embryological process occurs in every female.

The process permanently inactivates or blocks gene expression from one of the two X-chromosomes in every cell of her body. Which of the two X-chromosome becomes inactivated ("shut down") in each cell is completely random. For a female carrier of a mutated X gene, it is expected that 50% of her cells will have a functional copy of that gene on the active X-chromosome and 50% will have a mutated copy of that gene on the active X-chromosome, just by random X-inactivation. We can look at this a different way by using the example of a coin toss. When a coin is flipped there is a 50-50 chance that it will land "heads" up. In other words, we expect it to land "heads" up in about 50% of the flips, and "tails" up the other 50% of flips. Thus, due to this randomness, female carriers are usually unaffected by X-linked recessive disorders since on average half of their cells are making the necessary protein product, and this is usually sufficient to prevent disease symptoms.

Random X-Inactivation

Occasionally, the inactivation process may be skewed and a woman may have a larger than average proportion of her cells with the mutated gene on the active X-chromosome. This may result in signs of the disorder because she would not be producing enough of the protein necessary for the body's normal functioning, and she would be referred to as a manifesting female carrier. Using the coin toss example again, this would be similar to having 9 tails out of 10 coin tosses, or a skewed result. An example of how this might affect a disease process is seen in G6PD Deficiency.

X-linked Recessive Inheritance(Sex-Linked Inheritance)

X-linked Recessive Inheritance
(Sex-Linked Inheritance)