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Sex Linked Inheritance

Transmission Patterns in Disorders of X-Linked Inheritance

graphic representation of X-linked inheritance Image courtesy of Microbe Notes Opens in new window

All sex-linked diseases are disorders of X-linked inheritance. In medical genetics, genes on the X chromosome are identified as X-linked, whereas those on the Y chromosome are Y-linked.

There are many X-linked genes; approximately 1100 genes are thought to be located on the X chromosome, of which approximately 40% are presently known to be associated with disease phenotypes.

However, there is limited evidence for Y-linked genes save for determinants that dictate male differentiation. The only characteristic that may be located on the Y chromosome is the attribute of hairy ears, which is not altogether devastating.

Because males have one X chromosome but females have two, there are only two possible genotypes in males and three in females with respect to a mutant allele at an X-linked locus.

A male with a mutant allele at an X-linked locus is “hemizygous” for that allele, whereas females may be “homozygous” for either the wild-type or mutant allele or may be heterozygous.

For example, if XH is the wild-type allele for the gene for coagulation factor VIII and a mutant allele, Xh, causes hemophilia A, the genotypes expected in males and females would be as follows:

GenderGenotypesPhenotypes
MalesHemizygous XHUnaffected
Hemizygous XhAffected
FemalesHomozygous XH/XHUnaffected
Heterozygous XH/XhUnaffected (usually)
Homozygous Xh/XhAffected

Males can transmit X-linked genes to their daughters but not to their sons, and sons can receive X-linked genes only from their mothers.

Female offspring can be either homozygous or heterozygous for X-linked genes because of their dual X chromosomes. Males, on the other hand, are hemizygous for X-linked genes, because they have only one X chromosome.

X-linked inheritance in females is influenced by X-chromosome inactivation Opens in new window. In all of a woman’s somatic cells (but not in her germ cells), one of the two X chromosomes is inactivated, although about 15% of genes on the inactive X remain active.

The inactive X is reactivated in the oogonium, so that with gametogenesis the woman produces only ova with two active X chromosomes.

The inactivated X is random in each cell—it could be the X that the zygote received from the mother or the one it received from the father—and the same X is inactive in all descendants of that cell.

Exceptions to the random inactivation are seen in some single gene disorders such as Duchenne muscular dystrophy Opens in new window, in which the normal X tends to be the active one. Table X1 summarizes characteristics of X-linked inheritance.

X-Linked Recessive Inheritance

In males, an X-linked recessive gene is always expressed, because there is no corresponding gene on the Y chromosome.

In females, recessive genes of this nature are usually expressed only when the recessive allele is present in the homozygous form (i.e., on both of the woman’s X chromosomes). Occasionally a female may demonstrate the trait secondary to the random inactivation of one of the X chromosomes in each cell.

The degree to which this individual expresses the trait depends on the proportion of cells in which the X with the dominant gene has been inactivated. The larger the proportion is, the greater the likelihood that the X-linked trait will be visible.

Examples of X-linked recessive inheritance Opens in new window include hemophilia Opens in new window, color blindness Opens in new window, and Duchenne muscular dystrophy Opens in new window.

X-Linked Dominant Inheritance

In this type of inheritance, the trait will be demonstrated in both males and females. Who will be affected and to what degree depend on the genotype of the parents.

All the daughters of an affected father will receive the X chromosome with the dominant gene and will express the disease. However, none of the sons of this father will be affected.

When the mother is heterozygous and the father is not affected, the probability is 50% that offspring will be affected.

If the mother is homozygous, the probability is 100% that children of either gender will be affected.

If the father is also affected, the daughters will be homozygous for the disease.

X-linked dominant disorders are rare; an example is X-linked hypophosphatemia, or vitamin D-resistant rickets.

Table X1 | Major Characteristics in Disorders of X-Linked Recessive– & X-Linked Dominant Inheritance
X-Linked Recessive InheritanceX-Linked Dominant Inheritance
The mutant gene is on the X chromosome.The mutant gene is located on the X chromosome.
One copy of the mutant gene is needed for phenotypic effect in males.One copy of the mutant gene is needed for phenotypic manifestation.
Two copies of the mutant gene are usually needed for phenotypic effect in females.X inactivation modiefies the gene effect in females.
Males are more frequently affected than females. Often lethal in males and so may see transmission only in female line.
Table X1 Continues
X-Linked Recessive InheritanceX-Linked Dominant Inheritance
Unequal X inactivation can lead to manifesting heterozygote female carriers.Affected families show excess of female offspring.
Transmission is often through heterozygous (carrier) females.Affected male transmits gene to all his daughters and none of his sons.
All daughters of affected males are carriers.Affected males have affected mothers (unless it is a new mutation).
All sons of affected males are normal.There is no male-male transmission
There is no male-male transmission.There is no carrier state.
There may be fresh gene mutations.Disorders are relatively uncommon.
Adapted from Lashley, F.R. (1998). Clinical genetics in nursing practice (2nd ed.). New York: Springer.

Y-Linked Inheritance

Because only males have Y chromosomes and there is no corresponding allele on the X chromosome, these traits occur only in males.

If a Y-linked trait is present, it will be expressed. There is no dominance or recessiveness.

When a father with a Y-linked chromosome transfers genetic material, all the sons will be affected and non of the daughters will.

The Y chromosome also contains at least 12 testes-determining genes that control gonad development and spermatogenesis.

  1. Thompson & Thompson Genetics in Medicine E-Book By Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard
  2. Maternal, Fetal, & Neonatal Physiology4: Maternal, Fetal, & Neonatal Physiology By Susan Tucker Blackburn
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