Table of Contents
Overview of X-linked Recessive Inheritance
In X-linked recessive disorders, the disease-causing gene is located on the X chromosome and is recessive to the normal allele on that chromosome. Because humans have a chromosomal sex-determination system (females: XX, males: XY), this leads to characteristic patterns:
- Males (XY)
- Have only one X chromosome.
- A single mutant allele on their X is sufficient to cause the disease: they are hemizygous and therefore usually affected.
- Females (XX)
- Have two X chromosomes.
- Usually need two copies of the mutant allele (one on each X) to be affected.
- With only one mutant allele, they are typically carriers (heterozygous) and usually symptom-free or only mildly affected.
In a simplified notation:
- Normal allele on X: $X^\text{N}$
- Mutant allele on X: $X^\text{m}$
- Y chromosome: $Y$
Examples:
- Normal male: $X^\text{N}Y$
- Affected male: $X^\text{m}Y$
- Carrier female: $X^\text{N}X^\text{m}$
- Affected female: $X^\text{m}X^\text{m}$
Complete, clinically obvious X-linked recessive disorders in females are rare because they require either:
- An affected father and a carrier or affected mother, or
- Particular chromosomal situations (e.g., Turner syndrome, $45,X$) or extreme skewing of X-inactivation.
Typical Pedigree Characteristics
X-linked recessive traits show some characteristic family patterns:
- Predominantly males affected
- Many more affected males than females in a pedigree.
- No father-to-son transmission
- An affected man passes his Y chromosome to his sons, not his X.
- Therefore, he cannot directly transmit an X-linked recessive disorder to his sons.
- Transmission through unaffected carrier females
- Affected males often have mothers (and sometimes maternal grandfathers) who are carriers.
- The disorder can appear to “skip” generations if only carrier females are present.
- All daughters of affected males are carriers (if the mother is unaffected)
- Affected male $X^\text{m}Y$ × normal female $X^\text{N}X^\text{N}$:
- All daughters: $X^\text{N}X^\text{m}$ (obligate carriers)
- All sons: $X^\text{N}Y$ (unaffected)
- Carrier mothers have affected sons with a characteristic probability
- Carrier female $X^\text{N}X^\text{m}$ × normal male $X^\text{N}Y$:
- Sons: 50% $X^\text{N}Y$ (unaffected), 50% $X^\text{m}Y$ (affected)
- Daughters: 50% $X^\text{N}X^\text{N}$ (unaffected, not carriers), 50% $X^\text{N}X^\text{m}$ (carriers)
These patterns help distinguish X-linked recessive inheritance from autosomal recessive and X-linked dominant forms.
Genetic Crosses and Risk Calculations
Using simple crosses, we can determine the risk to children in typical situations.
1. Carrier Mother × Normal Father
Mother: $X^\text{N}X^\text{m}$
Father: $X^\text{N}Y$
Possible children (each combination has equal probability):
- Daughters:
- $X^\text{N}$ (from mother) + $X^\text{N}$ (from father) → $X^\text{N}X^\text{N}$ (unaffected, non-carrier)
- $X^\text{m}$ (from mother) + $X^\text{N}$ (from father) → $X^\text{N}X^\text{m}$ (carrier)
- Sons:
- $X^\text{N}$ (from mother) + $Y$ (from father) → $X^\text{N}Y$ (unaffected)
- $X^\text{m}$ (from mother) + $Y$ (from father) → $X^\text{m}Y$ (affected)
If we consider all children:
- 25% unaffected daughters
- 25% carrier daughters
- 25% unaffected sons
- 25% affected sons
In counseling, the risks are typically mentioned separately for sons and daughters:
- Each son has:
- 50% risk to be affected
- 50% chance to be unaffected
- Each daughter has:
- 50% risk to be a carrier
- 50% chance to be non-carrier and unaffected
2. Affected Father × Normal Mother
Father: $X^\text{m}Y$
Mother: $X^\text{N}X^\text{N}$
- Daughters:
- $X^\text{N}$ (from mother) + $X^\text{m}$ (from father) → $X^\text{N}X^\text{m}$ (carrier)
- Sons:
- $X^\text{N}$ (from mother) + $Y$ (from father) → $X^\text{N}Y$ (unaffected)
Results:
- All daughters are carriers, none are affected.
- All sons are unaffected and not carriers.
3. Carrier Mother × Affected Father
Mother: $X^\text{N}X^\text{m}$
Father: $X^\text{m}Y$
Possible children:
- Daughters:
- $X^\text{N}$ (from mother) + $X^\text{m}$ (from father) → $X^\text{N}X^\text{m}$ (carrier)
- $X^\text{m}$ (from mother) + $X^\text{m}$ (from father) → $X^\text{m}X^\text{m}$ (affected)
- Sons:
- $X^\text{N}$ (from mother) + $Y$ (from father) → $X^\text{N}Y$ (unaffected)
- $X^\text{m}$ (from mother) + $Y$ (from father) → $X^\text{m}Y$ (affected)
Among daughters:
- 50% carriers, 50% affected
Among sons:
- 50% unaffected, 50% affected
This is one of the few situations where female patients with an X-linked recessive disease are relatively common in a family.
Biological Basis for the Sex Difference
Two main biological features create the typical X-linked recessive pattern:
- Hemizygosity in males
- Males have one X and one Y.
- If the single X carries a mutant allele, there is no second allele to compensate.
- Result: phenotype directly reflects that one allele.
- X-inactivation in females (Lyonization)
- In each somatic cell of a female, only one X chromosome is active; the other is largely inactivated and forms a Barr body.
- This inactivation is random early in development:
- Some cells inactivate the maternal X
- Others inactivate the paternal X
- In a heterozygous female $X^\text{N}X^\text{m}$, this produces a mosaic of cells:
- Some cells express the normal allele
- Some express the mutant allele
Usually, the presence of many normal-expressing cells is enough to prevent full-blown disease. However, if X-inactivation is skewed, so that many more cells inactivate the X with the normal allele, a carrier female may show noticeable or even severe symptoms.
Examples of X-linked Recessive Disorders
Many well-known hereditary diseases follow an X-linked recessive pattern. Only typical features are summarized here; detailed molecular bases and pathophysiology belong to other chapters.
Hemophilia A and B
- Cause
- Hemophilia A: Deficiency or dysfunction of coagulation factor VIII (gene on Xq28).
- Hemophilia B: Deficiency or dysfunction of coagulation factor IX (gene on Xq27).
- Inheritance
- Classic X-linked recessive.
- Affected males usually have:
- Carrier mothers
- Often maternal grandfathers with the disease.
- Clinical core features
- Increased bleeding tendency:
- Deep muscle hematomas
- Joint bleeding (hemarthroses)
- Prolonged bleeding after injuries or surgery
- Female carriers
- Usually asymptomatic, but some have:
- Slightly prolonged bleeding times
- Heavy menstrual bleeding
- Symptomatic carriers often show skewed X-inactivation.
Duchenne and Becker Muscular Dystrophy
- Cause
- Mutations in the dystrophin gene on the X chromosome.
- Duchenne: near complete loss of functional dystrophin (severe).
- Becker: reduced or partially functional dystrophin (milder).
- Key features
- Progressive muscle weakness, mainly in boys.
- Duchenne:
- Onset in early childhood
- Loss of ability to walk usually before adolescence
- Becker:
- Later onset and slower progression.
- Inheritance pattern
- Affected boys typically born to carrier mothers; new mutations are also relatively common due to large gene size.
- Female carriers
- May show mild muscle weakness or elevated muscle enzymes in blood.
- Rarely, due to skewed X-inactivation, more severe symptoms.
Red–Green Color Blindness (Red–Green Color Vision Deficiency)
- Cause
- Mutations or rearrangements in opsin genes for red and green photopigments on the X chromosome.
- Features
- Difficulty distinguishing red and green hues.
- Most affected individuals are male.
- Population frequency
- Very common in some populations:
- Around 8% of men of European descent
- Much lower percentages of affected women
- Carrier females
- Often normal color perception, but subtle testing may reveal differences.
G6PD Deficiency
- Cause
- Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in red blood cells; gene on the X chromosome.
- Features
- Usually asymptomatic until red blood cells are exposed to certain triggers:
- Specific drugs
- Certain infections
- Favism (broad beans)
- Can cause acute hemolytic anemia.
- Inheritance
- X-linked recessive, but due to high frequency in some regions, affected females can also occur.
Other Examples
Other classical X-linked recessive disorders include:
- X-linked agammaglobulinemia (defect in B-cell maturation)
- Hunter syndrome (mucopolysaccharidosis type II)
- Some forms of X-linked intellectual disability
Each has its own specific gene defect and clinical picture, but the inheritance pattern is similar.
Female Manifestations and Special Cases
Although X-linked recessive disorders mainly affect males, several situations can make females more clearly affected:
- Homozygous mutation ($X^\text{m}X^\text{m}$)
- Possible if:
- Father is affected ($X^\text{m}Y$) and mother is at least a carrier ($X^\text{N}X^\text{m}$) or affected.
- Rare in most populations.
- Turner syndrome (45,X)
- A female with only one X and no second X to provide a normal allele.
- If the single X carries a mutant allele, she will be affected similarly to a male.
- Skewed X-inactivation
- As mentioned above, if most cells inactivate the X with the normal allele, the mutant allele is functionally dominant in tissues.
- The clinical picture can approach that of a fully affected individual.
- Structural abnormalities of the X chromosome
- Deletions, unbalanced translocations, or complex rearrangements can change which X is inactivated, sometimes favoring inactivation of the structurally normal X.
Applications: Genetic Counseling and Testing
Understanding X-linked recessive inheritance has practical implications in families where such a disease is known or suspected.
Risk Assessment in Families
Key steps:
- Pedigree analysis
- Identify affected males.
- Determine maternal lineage.
- Look for absence of father-to-son transmission.
- Identify obligate carriers (e.g., all daughters of an affected male and a normal mother).
- Carrier risk estimation
- For a woman with an affected brother and unaffected parents:
- The mother is likely a carrier.
- The woman’s own carrier risk can be estimated assuming Mendelian segregation.
- For a daughter of an affected male and non-carrier mother:
- Carrier risk is essentially 100%.
- Recurrence risks
- Example: Carrier mother, normal father:
- Each pregnancy:
- 25% affected son
- 25% unaffected son
- 25% carrier daughter
- 25% non-carrier daughter
- These probabilities help couples make informed reproductive decisions.
Molecular Diagnostics
For many X-linked recessive disorders, the specific gene and common mutations are known. This makes possible:
- Carrier testing
- To confirm whether a woman is a carrier.
- Prenatal diagnostics
- Examination of fetal DNA for known family mutations.
- Consideration of fetal sex (since only males are usually affected).
- Preimplantation genetic testing (PGT)
- Testing embryos created via in vitro fertilization before transfer to the uterus.
The decision to use these methods involves medical, ethical, cultural, and personal considerations and is typically accompanied by genetic counseling.
Population Aspects and Evolutionary Considerations
Some X-linked recessive mutations persist at relatively high frequency in human populations, despite causing disease:
- New mutations
- Large genes on the X chromosome (e.g., dystrophin) have a high mutation rate.
- Many affected males in each generation represent new mutations rather than inherited alleles.
- Heterozygote advantage (possible in some cases)
- For G6PD deficiency, there is evidence that carriers or mildly affected individuals may have partial protection against severe forms of malaria.
- Such advantages can help maintain the mutation in populations where malaria is or was common.
- Sex-linked selection
- Because the X chromosome is present in two copies in females but only one in males, selection acts differently on X-linked alleles compared to autosomal ones.
- Deleterious recessive alleles are more efficiently exposed and removed in males, but can “hide” in carrier females.
Understanding these dynamics helps explain why some X-linked recessive diseases are common while others are very rare.
Distinguishing X-linked Recessive from Other Inheritance Patterns
In practice, an observed family pattern must often be distinguished from:
- Autosomal recessive inheritance
- Both males and females affected equally.
- Affected individuals often born to unaffected carrier parents.
- Father-to-son transmission is possible.
- X-linked dominant inheritance
- Both sexes can be affected, but:
- Affected fathers transmit the disease to all daughters and no sons.
- Affected females often have about half of their children affected, regardless of sex.
- Affected females are generally more frequent than males.
Clues favoring an X-linked recessive explanation include:
- A clear excess of affected males.
- No father-to-son transmission.
- Carrier females in the maternal line.
- Obligate carrier daughters of affected men.
Recognizing these features is crucial for correct diagnosis, family counseling, and planning of genetic testing.