Sex linkage
Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome rather than a non-sex chromosome. Genes situated on the X-chromosome are thus termed X-linked, and are transmitted by both males and females, while genes situated on the Y-chromosome are termed Y-linked, and are transmitted by males only. As human females possess two X-chromosomes and human males possess one X-chromosome and one Y-chromosome, the phenotype of a sex-linked trait can differ between males and females due to the differential number of alleles possessed for a given gene. In humans, sex-linked patterns of inheritance are termed X-linked recessive, X-linked dominant and Y-linked. The inheritance and presentation of all three differ depending on the sex of both the parent and the child. This makes sex-linked patterns of inheritance characteristically different from autosomal dominance and recessiveness. This article will discuss each of these patterns of inheritance, as well as diseases that commonly arise through these sex-linked patterns of inheritance. Variation in these inheritance patterns arising from aneuploidy of sex chromosomes, sex-linkage in non-human animals, and the history of the discovery of sex-linked inheritance are briefly introduced.
Background
In humans, biological sex is determined by genetics. However this is not the case for all organisms. For instance, the biological sex of select reptiles is environmentally determined, and the sex of select worms is dependent on location.22 of the 23 pairs of human chromosomes are autosomal, while the 23rd pair of human chromosomes are the sex chromosomes. The possession of two X-chromosomes defines a biological female, while the possession of one X and one Y chromosome defines a biological male. The two sex chromosomes differ in size and gene content, and unlike the sets of autosomal chromosomes, are not homologous. The X-chromosome contains an estimated 1400 genes, most of which are involved in tissue development and the development of human disorders. The Y-chromosome is host to the SRY gene, which is involved in the development of several male sex characteristics, while the identified functions of many of the remaining approximately 200 genes on the Y-chromosome are associated with human disease. Sex linkage thus refers to the association of a trait encoded by one of the genes on these sex chromosomes. There are many more X-linked conditions than Y-linked conditions due to the larger size of the X-chromosome and greater number of genes encoded within it.
In classical genetics, a mating experiment called a reciprocal cross is performed to test if an animal's trait is sex-linked.
X-linked patterns of inheritance
A disease or trait determined by a gene on the X-chromosome demonstrates X-linked inheritance. Historically, X-linked inheritance has been divided into the patterns of X-linked dominant inheritance and X-linked recessive inheritance as synonymous with classical Mendelian inheritance of genes on autosomal chromosomes. However, more recently scholars have suggested the discontinuation of the use of the terms dominant and recessive when referring to X-linked inheritance, stating that the highly variable penetrance of X-linked traits in females as a result of mechanisms such as skewed X-inactivation or somatic mosaicism is difficult to reconcile with standard definitions of dominance and recessiveness.X-linked dominant inheritance
X-linked dominant inheritance is the pattern by which a trait encoded by an allele on the X-chromosome is passed down through generations, wherefore only one copy of that allele is sufficient for an individual to be affected. Unlike with X-linked recessive traits, females are more often affected by X-linked dominant traits than males as females have two X-chromosomes as opposed to one. Moreover, some X-linked dominant conditions are embryonically or neonatally lethal in hemizygous males, and thus can be seen to only affect heterozygous females, who experience less severe symptoms.Frequency and patterns of inheritance
In X-linked dominant inheritance, the transmission of the gene depends on the genotype of each of the parents. A mother heterozygous for an X-linked dominant trait will be affected, and half of her children will inherit her affected X-chromosome and be affected themselves, assuming an unaffected father. Of the children of a father affected by an X-linked dominant trait and an unaffected mother, all daughters will be affected, while no sons will be affected. A child affected by an X-linked dominant condition will always have at least one affected parent, and an affected son will always have an affected mother.X-linked recessive inheritance
describes one of the patterns of inheritance of genetic traits or disorders encoded by an allele situated on the X-chromosome. In X-linked recessive inheritance, females must have two copies of the allele, while males require only one copy of the allele to display the phenotype. Thus, it is far more common for males to be affected by X-linked recessive traits.A female heterozygous for an X-linked recessive trait is considered a carrier. While a carrier female most often does not display the phenotype, rare cases of skewed X-chromosome inactivation, can lead to varied levels of expression. This would occur when, during the normal process of inactivating half of a female's X-chromosomes, inactivation preferentially targets X-chromosomes inherited from a single parent, thus the remaining active X-chromosomes from the other parent are disproportionately expressed.
There are characteristic patterns for X-linked recessive inheritance. As each parent contributes one sex chromosome to their offspring, sons cannot receive the X-linked trait from affected fathers, who provide only a Y-chromosome. Consequently, affected males must inherit the X-linked recessive trait from their mothers. Sons of a healthy carrier female have a 50% change of being affected, while sons of an affected female will always be affected. Females must inherit a X-linked recessive allele from each parent. All daughters of an affected father and healthy non-carrier mother will be carriers. Daughters of an affected father and carrier mother will have a 50% chance of being affected, and daughters of two affected parents will always be affected. While there is no male-to-male transmission of X-linked recessive traits, an affected male can pass his recessive X allele to a grandson through his unaffected carrier daughter.
X-linked diseases
X-linked dominant diseases
- Aicardi syndrome
- Alport syndrome
- Coffin–Lowry syndrome
- Fragile-X syndrome
- Goltz syndrome
- Idiopathic hypoparathyroidism
- Incontinentia pigmenti
- Porphyria
- Rett syndrome
- Vitamin D resistant rickets
Alport syndrome
It is caused by inherited mutations in the COL4A3, COL4A4, and COL4A5 genes, which are responsible for producing type IV collagen. These mutations disrupt the formation of basement membranes, particularly in the kidneys, inner ears, and eyes, where this collagen network plays a key structural role. The specific gene affected determines the form of Alport syndrome: mutations in COL4A5 cause the X-linked form, while mutations in COL4A3 or COL4A4, located on chromosome 2, are associated with autosomal recessive or autosomal dominant forms.
Common signs and symptoms of Alport syndrome include hematuria, proteinuria, hearing loss, and eye abnormalities.
Diagnosis typically involves urine and blood tests, hearing and vision assessments, and genetic testing to confirm the mutation and identify the specific type of Alport syndrome. Kidney biopsy can reveal a characteristic 'basketweave' appearance of the glomerular basement membrane under electron microscopy. In some cases, skin or kidney tissue may be tested for the absence of type IV collagen proteins. Genetic testing is especially useful when biopsy is inconclusive or unavailable.
While there is no cure, treatments focus on slowing the progression of the kidney disease and managing symptoms. ACE inhibitors are commonly used to control blood pressure and reduce proteinuria. If kidney failure develops, dialysis or kidney transplant is often effective. Rarely, transplant recipients may develop anti-GBM disease due to antibodies against type IV collagen.
Fragile X syndrome
Fragile X syndrome is a genetic neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the FMR1 gene on the X chromosome. It is inherited in an X-linked dominant pattern and is the most common known inherited genetic cause of autism spectrum disorder. The condition affects approximately 1 in 3,600 males and 1 in 4,000 to 6,000 females.Fragile X syndrome occurs when the CGG repeat expansion exceeds 200 repeats, causing methylation and silencing of the FMR1 gene. This leads to a deficiency of FMRP, a protein essential for normal synaptic development and brain plasticity.
Fragile X syndrome typically presents with learning disabilities to severe intellectual impairment, along with distinct physical features such as a long face, large or protruding ears, flat feet, and low muscle tone. Many individuals, especially males, also exhibit behavioural traits including social anxiety, hyperactivity, hand-flapping, and self-injurious behaviors such as biting. Females, who have two X chromosomes, are generally less severely affected due to X-inactivation.
Diagnosis typically involves identifying a mutation in the FMR1 gene using polymerase chain reaction and Southern blot analysis to measure CGG repeat expansions and methylation status. Earlier cytogenetic methods, such as detecting "fragile sites" on the X chromosome, have largely been replaced due to low reliability, particularly in females. Early diagnosis is important to support timely intervention and genetic counseling.