The X Chromosome in Humans:

 

Humans generally have 46 total chromosomes, or 23 pairs. Each pair is numbered 1 through 22, and the last set is typically either a pair of X chromosomes or one X chromosome and one Y chromosome. Those with greater than or fewer than 46 chromosomes have one of many conditions classified as aneuploidy. Those with X-linked genetic disorders have a disease causing genetic change within the genes of one or more X chromosomes.

There are currently an estimated 533 identified disorders involving one or more of the 867 known genes on the X chromosome (1). The majority of X-linked disorders have a recessive inheritance pattern. This means that those with a single X chromosome that contains a pathogenic genetic change will have the disorder. However, if an individual with two X chromosomes has only one pathogenically altered X chromosome, often, the non-altered X chromosome can compensate for the altered copy. This is why those with a single X chromosome, including those with Turner syndrome, or X0, have higher rates of X-linked recessive disorders (1).

 

Assigned Sex At Birth

Either before or after birth, not all prospective parents choose, or are offered, genetic testing to screen their offspring’s chromosomes for unexpected results. For babies who have not had any genetic testing, their chromosomal picture is unclear, so they are assigned a sex at birth based on the outwardly visible appearance of the baby’s sex organs. For babies whose chromosomes are already known and have an expected appearance of the external sex organs are assigned either male or female at birth. Those with one X chromosome and one Y chromosome per cell have a genotype of XY and are Assigned Male at Birth (AMAB). Babies with genotypes of two X chromosomes per cell, XX, with matching external phenotypes are Assigned Female at Birth (AFAB). Those with X or Y chromosomal aneuploidies, as in unexpectedly greater or fewer than a pair of X chromosomes or one X and one Y chromosome may have different sex assignments at birth depending on their individual circumstances.

X and Y Chromosome Variations and X-Inactivation

Generally, people have either one or two X chromosomes. However, X or Y chromosome variations can lead to additional or fewer X or Y chromosomes than the typical XX or XY pattern (2). For those with more than one X chromosome, including typical XX inheritance patterns, X-inactivation ensures only one of the X chromosomes is functioning per cell. This process functions by randomly inactivating all but one X chromosome in each of the fewer than ten developing cells that form the embryo at this stage. One X chromosome is left fully functional, and one is completely inactivated, becoming a “Barr Body (1).” 

While X-inactivation is typically random, a phenomenon called skewed X-inactivation causes the process to be non-random, showing preferential activation of one of the two inherited X chromosomes. Skewed X-inactivation can contribute to increased expressivity of symptoms in carriers of X-linked diseases; if a healthy X chromosome is preferentially inactivated, then the X chromosome with the pathogenic change is expressed in more body cells, often meaning an increase in disease symptoms (3).

X-Linked Disorders:

X-Linked Inheritance

Spontaneous Genetic Changes

X-linked disorders can also occur from spontaneous changes of a gene or genes in the X chromosome. Spontaneous changes to the DNA are called de novo genetic changes. These genetic changes typically occur due to mistakes in DNA repair, replication, or recombination, and can add about 70 new changes per generation. Thankfully, the majority of these changes are not actually disease-causing. However, some X-linked disorders do occur through de novo changes in the DNA, including Hemophilia A and X-linked related Charcot-Marie-Tooth disease (1).

A person with one altered (pathogenic) copy and one healthy copy is often called a “carrier.” There are both asymptomatic carriers, meaning they show no symptoms of the disorder, and expressive carriers, also called manifesting carriers, who experience symptoms of the disorder. Generally, expressive carriers have less severe symptoms than typical of someone who has fully inherited the X-linked disorder themselves. However, some conditions like DMD-Associated Cardiomyopathy, or DCM, can occur in individuals with X0 or XX chromosomes who have an alteration on an X chromosome known to cause Becker or Duchenne Muscular Dystrophy (BMD or DMD)(19).

There is a one-in-two chance that a person with an altered X chromosome will pass their altered X chromosome to their offspring, meaning that there is a 50% chance that an XY child will inherit the X-linked disorder, and a 50% chance that XX children will be carriers, or possibly manifesting carriers. 

Family members who carry genetic variants often feel a sense of guilt about passing down a genetic condition. It is important to keep in mind that passing along an altered X chromosome is no one’s fault; there is nothing that either partner could or could not have done during the pregnancy to reduce this risk. 

Very rarely, X-linked disorders can display a dominant inheritance pattern. This means that those with a single altered copy of a gene on the X chromosome will have the disease. In contrast to X-linked recessive disorders, X-linked dominant disorders are more common in those with two X chromosomes. These typically present with less severe expressions of symptoms than the symptoms seen in individuals with a single pathogenically altered X chromosome. The absence of X-linked dominant conditions in those with a single X chromosome is often because some genetic changes to the X chromosome are fatal to either the embryo or fetus during development without a second healthy chromosome to compensate. 

 

Common X-linked Disorders:

The prevalence of X-linked disorders ranges from relatively common to extremely rare. The majority display a recessive inheritance pattern and have a neonatal, childhood, or adolescent onset. Each disorder has varying degrees of expressivity experienced by carriers. 

Common X-linked Recessive Disorders:

Common X-linked Dominant Disorders:

 

Written by Abigail Sayers; Images by Abigail Sayers unless otherwise noted

Reviewed and Edited by Rachel Baer, MSc, and Andy McCarty, MS, LGC, CGC

Citations

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