What Are X-linked Recessive Disorders?

Introduction

X-linked recessive disorders are conditions that occur when a disease-causing (pathogenic) genetic variant found on the X chromosome is inherited. There are many different types of X-linked recessive disorders, ranging from red-green colourblindness to Duchenne and Becker muscular dystrophies and the blood clotting disorder, haemophilia. As people assigned male at birth (AMAB) have one X chromosome, they will be affected if they carry the recessive mutation. People assigned female at birth (AFAB) have two X chromosomes and are more likely to be unaffected but can remain a disease carrier if they have a mutation on a single X chromosome. This article will delve into the specifics of X-linked recessive inheritance, examples of such conditions and how they are diagnosed. 

X-chromosomes and Y-chromosomes

People AFAB have two X chromosomes. Each X chromosome is inherited from one parent. There are 867 known genes on the X chromosome that code for proteins and can carry mutations for certain disorders. People with AFAB will generally not show symptoms for X-linked recessive disorders, yet can be carriers for the disease. A carrier means the individual has one copy of the disease-causing mutation on one X chromosome but a normal copy on the other X chromosome; as such, they can pass genetic disease onto their children but remain asymptomatic themselves. Sometimes, people with AFAB have two copies of the mutation, which causes severe manifestations of the disease.¹

People AMAB have one X chromosome (inherited from the mother) and one Y chromosome (inherited from the father). The Y chromosome is smaller than the X chromosome and contains less genetic information. People with AMAB are more likely to inherit X-linked recessive disorders as a single copy of a mutated gene on the X chromosome is enough to have the condition. People with AMAB can only inherit these disorders from their mothers.¹

Inheritance pattern

Recessive inheritance means that to inherit the disease, one must inherit two copies of the mutated gene. When only one gene is abnormal, the disease does not occur, or the person will have milder symptoms.²

Inheritance with an affected person AMAB and an unaffected person AFAB

When the father (AMAB) has the condition, but the mother (AFAB) is unaffected, the children will be carriers if they are female and will be unaffected if they are male, as the Y chromosome that is passed onto AMAB children does not carry the abnormal gene.

Inheritance with an unaffected person AMAB and a carrier AFAB

Individuals AFAB that carry a disease-causing mutation on an X chromosome will have a 50% chance of passing the mutation onto their children. This is because one X chromosome will be passed down from the mother, and the other chromosome, which can be an X or a Y chromosome, will be passed down from the father. If the child is female, they will be a carrier or unaffected, and if the child is male, they will be affected or unaffected.²

Examples of X-linked recessive disorders

Red-green colour blindness

Red-green colour blindness is caused by mutations in genes on the X-chromosome that encode the red and green cones. Cones are specialised cells within the eye that allow colour vision (photoreceptors). There are three cones, each responsible for sensing different wavelengths of light corresponding to red, brown, and blue visible light wavelengths. People with red-green colour blindness have difficulty distinguishing between the two colours; defects on the X-chromosome can affect the pigment-sensing molecule opsin in either red or green cones. Red-green colour blindness mostly affects people AMAB.³

Haemophilia

Haemophilia A and B are X-linked recessive disorders that affect the process of blood clotting,  an essential process that stops bleeding during injuries. In response to bleeding from a cut or injury, clotting factors, together with platelets, form blood clots. However, in people with haemophilia, this process is impaired, causing prolonged bleeding. Haemophilia A is caused by a missing clotting factor VIII, while haemophilia B is caused by a missing clotting factor IX. As the condition is X-linked recessive, it usually affects people with AMAB. 

Duchenne muscular dystrophy

Duchenne muscular dystrophy causes muscle weakness, which worsens as the disease progresses. The disease is caused by mutations in genes on the X-chromosome that affect muscle function. Duchenne muscular dystrophy affects people with AMAB in childhood. People with the condition will generally only live into their 30s, as once the disease progresses, it can affect the muscles aiding breathing and heart function. 

Becker muscular dystrophy

Becker muscular dystrophy is another X-linked recessive condition that causes progressive muscle weakness. It is similar to Duchenne muscular dystrophy in symptoms and in the cause of the disease. Becker muscular dystrophy is less severe, beginning in late childhood. Life expectancy is less affected than in Duchenne muscular dystrophy.

X-linked ichthyosis

X-linked ichthyosis is a skin condition that is caused by mutations that cause a deficiency of steroid sulfatase, an enzyme that breaks down sulphates and regulates skin permeability. Ichthyosis causes dry, scaly, and rough skin all over the body. Ichthyosis usually begins from birth and affects mostly people AMAB.⁴

Rare X-linked recessive disorders

There are over 500 identified X-linked recessive disorders.² Some of these conditions occur in a small percentage of the population and are considered rare diseases. Here is a list of some rare X-linked recessive disorders:

• Adrenoleukodystrophy
• Alport syndrome
• Charcot-Marie-Tooth disease (X-linked types)
• Choroideremia
• Glucose-6-Phosphate Dehydrogenase Deficiency⁵
• Hunter Syndrome (mucopolysaccharide disease II)
• Lesch-Nyhan syndrome
• X-linked agammaglobulinemia⁶

Diagnosis  

Genetic testing

Diagnosis of X-linked recessive conditions involves taking a medical and family history, a clinical assessment, and genetic testing. Taking a family history of the disorder is important to identify the pattern of inheritance. A medical history will help to identify symptoms associated with a specific X-linked recessive condition. Genetic testing involves identifying mutations on the X-chromosome that increase the risk for the suspected condition.

Carrier screening

Carriers do not show symptoms of the disease. This means a condition can go undetected in a family for generations if only carriers and unaffected individuals are present. Genetic testing is crucial for identifying carriers in these cases. Carrier screening involves analysing a sample of DNA to check for mutations in the X-chromosome that are associated with specific conditions. 

People may want to consult a genetic counsellor to identify whether they are a carrier for an X-linked disorder to make informed decisions about family planning. In cases where parents are carriers, choosing to have prenatal testing may be beneficial to diagnose a condition before it shows symptoms.⁷

FAQs

What are examples of X-linked recessive disorders?

There are a range of diseases that are inherited in an X-linked recessive pattern. The following are some examples of these disorders: 

• Adrenoleukodystrophy
• Alport syndrome
• Becker muscular dystrophy
• Charcot-Marie-Tooth disease (X-linked types)
• Choroideremia
• Duchenne muscular dystrophy
• Glucose-6-Phosphate Dehydrogenase Deficiency
• Haemophilia
• Hunter Syndrome (mucopolysaccharide disease II)
• Lesch-Nyhan syndrome
• Red-green colour blindness
• X-linked agammaglobulinemia
• X-linked ichthyosis

Why do X-linked recessive disorders mostly affect people assigned male at birth (AMAB)?

X-linked recessive disorders mostly affect people with AMAB because they inherit only one X chromosome from their mother (AFAB). If that X chromosome carries the mutation, it lacks a second X chromosome to compensate for it. In contrast, individuals with AFAB have two X chromosomes, making it less likely for them to show symptoms as they would need mutations on both X chromosomes to manifest the disorder.

Summary

X-linked recessive disorders arise from mutations on the X-chromosome, predominantly affecting people AMAB. Individuals with AFAB generally do not show symptoms of these conditions despite being carriers. Examples include red-green colour blindness, haemophilia, Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked ichthyosis. Fathers AMAB cannot pass X-linked recessive disorders on to their children AMAB as they inherit the X-chromosome from their mother AFAB. Diagnosis of X-linked recessive disorders involves genetic testing with carrier screening, medical history, and family history. Consulting genetic counsellors helps with informed family planning, particularly when both parents are carriers.