Fragile X syndrome (FXS) results from changes in the FMR1 gene, causing a deficiency in fragile X mental retardation protein (FMRP). This deficiency leads to intellectual disabilities, which typically present more severely in people assigned male at birth (AMAB) than people assigned female at birth (AFAB).

Overview

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, with a prevalence worldwide of approximately 1 in 4000 AMAB people and 1/5000-8000 AFAB people. It occurs more frequently in AMAB people due to its X-linked genetic nature. FXS is usually associated with cognitive dysfunction (language delay, learning difficulties), social and behavioural problems, autism, neurological problems (abnormal sleep patterns and seizures) and a characteristic physical appearance which becomes more noticeable with age.

The syndrome arises from the loss of a protein called fragile X mental retardation protein (FMRP), necessary for brain development. This loss results from the expansion of a specific sequence of “chemical letters”, known as the CGG-repeat motif, in the FMR1 gene on the X chromosome, occurring more than 200 times. This expansion leads to gene hypermethylation, a process where DNA accumulates more methyl groups (-CH3) than usual, resulting in the “turning off” of the FMR1 gene and with the consequent absence of FMRP, which leads to the syndrome.

This repeat expansion is observed in over 99% of affected individuals, whilst individuals unaffected by the condition typically have 6–44 CGG repeat motifs. Carriers of FXS have a CGG repeat between 55 and 200, referred to as a premutation.  Rare genetic changes (mutations) in the FMR1 gene that result in non-functional X mental retardation protein (FMRP) have also been associated with FXS.^1,2 

This article describes how both AMAB and AFAB people can pass on the mutated gene carried on the X chromosome to their children, as well as how the disorder is diagnosed, including prenatal screening methods.

How is fragile X syndrome inherited?

The American College of Medical Genetics and Genomics categorises FMR1 genetic variations (alleles) into four groups based on the number of CGG repeats. Each individual is assigned to one of the four groups listed below, depending on the number of CGG repeats in their FMR1 gene. The number of CGG repeats within an individual can be determined by a blood test prescribed by a healthcare provider or genetic counsellor. Individuals with different numbers of CGG repeats carry varying risks of developing fragile X-associated disorders and of having children with FXS.

In a person assigned female at birth (AFAB), there are typically two copies of the FMR1 gene, one on each of their two X chromosomes. The number of CGG repeats on each copy of the FMR1 gene usually differs. The group an AFAB person falls in is determined by the FMR1 gene with the highest number of CGG repeats. A person assigned male at birth's (AMAB) genetic classification is determined by the number of CGG repeats found in the sole copy of the FMR1 gene on their single X chromosome.

Group 1: 5 to 44 repeats (normal)

Most individuals, both AMAB AND AFAB, typically have about 5 to 44 CGG repeats in their FMR1 gene. This number falls within the normal range of repeats, indicating that individuals in this group do not have fragile X syndrome and do not have an elevated risk of passing FXS to their children.

Group 2: 45 to 54 repeats (intermediate)

Individuals in this category, with an intermediate number of repeats (45 to 54), do not have FXS and do not face a risk of having children with FXS. However, they may be slightly more prone to experiencing certain symptoms related to other fragile X-associated disorders and may pass the slightly elevated risk of having these disorders to their children.

Group 3: 55 to 200 repeats (premutation)

Individuals with 55 to 200 repeats are described as having a “premutation” in the FMR1 gene. They do not present with the syndrome, but they may be susceptible to or develop other fragile X-associated disorders in the future. In addition, premutation carriers can have children with a premutation or full mutation (FXS). Yet, the probability of having a child with a premutation or full mutation varies between people harbouring a premutation as explained below.

The repeat count in the egg cells of an AFAB person with a premutation can progress from the premutation range (55 to 200 repeats) to exceeding 200 repeats, transitioning into the full mutation range. Consequently, an AFAB person with a premutation can transmit a full mutation. The greater the number of CGG repeats in an AFAB person with a premutation, the higher the likelihood that their child will inherit an FMR1 gene with a full mutation, resulting in FXS.

With every pregnancy, an AFAB person carrying a premutation in one of their FMR1 genes has a 50% chance of passing either the premutation or a full mutation to their child (regardless of the child’s sex) and a 50% chance of not transmitting either the premutation or the full mutation.

An AMAB person with the premutation will transmit their premutation to their AFAB children, but not to their AMAB children. An AMAB person carrying a premutation will not transmit a full mutation to any of their children.

Group 4: More than 200 repeats (full mutation, FXS)

Individuals with a full mutation (more than 200 repeats) develop FXS. With each pregnancy, AFAB people have a 50% chance of transmitting the syndrome to their children (irrespective of sex at birth).

Do carriers of FXS face any health risks?

Individuals who are potential carriers have a higher risk of:

• Premature menopause (before the age of 40)
• High blood pressure (hypertension)
• Dementia
• Depression
• Migraines
• Anxiety
• Hypothyroidism
• Sleep apnoea
• Chronic pain

How is fragile X syndrome diagnosed? 

FXS can be diagnosed by analysing the sequence of a person’s DNA obtained from a blood test through molecular genetic testing. However, diagnosing the syndrome is challenging, primarily because detecting genetic variations with large repeat numbers has, until recently, been either time-consuming or unreliable.³ 

Testing also can be done to identify changes in the FMR1 gene that may result in fragile X-associated disorders such as fragile X-associated primary ovarian insufficiency and fragile X-associated tremor/ataxia syndrome.

Is prenatal testing an option?

Prenatal screening involves pregnant people to determine if they are carriers of a premutation during pregnancy, and possibly also undergoing foetal testing if they are identified as carriers.

Pregnant people may undergo the following prenatal tests as recommended by a genetic counsellor:

• Amniocentesis: A healthcare provider collects a sample of the amniotic fluid for testing
• Chorionic villus sampling: A healthcare provider collects a cell sample of the placenta for testing

Summary 

Fragile X syndrome is an X-linked genetic disorder with variable expression in AMAB and AFAB individuals, impacting around 1 in 4000 AMAB people and 1 in 5000-8000 AFAB people worldwide. It predominantly affects males due to its X-linked genetic characteristics. FXS is associated with cognitive, social, and behavioural challenges, along with physical traits that become more evident with age.

The condition arises from the absence of fragile X mental retardation protein (FMRP), which is crucial for brain development. This absence results from an expansion of a trinucleotide repeat( a specific DNA sequence known as the CGG-repeat motif) in the FMR1 gene, occurring more than 200 times, which then causes gene hypermethylation and “silencing”. Over 99% of affected individuals exhibit this repeat expansion, while unaffected individuals typically have 6–44 repeats. Carriers of FXS possess between 55 and 200 repeats, known as a premutation.

Rare mutations in the FMR1 gene leading to non-functional FMRP have also been linked to FXS. Diagnosis involves molecular genetic testing of DNA obtained from a blood sample, although it poses challenges due to the difficulty in detecting large repeat numbers. Prenatal screening options are available for carriers, including amniocentesis and chorionic villus sampling, allowing for early detection.