Fragile X Syndrome Inheritance Pattern
Fragile X syndrome (FXS) is a rare hereditary disorder transmitted from parent to child. FXS is the known leading cause of inherited intellectual disability and the leading single-gene cause of autism spectrum disorder (ASD).
What Causes Fragile X Syndrome?
Fragile X syndrome is a single-gene disorder caused by the full mutation of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene located on the X chromosome. This gene helps produce Fragile X RNA-binding protein (FMRP), which plays a crucial role in brain development and the biological mechanisms involved in learning and memory. 1
The FMR1 gene has a “CGG repeat” segment of DNA, representing the combination of the cytosine, guanine and guanine building blocks of the DNA, that are repeated many times. This DNA region is normally duplicated less than 45 times in unaffected individuals.2 However, in individuals with FXS, the CGG segment is repeated over 200 times, much larger than the normal range. The abnormally enlarged CGG segment silences (inactivates) the FMR1 gene, preventing the gene from creating sufficient amounts of FMRP the body requires.2
Each person may fall into one of the following groups based on the number of CGG repeats in their FMR1 gene:2
- Normal (below 44 repeats) – Most people have around five to 44 CGG repeats in their FMR1 gene. This is considered a normal range of repeats, and people within this range do not have FXS and are not carriers of the mutated FMR1 gene.
- Intermediate (45 to 54) – People with an intermediate number of CGG repeats do not have FXS and are not at risk of having children with FXS. However, they may have a slightly higher chance of having some symptoms related to other Fragile X-associated disorders and may pass the slightly higher chance of having these disorders to their children.
- Premutation (55 to 200) – People with 55 to 200 CGG repeats are regarded as premutation carriers of the FMR1 gene. Although these individuals do not have FXS, they risk developing othe Fragile X-associated disorders and having children with an FMR1 gene premutation or full mutation (FXS). Females with premutation are more likely to develop Fragile X Premature
- Ovarian Insufficiency (FXPOI), which results in an early onset of menopause. Males and females with a premutation are at risk for developing Fragile X-associated Tremor/Ataxia syndrome (FXTAS), a condition that can manifest in late adulthood and is characterized by neurological difficulties such as tremors and balance and coordination difficulties.
- Full mutation (Above 200 repeats) – People with more than 200 CGG repeats have a full mutation of the FMR1 gene, indicating Fragile X syndrome. Males with a full mutation will likely experience many symptoms of FXS, whereas females with a full mutation will generally exhibit fewer symptoms.As females with FXS may demonstrate minimal behavioral and cognitive symptoms, these females may frequently be detected through genetic diagnosis after another family member has been diagnosed with the condition.3
How Is Fragile X Syndrome Inherited?
Fragile X syndrome is passed down from parent to child through a gene mutation in their sex chromosome X. Among those affected by FXS, males are more likely to be severely impacted than females. This is because males possess a single X chromosome (XY), and females possess two X chromosomes (XX). Therefore, if males inherit their mother’s fully mutated X chromosome, their only X chromosome is affected. On the other hand, females may be able to compensate for the consequences of the mutated X chromosome by carrying an intact X chromosome.4
Those born to mothers with the Fragile X mutation have a one-in-two chance of inheriting the disorder. These children will either inherit the abnormal gene and become Fragile X carriers or experience the effects of the full mutation FXS. The male premutation carrier’s daughters will inherit the FMR1 premutation, but none of his sons will. The daughters will be carriers but will not develop FXS themselves.5, 6
It’s important to note that a father can only pass on the premutation form of the FMR1 gene to his daughters, not the full mutation. Even if the father has a full mutation of the FMR1 gene, it appears that the sperm can only carry the premutation. Scientists still don’t understand how or why fathers can only pass on the premutation to their daughters; thus, it remains an area of focused research.6
In addition, having one child with the FMR1 mutation does not increase or decrease the likelihood of having another child with the altered gene. Further, having one child with mild symptoms does not mean the other child will have severe symptoms or vice versa. However, researchers have identified that Fragile X premutation passed on by mothers can expand to the full mutation range with each successive generation.6
Who Can Be a Fragile X Carrier?
A person with an abnormal gene that increases the risk of having a child or grandchild with a genetic disorder is known as a “carrier.”7 Anyone can be a carrier of FXS or Fragile X premutations. Fragile X carriers are found among all ethnic backgrounds and racial groups.8
The risk of having a Fragile X premutation is higher if you have the following:8
- A family history of FXS
- A family history of intellectual diability, developmental milestone delays, or autism spectrum disorders
- Infertility problems associated with elevated follicle-stimulating hormone (FSH) levels or premature ovarian failure (POF)
- A family history of adult-onset ataxia or tremors
Although a carrier of a genetic mutation is traditionally described as a person who inherits an abnormal form of a gene but does not exhibit clinical symptoms, in the instance of Fragile X, some Fragile X premutation carriers are prone to Fragile X-related disorders. These disorders are linked to various emotional and physical issues that may become more noticeable throughout middle and old age.7
Other Fragile X-Associated Disorders
Even if a person has a premutation in their FMR1 gene, they still produce FMRP. Although the FMR1 gene is not silenced completely in these individuals, it also does not function normally. Due to this, Fragile X premutation carriers are at risk of other Fragile X-related disorders.
Other Fragile X-related disorders include:
- Fragile X-associated Tremor/Ataxia syndrome (FXTAS) – Approximately 40% of male premutation carriers over 50 years develop FXTAS, while around 8% to 16% of female premutation carriers over the age of 40 develop the condition.9 FXTAS is a late-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, intention tremor, and cognitive decline.10 Other symptoms may include short-term memory loss, executive function deficits,peripheral neuropathy, lower limb proximal muscle weakness, parkinsonism, and autonomic dysfunction. The condition typically affects males more frequently and more severely than females.10
- Fragile X-associated Primary Ovarian Insufficiency syndrome (FXPOI) – This is a condition in which the ovaries of females with premutation are not functioning fully. About 20% of females who are premutation carriers develop primary ovarian insufficiency throughout their reproductive lifespan , compared with only 1% of the general population. FXPOI is a cause of infertility and premature menopause among adult females. Most females with this condition may stop having menses before age 40 (the average age of menopause is between 45 and 55).11
Signs and Symptoms of Fragile X Syndrome
Individuals with FXS may not exhibit identical clinical symptoms but may share certain traits. FXS can cause intellectual disabilities, developmental delays, physical characteristics, behavioural symptoms and other co-occurring conditions.
Intellectual disabilities and developmental delays
Most individuals with FXS experience intellectual diabilities and developmental delays. Males with FXS may have significant intellectual disability, speech and language delay, and motor delay (late crawling, walking, toileting).3 Due to having one normal FMR1 gene on their second X chromosome, females with FXS often exhibit less cognitive impairment than males with FXS. Around 25% of females with FXS have an intelligence quotient (IQ) below 70,12 while most males with FXS have an average IQ score under 55.13 Males with language delays may eventually talk with the help of speech therapy, but some may remain nonverbal throughout their lives. Females, on the other hand, do not usually have as severe challenges with speech or language.
Infants and younger children with FXS may not have any specific physical features of the syndrome. When boys go through puberty, however, they may develop certain physical characteristics that are atypical to those with FXS.14 Connective tissue issues may be responsible for such physical features as:3, 14
- Narrow or long face
- Large head
- Large ears
- Soft skin
- Flexible joints
- Low muscle tone
- Flat feet
- Prominent forehead
- High-arched palate
- Large testicles (macroorchidism)
Common behavioral symptoms in individuals with FXS include:3
- Autism and autistic behaviors such as poor eye contact, hand flapping, or biting
- Attention deficit hyperactivity disorder (ADHD)
- Increased risk for aggression
- Sensory processing challenges (sensitivity to fabrics or clothing, loud noises, crowds, food textures, etc.)
Although females are typically more mildly affected than males, particularly in cognitive functioning and behavioral characteristics, they may still be at risk for emotional problems, such as social anxiety, social avoidance, shyness, withdrawal, depression, language deficits, and mood swings.15
A national parent survey by the CDC found that 46% of males and 16% of females with FXS have been diagnosed with or treated for Autism Spectrum Disorder (ASD). Approximately 84% of males and 67% of females have been diagnosed with or treated for problems with attention.16
The first diagnostic genetic test for FXS involved using a microscope to examine the X chromosome. During the 1970s, it was observed that some males with inherited intellectual disabilities had an X chromosome that looked fragile as if the end had broken off. This is how the name “Fragile X” originated. This genetic testing was fairly accurate in identifying males with FXS but could not reliably identify females with FXS or a premutation carriers.17
In the 1990s, genetic testing technologies improved, and the FMR1 gene associated with FXS was discovered. Since then, highly accurate Fragile X DNA testing has been widely available to identify people with all types of changes in the FMR1 gene. Fragile X testing must be requested as a separate test since repeat expansions in the FMR1 gene cannot be identified through microarray or exome sequencing.17 Hence, two main genetic testing methods are utilized to diagnose Fragile X-related disorders.
- Polymerase chain reaction (PCR) – This identifies the extent of the repetitive section of the FMR1 gene, including CGG repeats in the normal, intermediate, premutation, and full mutation ranges.17
- Southern blot analysis – In instances of full mutations, labs usually follow up with a southern blot analysis to determine the gene’s methylation status. Abnormal methylation associated with FXS can prevent the FMR1 gene from producing FMRP.17
Laboratories generally report the number of CGG repeats within the FMR1 gene and, if detected, the presence of methylation and mosaicism. Mosaicism is the presence of different-size CGG repeats or when the methylation status of some chromosomes may vary. However, since Fragile X testing is available through many different laboratories, not all lab reports look the same.17
What Is a Fragile X Carrier Test?
The Fragile X carrier test determines whether or not an individual is a Fragile X carrier and their risk of having children with FXS. The test requires a small blood sample. Fragile X carrier testing provides accurate information about carrier status almost 99% of the time. 8
The results of a Fragile X carrier test usually fall into one of the following:8, 18
- Normal – Individual is not a Fragile X carrier, and individual’s children are not at risk for FXS.
- Intermediate – Individual’s results fall within the range between normal and premutation. Although an individual’s children are not at an increased risk of FXS, future generations may be at risk for the condition.
- Premutation – Individual is a carrier of the altered FMR1 gene. They may be at risk for FXPOI, FXTAS, and females have a 50% chance of having children with FXS or a premutation.
- Full mutation – An individual with a full mutation of Fragile X is diagnosed with FXS.
Due to the intricacies of FXS, families dealing with Fragile X-associated disorders may wish to consult with a genetic counselor or geneticist, their health care provider, or a Fragile X clinic to discuss what a positive result means for the affected person and their loved ones.
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. What is Fragile X Syndrome? Retrieved Oct 17, 2022, from https://www.cdc.gov/ncbddd/fxs/facts.html#:~:text=Fragile%20X%20syndrome%20(FXS)%20is,do%20not%20make%20this%20protein.
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. How Fragile X Syndrome is Inherited. Retrieved Oct 17, 2022, from https://www.cdc.gov/ncbddd/fxs/inherited.html
- National Fragile X Foundation, Fragile X 101. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/
- Bartholomay KL, Lee CH, Bruno JL, Lightbody AA, Reiss AL. Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings. Brain Sci. 2019 Jan; 9(1): 11. 2019 Jan 12. doi: 10.3390/brainsci9010011.
- FRAXA Research Foundation, What Is Fragile X Syndrome? Retrieved Oct 17, 2022, from https://www.fraxa.org/fragile-x-syndrome/
- Eunice Kennedy Shriver National Institute of Child Health and Human Development. Other Fragile X Syndrome FAQs. Retrieved Oct 17, 2022, from https://www.nichd.nih.gov/health/topics/fragilex/more_information/faqs
- National Fragile X Foundation. Premutation Carriers. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/premutation-carriers/
- University of California, San Francisco. Carrier Testing for Fragile X Syndrome. Retrieved Oct 17, 2022, from https://www.ucsfhealth.org/en/education/carrier-testing-for-fragile-x-syndrome
- National Fragile X Foundation, Fragile X–Associated Tremor/Ataxia Syndrome | FXTAS. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/tremor-ataxia-syndrome-fxtas/
- Leehey MA. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): Clinical Phenotype, Diagnosis and Treatment. J Investig Med. 2009 Dec; 57(8): 830–836.doi: 10.231/JIM.0b013e3181af59c4.
- National Fragile X Foundation, Fragile X-Associated Primary Ovarian Insufficiency| FXPOI. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fxpoi-primary-ovarian-insufficiency/
- Reiss S, Zalles L, Gbekie C, Lozano R.Identity and Reproductive Aspects in Females with Fragile X Syndrome.Women’s Health Reports.Dec 2021.500-506.http://doi.org/10.1089/whr.2021.0059.
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Data and Statistics on Fragile X Syndrome. Retrieved Oct 17, 2022, from https://www.cdc.gov/ncbddd/fxs/data.html
- Eunice Kennedy Shriver National Institute of Child Health and Human Development. What are the symptoms of Fragile X syndrome? Retrieved Oct 17, 2022, from https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/commonsymptoms
- Garber KB, Visootsak J, Warren ST. Fragile X syndrome. PMC4369150. Eur J Hum Genet. 2008 Jun; 16(6): 666–672. Published online 2008 Apr 9. doi: 10.1038/ejhg.2008.61
- Bailey, D.B., Jr, Raspa, M., Olmsted, M. and Holiday, D.B. (2008), Co-occurring conditions associated with FMR1 gene variations: Findings from a national parent survey. Am. J. Med. Genet., 146A: 2060-2069. https://doi-org.libproxy.lib.unc.edu/10.1002/ajmg.a.32439
- National Fragile X Foundation, Genetic Testing for Fragile X Syndrome and Associated Disorders. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/testing-diagnosis/
- National Fragile X Foundation, Genetics & Inheritance. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/genetics-inheritance/