Handbook of Genetic Counseling/Fragile X Syndrome

NOTE: This has not been reviewed since 2002 and many new discoveries have been made in that time. This handbook needs a full review for errors. Cited text is new as of Jan. 7, 2022.

General Information about Fragile X syndrome

• Most common form of genetically inherited mental impairment.
• It is inherited in a non-standard X-linked fashion (gene clinics states it is X-linked dominant other sources refer to it as X-linked recessive)
• FMR1 gene on X chromosome at Xq27.3 was sequenced in 1991
• It makes the protein FMRP (fragile X mental retardation protein). There is evidence that FMRP plays a role in regulating protein synthesis.
• The number of CGG repeats in the FMR1 gene determines whether someone is classified as normal, intermediate, premutation, or full mutation (fragile x syndrome):
  • Normal 5–44 repeats is typical (gene is active and not methylated)
  • Intermediate 45–54 repeats: People with intermediate repeats do not have fragile x syndrome and are not at risk for having children with fragile x syndrome. They may have a slightly higher chance of having some symptoms related to other fragile X-associated disorders (fragile x-associated tremor/ataxia syndrome, fragile x-associated primary ovarian insufficiency) and may pass the slightly higher chance of having these disorders to their children.
  • Premutation 55–200 (gene is not usually methylated) males and females usually unaffected
  • Full mutation >200: People with a full mutation have fragile x syndrome (gene is usually fully methylated and therefore inactive)

Genotype-Phenotype Correlations

• The phenotype of males with an FMR1 mutation is almost entirely dependent on the nature of the mutation; the phenotype of females with an FMR1 mutation is dependent on both the nature of the FMR1 mutation and random X-chromosome inactivation

Premutation

• Males and females who have a fragile X premutation have normal intellect and appearance.
• There have been multiple reports of individuals with a premutation and typically subtle intellectual or behavioral symptoms.

Full mutation

• Males who have a full fragile X mutation generally have moderate to severe intellectual disability (average IQ of 41) and may or may not have a distinctive appearance.
• About 50% of females who have a full fragile X mutation have intellectual disability; however, they are usually less severely affected than males with a full mutation. (Some sources quote 1/3 or 33% they are usually older references)
• Conversely, about 50% of females who are heterozygous for the full mutation are intellectually normal. This variability among females is believed to result from the distribution of X chromosome inactivation ratios in the brain. (Some sources quote 2/3 or 66%)

Repeat size mosaicism

• Although some data suggest that individuals with mosaicism perform at a higher intellectual level than individuals with completely methylated full mutations, these individuals have mild to severe intellectual disability. (Average IQ 60)
• Rarely, patients with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported
• Mosaicism is present in about 15% to 20% of individuals with FMR1 mutations.
• Presumably these individuals produce at least some FMR1 protein because the FMR1 gene is unmethylated.
• The existence of these exceptional patients suggests that repeat expansion and methylation of the gene are not absolutely coupled.

Risks of expansion

• Factors influencing likelihood of expansion include:
  • Gender -- expansion nearly always occurs in female meiosis
• Women with the premutation may pass fragile X to their offspring due to genetic anticipation (when egg is made # of repeats increases and expansion occurs).
• Males with the premutation will pass this premutation to their daughters without it expanding to a full mutation in the process. However, expansion can occur in her offspring and can therefore lead to affected grandchildren.
• Size of repeat: the larger the repeat, the more likely it is to expand
• Presence of AGG interruptions --Sequences of uninterrupted CGG repeats are at higher risk to be expanded-explains why alleles with same CGG copy number have different risks for instability

Risk that a Mother with a Premutation will have an Affected Child with a Full Mutation

Number of Maternal Premutation CGG Repeats	Approximate % Risk of Having an Affected Son	Approximate % Risk of Having an Affected Daughter 1
56-59	7%	3.5%
60-69	10%	5%
70-79	29%	15%
80-89	36%	18%
90-99	47%	24%
>100	50%	25%

• Taken from
• Unlike classical X-linked dominant disorders where all females with a mutation are affected, only about 50% of females with a full mutation have intellectual disability. This variability in phenotype is likely to be related to variability in X chromosome inactivation, a phenomenon independent of FMR1 mutations.

Characteristics

• Males are more likely to exhibit the characteristics of fragile X because they have only one X chromosome. However, females may also exhibit a few of these characteristics.

Physical Characteristics:

• Physical features may be quite subtle and people with fragile X may be normal in appearance
• See chart below for common physical features in males (From Fragile X Syndrome Diagnosis, Treatment, and Research)
• Females share some of the same features

Cognitive Characteristics

• Majority of boys (80%) and 50% of girls have mild to moderate intellectual disability (IQ below 70). Other girls may show signs of specific learning difficulties such as in math.
• Common problems include delayed milestones (speech and language delays are common in males, but less common in females)

Behavioral Characteristics

• Behavior ranges from socially engaging and friendly to autistic-like and occasionally aggressive.
• They may display some or all of the behavioral characteristics in the chart on the side
• Behaviors also include short attention span and they are often initially diagnosed as ADHD (often treated with adderall, or clonidine)
• They may also have difficulty adjusting to change.
• Obsessive compulsive behavior is quite common (preservative or repetitive behavior) this may improve with SSRI's
• Psychosis may occur and is often precipitated by aging or severe stress

Medical Concerns

• Table from Fragile X Syndrome Diagnosis, Treatment, Research

Treatment/Therapy/Prevention/Anticipatory guidance

• Currently, there is no specific treatment for Fragile X. Therapy tends to focus on the behavioral and learning issues that are often associated with Fragile X Syndrome. These may include:
• Behavioral techniques to manage hyperactivity and temper tantrums
• Some boys don't sleep for long periods of time and meds can be given for this
• Medicinal treatment for management of behavioral issues
• Educational intervention (special classes, etc.)
• Therapy including: speech therapy, occupational therapy, physical therapy, and sensory integration therapy (to manage sensitivity to sensory input)
• Therapeutic calming techniques and a regular routine may also help with behavior problems.

Adults with fragile X

• Hyperactivity tends to improve in adolescents and adults with fragile X
• Anxiety, (particularly social anxiety) is present and more common in individuals who are not impulsive or hyperactive
• Anxiety or uncertainty often leads to aggressive outbursts in new situations
• Treatments for anxiety may help
• Possibly up to 50% of adult males experience mitral valve prolapse
• Mild aortic root dilation may also occur
• Hypertension is relatively common, but may be the result of anxiety.

Testing

Two main DNA testing approaches:

• PCR-- (size indicates approximate number of repeats present) It is very accurate in sizing normal and premutation alleles. The efficiency is inversely related to number of CGG repeats present Large permutations and mutations difficult to analyze and may fail to yield detectable product. It also does not give information about FMR1 methylation
• Southern blot analysis - Doesn't allow precise sizing, but accurately detects alleles in all size ranges and estimates size. It also allows methylation status to be assayed.
  • Labs often do both
• Research based testing available for other mutations in the FMR1 gene

Prenatal testing

• Possible via both CVS and amniocentesis once genetic status of parents is confirmed.
• Results from CVS testing must be interpreted with caution because the methylation status of the FMR1 gene is often not yet established in chorionic villi at the time of sampling.
• CVS may lead to a situation in which follow-up amniocentesis is necessary to resolve an ambiguous result.

Preimplantation genetic diagnosis

• Expensive and chance of no pregnancy
• Chance of pregnancy best determined by a reproductive endocrinologist: A woman's age and fertility potential are great determinants of chance of pregnancy with IVF-PGD
• Only performed at specific centers (needs verification)

Indications for Fragile X screening

• Individuals of either sex with intellectual disability, developmental delay, or autism, especially if they have any physical or behavioral characteristics of FXS, a family history of FXS, or male/female relatives with an intellectual disability of unknown etiology
• Any person who has a family member with a diagnosis of fragile X syndrome or a family history of intellectual disability
• Fetuses of known carrier mothers
• Patients with cytogenetic fragile X test result that is discordant with their phenotype. These include patients with strong clinical indication and who have had negative or ambiguous cyto test result, and patients with an atypical phenotype with positive cytogenetic test result
• population screening not recommended at this time (needs verification)

Differential Diagnosis

• MR, ADHD, autistic like features can be seen in Asperger, FAS, and autism
• Coffin-Lowery shares features of prominent ears, coarse features
• Lujan Fryns syndrome - marfanoid habitus and machroorchidism
• Atkin syndrome - large ears, short stature, machroorchidism
• Fragile X has been seen in conjunction with chromosomal aneuploidy syndromes

Resources

• National Fragile X Foundation

1861 International Drive, Suite 200 McLean, VA 22102

Phone: (800) 688-8765

Email: contact@fragilex.com

Web: https://fragilex.org

• FRAXA Research Foundation

Newsletter: FRAXA Research Foundation Newsletter. Subscription through FRAXA

45 Pleasant St

Newburyport, MA 01950

Phone: 978-462-1866

Fax: 978-463-9985

Email: info@fraxa.org

www.FRAXA.org

www.yourgenesyourhealth.org/ygyh/ (site with great animation and simple to follow explanation showing everything step by step)

References

• L. Elbaum. A "Fragile X" plantation. The Great Lakes Regional Genetics Group.(1993).
• Fragile X Syndrome: Understanding the Most Common Cause of Inherited Mental Impairment. Published by The National Fragile X Foundation sometime after 1996.
• McIntosh N, Gane LW, McConkie-Rosell A, Bennett RL (2000). Genetic Counseling for Fragile X Syndrome: Recommendation of the National Society of Genetic Counselors. Journal of Genetic Counseling. 9(4): 303-325.
• Hagerman RJ, Cronister A. Fragile X Syndrome: Diagnosis, Treatment, and Research. The Johns Hopkins University Press: Baltimore, MD, 1996.
• Management of Genetic Syndromes. Cassidy, S.B. and Allanson, J.E.editors. Chapter 10 written by Hagerman R.J. Wiley-Liss Inc. 2001.

Web references

• fragilex.org

Notes

The information in this outline was last updated in 2002.