Fragile X Syndrome

Question 1

Fragile X is otherwise known as

Answer 1

FRAXA

Fragile Site, Folic Acid Type, Rare, Fra(x)

Question 2

Fragile causes what type of disability in both males and females

Answer 2

intellectual disability from learning impairment to severe cognitive disability to intellectual disability. Its common in autism and ASD.

Question 3

FRAXA mutation testing is common in which type of individuals

Answer 3

in males and female with developmental delays, mental disability and behavioural problems.

Question 4

What are the physical features of fragile x

Answer 4

• Large ears
• long narrow faces with prominent forehead
• Mitral Valve prolapse
• Seizures
• Eye problems

Question 5

What are the cognitive clinical features of fragile X

Answer 5

affects the brain development can lead to:

• Developmental delays
• Mental impairment
• learning disabilities

Question 6

what is the prevalence of Fragile X in males and female

Answer 6

Males : 1 in 400

Females: 1 in 5000-8000

Question 7

where is the fragile X site on the X chromosome

Answer 7

Xq27.3 (long arm of the X chromosome)

Question 8

What is a major mutation causing fragile X

Answer 8

Mutation in the FMR1 gene (causes 99% of fragile X)

Question 9

What does the FMR1 gene code for

Answer 9

FMRP (fragile x mental retardation protein)

Question 10

what kind of mutation is the most common in the FMR1 gene causing fragile X

Answer 10

an expansion mutation

Question 11

What repeat sequence is found in the expansion mutation of the FMR1 gene

Answer 11

CGG (region is in the 5 UTR of the FMR1 promoter)

Question 12

What is the normal number of CGG repeats

Answer 12

about 30.

Question 13

Describe the mechanism causing fragile X in the case of greater than 200 CGG repeats

Answer 13

Hyper-methylation of the cytosine of the CGG repeat.
Deactivation of the FMR1 gene
NO FMRP is produced
This results in fragile X.

Question 14

Describe the normal number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.

Answer 14

Number of repeats: <45
mRNA produced: normal
FMRP produced: normal
clinical phenotype: normal

Question 15

Describe the premutation number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.

Answer 15

Number of repeats: 55-200
mRNA produced: increased mRNA produced
FMRP produced: reduced
clinical phenotype: Premature ovarian failure, FXTAS

Question 16

Describe the full mutation number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.

Answer 16

Number of repeats: >200
mRNA produced: reduced
FMRP produced: none produced
clinical phenotype: Fragile X syndrome (varies between males and females)

Question 17

what is 45-55 repeats classed as

Answer 17

the intermediate allele

Question 18

with the full mutation what is the chance of developing fragile X

Answer 18

All males will develop FXS

50% of females will develop fragile X.

Question 19

those with 55-200 repeats are at risk of FXPOI and FXTAS, what is FXPOI

Answer 19

FXPOI: fragile x associated primary ovarian insufficiency.

• is a toxic RNA gain of function (in the premutation there is an increase in mRNA while a decrease in protein)
• Females with 55-200 mutations have a 21% risk of developing FXPOI
• Menopause before 40.

Question 20

those with 55-200 repeats are at risk of FXPOI and FXTAS, what is FXTAS

Answer 20

FXTAS: fragile X associated tremor/ataxia syndrome.

• late onset neurodegenerative disorder that effects old adult carriers (usually over 55), the risk increases with age in those with the premutation
• there is an intention tremor and a cerebral gait ataxia.
• Occurs in 40% of males with the premutation and 8-16% of women with the premutation.
• occurs via a similar mechanism to FXPOI.

Question 21

What laboratory tests are used to diagnose fragile syndrome

Answer 21

CGG repeat expansion via: PCR, southern blot, Repeat primed PCR and capillary separation. RT-PCR.
deletions: microarray MLPA (multiplex ligation-dependent probe amplification).
Future testing: next gen sequencing.

Question 22

What is the gold standard of FXS lab tests

Answer 22

Southern Blot.

Question 23

What is the function of the FMRP protein

Answer 23

repressor of target mRNA translocation at the neural synapses, shuttles target mRNA through dendrites and is important in the generation of synapses during the development.