Fragile X Syndrome

Question 1

What is fragile X syndrome?

Answer 1

-X-linked
-FMR1 gene
-Intellectual disability
_____________________
X-linked disorder of intellectual disability that is caused by mutations in the FMR1 gene.

Question 2

What ultrasound abnormalities can be identified in a fetus with fragile X syndrome?

Answer 2

• Prominent jaw/forehead
• Long face/large ears
• Macroorchism

Question 3

What patients should be screened for their fragile X status?

Answer 3

Family history of premature ovarian failure
Family history of tremor/ataxia syndrome
Family history of unexplained intellectual disability
History of child with autism
History of child with fragile x

Question 4

What are the phenotypic features of Fragile X Syndrome?

Answer 4

• Mild to moderate intellectual disability
• Autism
• Large ears
• Prominent jaw
• Long face
• Macroorchism
• Cross eyed
• Flat feet

Question 5

What phenotype do women express who are premutation carriers for fragile X?

Answer 5

20% will experience premature ovarian failure

Tremor/ataxia syndrome (male > female)

Question 6

What is the inheritance of Fragile X?

Answer 6

X-linked.

For premutation females, there is a 50% chance of fragile X for boys and 25% for girls depending on size of mutation

Question 7

What is a premutation carrier for fragile X?

Answer 7

Normal: 6-50 repeats
Intermediate: 51-58 repeats
Premutation: 59-200 repeats
Disease: >200 repeats

Question 8

What does it mean to say someone carries the full mutation for fragile X

Answer 8

Premutation carrier with 200 repeats

Question 9

What gene is affected with fragile X?

Answer 9

FMR1 gene

Question 10

How does methylation of the FMR1 gene lead to Fragile X syndrome?

Answer 10

More than 200 CGG repeats lead to hypermethylation which inactivates the FMR1 promoter causing a loss of FMRP expression.

Question 11

What are characteristics of a trinucleotide expansion repeat disorder?

Answer 11

Progressive degeneration of nerve cells leading to ataxia and muscle weakness

Question 12

What are other examples of trinucleotide expansion repeat disorders?

Answer 12

Myotonic dystrophy - CTG
Huntington - CAG
Spinal cerebellar ataxia

Question 13

Is fragile X syndrome inherited through the mother or the father?

Answer 13

Both

Question 14

Explain the concept of anticipation

Answer 14

Progressive increase in severity of mutation as it is passed from parents to their offspring.