Human biomonitoring: prenatal exposure and early effects on the newborn By Greet Schoeters

1. Preconceptional Fragile X syndrome screening
19 years experience
in a Belgian Center for Human Genetics

2.  Fragile X : Clinical features
Most frequent cause of inherited intellectual disability
 Mental retardation
 Autism
 Large ears
 Long and narrow face
 Macroorchidism
 Walk delay
 Speech delay
 Behavioural troubles
 Hyperkinetism
 PC +2SD

3.  Fragile X syndrome
Prevalence
Males : 1/4000 (/2000-1/6250)
Females : 1/8000, attenuated phenotype
X-linked
Maternal transmission
Triplet expansion

4.  Fragile X : Molecular mechanisms
CGG CGG CGG CGG
n

5. Transmission
Normal
Prémut.
Repeat Number Expansion Risk
• 55 - 59 rep 0%
• 60 - 69 rep 4 % Expansion
• 70 - 79 rep 44 %
• 80 - 89 rep 54 %
• >90 rep 100 %
Risk increases with the premutation size

6.  Molecular Diagnosis
Normal
(CGG)n Premutation
Mutation
Normal Premutation
Normal
Normal

7.  Preconceptional Screening
- A total of 14654 women
- No known family history of fragile X syndrome.
- On request from clinicians, mainly geneticists and
gynaecologists.

8.  Results : Premutation frequency
1 Full mutation and 79 premutations were found
Number
of women
Rep Frequency Risk
70
59 > 55 1/185 Frequently used
threshold
60
50
40
> 59 1/266 Risk threshold
30
> 70 1/697 High risk threshold
20
10 > 90 1/2442 Very high risk
10
5 6
0 threshold
55-69 70-79 80-89 >90
Repeats

9.  Premutation frequency
Genetic counselling was recommended to all premutated women
The availability of a prenatal diagnosis was discussed with all
the women with more than 55 repeats.
Familial screening was performed
 Familial screening
 Realized in less than 50 % of the families identified !
Lack of information to the family ?
Testing in another center ?
Better follow up in the last years
Led to the discovery of 7 sisters and 1 cousin with
premutation ranging from 63 to 75 rep

10.  Prenatal testing
• On 52 foeti (39 mothers)
Number Allele size distribution
of fœti
Normal allele transmitted
40
35
35
14 PM allele transmitted
30 No expansion
25
PM allele transmitted
20 6
Expansion to bigger PM
15
15
8 PM allele transmitted
10
6 Expansion to Full MT
3 3
5
5 Fragile X
0
55-69 70-79 80-89 >90
Repeats

11.  Conclusion and perspectives
# tests
3000
2500
2000
1500
1000
500
0
98 99 00 01 02 03 04 05 06 07 08 09 Year
The debate on the eventuality of wide-scale fragile X
syndrome screening in childbearing age women is still
unresolved.

12. Thank you for your attention !
IPG Charleroi (Gosselies)
BELGIUM