1. Discuss the relationship between phenotype and genotype in Fragile X syndrome. Louise Williams 06/03/2008

2. What is Fragile X syndrome? Most common form of inherited cognitive impairment Autosomal dominant inheritance Classical Fragile X Syndrome Mild to severe mental retardation (IQ 20-60), prominent jaw, large ears, macroorchidism, autistic spectrum behaviour, hand flapping, soft smooth skin Other disorders associated with the FMR1 CGG repeat - FXTAS and POF

3. Genetics of Fragile X 99% - Expansion/Methylation of CGG repeat in exon 1 of FMR1 which causes lack of protein product Some cases caused by deletions or missense mutations confirming lack of protein is cause of disease Alleles of FMR1 are categorised according to CGG repeat number Normal alleles = 5-40 Intermediate alleles = 41-58 (grey zone) Premutation alleles = 59-200 Full mutation = >200

4. ‘Normal’ alleles Normal alleles are stably transmitted without any increase or decrease in size/repeat number In these alleles, the CGG repeat is interupted every 9-10 repeats by an AGG which maintains integrity These alleles tend to be transmitted stably Any change in repeat number tends to be small The number of pure (CGG) repeats in a tract determines its stability – pure repeats of more than 35 uninterrupted CGGs are more likely to become unstable Intermediate alleles

5. Premutation alleles Alleles of this size may be associated with subtle symptoms, but increase risk of FXTAS and POF Expansion of premutation alleles to full mutation alleles only occurs on maternal transmission Women with alleles in this size range are said to be at risk of having an affected child due to the potential for the allele to expand

6. Full mutations Males generally have moderate to severe learning difficulties with or without other features 50% of females will be affected, although more mildly than males This is due to the ratio of active to inactive FMR1 in the brain which results from X inactivation

7. Mosaicism 15-20% of FMR1 mutations are mosaic 2 types of moaicism Repeat size mosaicism Both full and pre mutations are present Methylation mosaicism Full mutations variably methylated These individuals will be affected but tend to be higher functioning There have also been reports of unmethylated full mutation males who also tend to be higher functioning

8. Anticipation Like other triplet repeat disorders, Fragile X shows anticipation This occurs when less severely affected premutation carriers or full mutation mosaics transmit unstable alleles This is not ‘classical’ anticipation as seen in other disorders, as premutation alleles can be transmitted stably for generations

9. Fragile X-associated tremor/ataxia syndrome Late onset progressive cerebellar ataxia and intention tramor Affects both males and females Associated with premutation alleles Shows age related penetrance in males (overall 40% at >50 yoa) Lower risk in females

10. Premature ovarian failure Cessation of menses at <40 yoa Associated with high normal and intermediate alleles 21% compared to 1% in general pop Risk increases with repeat size but plateaus after about 100 59-79, 6.9; 80-99, 25.1; >100, 16.4

11. Conclusion Size or classification of FMR1 CGG repeat generally correlates with fragile X syndrome phenotype (other than mosaicism) – Not surprising really, as alleles have been allocated according to their phenotype Additional phenotypes found more recently to be associated with the expansion do not fall neatly into these brackets

12. References Reference given in question Gene Clinics