FraX Flashcards
Gene and location associated with Frax
FMR1 within FRAX A fragile site at Xq27.3
Cause of Fragile X syndrome
99% is CGG repeat expansion in 5’ UTR of FMR1 gene
1% is FMR1 point mutations/deletions
Underlying pathogenesis of Fragile X syndrome
> 200 CGG repeats causes hypermethylation of FMR1 promotor, turning gene off.
FMRP expressed at highest levels in brain and testes > most functional in neurons where is it has role in functional and structural maturation of synapses
Interspersions in CGG tract
AGG interuptions thought to confer stability
Often found in normal size alleles
What proportion of Fragile X is mosaic?
15-20% of mutations are mosaic
What types of mosaicism are there in Fragile X?
repeat size (full mut/pre mut) methylation (full mut meth / full mut unmeth)
Symptoms of FXTAS
Late onset progressive neuromuscular disorder
- cerebellar ataxia
- intention tremor
- parkinsonism
Cause of FXTAS
CGG premutation (55-200) in FMR1 in both males and females
Underlying pathogenesis of FXTAS
Transcription of premutation alleles is higher than normal resulting in increase mRNA, but translation is less efficient
Less FMRP, more FMR1 mRNA; toxic - leads to cellulat injury
Clinical features of FXPOI
Early menopause (<40 years)
Cause of FXPOI
CGG premutation (55-200) in FMR1 in females only
Expansion in FMR1
Expansion can only occur when maternally transmitted
>90 CGG have 90% risk of expansion upon transmission
Considerations in prenatal FraX testing (CVB)
MCC
Methylation pattern not fixed
Testing strategy in FraX
1) Flourescent PCR (sizing) - run with known controls, can only identify normal alleles
2) TP-PCR
Limitations of flourescent PCR in FraX
- preferential amplification of the smaller allele
- SNP under primer binding site could cause allele drop out
- Cannot detect full mutations, including mosaic N/FM
- Cannot detect deletion/point mutation (1%)
- Cannot distinguish N/N hom female
