Last update: 12/12/2007
Background to disease
OMIM #309550
Fragile X Syndrome is a trinucleotide repeat-expansion disorder and the most common cause of X-linked mental retardation. The clinical symptoms in males are moderate to severe mental retardation, macro-orchidism, mild dysmorphic features and high pitched jocular speech. Expression is variable with mental retardation being the most common feature. Approximately one third of heterozygous females are manifesting carriers and show signs of mild mental retardation, other female carriers are phenotypically normal.
It has a prevalence of about 1 in 4000 in males and 1 in 6000 in females. Unusually for an X-linked disorder it may be passed from phenotypically normal males carrying a premutation allele (normal transmitting males) and affect their grandchildren.
The disease is associated with a fragile site at Xq27.3, FRAXA, caused by the expansion of an unstable CGG repeat in the 5’ untranslated region of the FMR-1 gene. The trinucleotide repeat is polymorphic in the normal population (CGG repeat range 5-56). Mutant alleles (>50) show instability and can be separated into two categories: premutations which are between 50 and 200 repeats and full mutations which have more than 200 repeats and a methylated upstream CpG island. Only the full mutation is associated with phenotypic manifestations which is thought to be due to the methylation of the CpG island which turns off the transcription of the FMR-1 gene. The gene product FMRP is an RNA-binding protein involved in translational control.
Laboratory Analysis
Analysis for this disease is now carried out by the Northern Genetics Laboratories under a reciprocal arrangement (GENLYNC). Please contact them directly regarding information regarding turnaround time and sensitivity. Local samples should still be sent via the Yorkshire Regional Genetic Laboratory where they will be forwarded as whole blood as appropriate. DNA from these samples can be stored in the Yorkshire Regional Genetic Laboratory if it is anticipated that future tests may be required (please indicate clearly on referral card if required).