FRAXE (FMR2) DNA Analysis
FRAXE intellectual disability syndrome is a genetic condition that leads to a wide range of developmental problems including learning disabilities, speech and writing difficulties, and behavioral problems.
PrintFRAXE intellectual disability syndrome is a genetic condition that leads to a wide range of developmental problems including learning disabilities, speech and writing difficulties, and behavioral problems.
FRAXE has been associated with the silencing of the FMR2 gene, which lies just beyond the FMR1 gene on the X chromosome; CGG repeat expansion of the FMR1 gene is associated with Fragile X Syndrome. The expansion and hypermethylation of the CCG repeats in the 5'UTR of FMR2 leads to non-specific forms of intellectual disability.
The Ambry Test: FRAXE intellectual disability syndrome is a CCG repeat expansion and promoter methylation analysis of FMR2. Greater than 99% of the mutations in FMR2 responsible for FRAXE syndrome are due to CCG repeat expansions.
The incidence of FRAXE intellectual disability syndrome is estimated at approximately 1/23,000-1/50,000 males.2 FRAXE is a genetic condition that leads to a wide range of developmental problems including learning disabilities, communication, attention problems, hyperactivity and autistic tendencies.3,4 FRAXE has been associated with the silencing of the FMR2 gene, which lies ~600 kb distal to the FMR1 gene known to cause fragile X syndrome.5 This silencing specifically involves the hypermethylated expansion of an unstable CCG trinucleotide repeat sequence at the 5’UTR end of the FMR2 gene.6 As with fragile X syndrome, the general unaffected population may carry 4-39 CCG repeats, while individuals affected with FRAXE have >200 methylated repeats.6,7 The expansion and hypermethylation of the CCG repeats leads to non-specific forms of mental deficiency.
FRAXE (FMR2) CCG repeat expansion testing should be considered for any individual with intellectual disability, developmental delay, learning disabilities of unknown cause, autism or autism-like characteristics. Testing should also be considered for families with a history of FRAXE or intellectual disability due to unknown cause.
Prenatal testing is recommended for fetuses of mothers known to be FRAXE carriers, as well as for those with a family history of FRAXE.
DNA from the patient’s specimen is analyzed by the use polymerase chain reaction (PCR) analysis to determine the size of the CCG repeat segment and methylation status of the FMR2 gene. Southern Blot analysis is used for females with equivocal results.
CCG expansion mutation in the FMR2 gene have been associated with 99% of clinically affected FRAXE patients. A small portion (<1%) of FRAXE cases are due to rare mutations in areas of the FMR2 gene not evaluated by this test.
Blood: Collect 5 ml minimum, 8-10 ml preferred, in an EDTA purple/lavender-top tube. Store at room temperature or refrigerate. Ship at room temperature. Specimens must be less than 5 days old.
| Technique | Days |
|---|---|
| Fragile X DNA Analysis (FMR2) |
1. Santos et al. A new PCR assay useful for screening of FRAXE/FMR2 mental impairment among males. Hum Mutat. 2001;18:157-162. [PMID: 11462240]
2. Youings et al. FRAXA and FRAXE: the results of a five year survey. J Med Genet. 2000;37:415-42. [PMID: 10851251]
3. Bensaid M et al. FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure. Nucleic Acids Res. 2009;37(4):1269-79. [PMID: 19136466]
4. Hillman M, Gecz J. Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. J Hum Genet. 2001;46:251-259. [PMID: 11355014]
5. Knight SJL et al. A study of FRAXE in mentally retarded individuals referred for fragile X syndrome (FRAXA) testing in the United Kingdom. Am J Hum Genet.1996;58:906-913. [PMID: 8651274]
6. Santos CB et al. A new PCR assay useful for screening of FRAXE/FMR2 mental impairment among males. Hum Mutat. 2001;18:157-162. [PMID: 11462240]
7. Lo Nigro C et al. FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother. Eur J Hum Genet. 2000;8(3):157-62. [PMID: 10780779]