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FMR1-Related Disorders

Includes: Fragile X Syndrome, Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS), FMR1Related Primary Ovarian Insufficiency (POI)
Robert A Saul, MD, FACMG and Jack C Tarleton, PhD, FACMG.
Author Information
Initial Posting: June 16, 1998; Last Revision: April 26, 2012.

Clinical Diagnosis

Fragile X syndrome. A definite diagnosis of fragile X syndrome requires the presence of a lossof-function mutation in FMR1, usually in a male with moderate intellectual disability or a female
with mild intellectual disability.
Note: Because FMR1 mutations are complex alterations involving non-classic gene-disrupting
alterations (trinucleotide repeat expansion) and abnormal gene methylation, affected individuals
occasionally have an atypical presentation with an IQ above 70, the traditional demarcation
denoting intellectual disability.
Affected individuals have normal growth and stature and no associated malformations.
Fragile X-associated tremor/ataxia syndrome (FXTAS) (see Table 1)

A definite diagnosis of FXTAS requires the presence of a premutation in
FMR1 and white matter lesions on MRI in the middle cerebellar peduncles
and/or brain stem (the major neuroradiologic sign) with either intention
tremor or gait ataxia (the two major clinical signs).
Other minor neuroradiologic criteria include MRI white matter lesions in the
cerebral white matter or moderate to generalized atrophy.
Other minor clinical criteria include parkinsonism, moderate to severe
working memory deficits, or executive cognitive function deficits.

A probable diagnosis of FXTAS requires either one major neuroradiologic
sign and one minor clinical sign or two major clinical signs.

A possible diagnosis of FXTAS is based on one minor neuroradiologic sign
and one major clinical sign [Grigsby et al 2005].

Table 1. FXTAS: Major and Minor Diagnostic Criteria

Neuroradiologic Signs

Clinical Signs

• Premutation in FMR1 and white matter lesions on
• Intention tremor
MRI in the middle cerebellar peduncles and/or brain
• Gait ataxia
• MRI white matter lesions in the cerebral white
• Moderate to generalized atrophy

• Parkinsonism
• Moderate to severe
working memory deficits
• Executive cognitive
function deficits

FMR1-related primary ovarian insufficiency (POI). FMR1-related POI is defined as cessation
of menses before age 40 years in a woman who has one FMR1 allele with trinucleotide repeats
from 55 to 200 (premutation). The earlier findings that alleles in the high normal and
intermediate range conferred an increased risk for FMR1-related POI [Bretherick et al 2005,
Bodega et al 2006] were not supported by a recent more robust study [Bennett et al 2010].

Chromosome analysis. Chromosome analysis using modified culture techniques to induce
fragile sites is no longer used for diagnosis of fragile X syndrome because it is less sensitive and
more costly than molecular genetic testing (see Molecular Genetic Testing).
Protein testing. Although protein testing is not performed routinely in most clinical laboratory
settings, a few laboratories provide assays that qualitatively measure the production of the
protein product of FMR1, fragile X mental retardation 1 protein (FMRP) [Willemsen et al 1997].
Situations in which FMRP testing may be useful include screening of males with intellectual
disability and characterization of cellular production of FMRP in males having unusual
phenotypes. Because severity of the fragile X syndrome phenotype appears to correlate with
FMRP expression in peripheral blood lymphocytes, assessment of FMRP production in some
affected males has been proposed as a potential prognostic indicator of disease severity [Tassone
et al 1999].
Molecular Genetic Testing

Gene. FMR1 is the only gene in which mutation is known to cause FMR1-related disorders.
Allele sizes. FMR1 alleles are categorized according to the number of CGG trinucleotide repeats
in exon 1 and the methylation status of the repeat region. However, the distinction between allele
categories is not absolute and must be made by considering both family history and repeat
instability. The boundary between intermediate and premutation categories listed below is not
precise and caution is advised. See Table 4 for a summary of the types of FMR1 alleles and
clinical status of individuals with expanded alleles. See Molecular Genetic Pathogenesis for
detailed information on types of FMR1 alleles and their behavior during transmission.

Normal alleles. Approximately 5-44 repeats

Alleles of this size have no meiotic or mitotic instability and are
transmitted without any increase or decrease in repeat number.


The population distribution of FMR1 repeat alleles shows the highest
percentage of individuals with approximately 29-31 repeats and
smaller but significant percentages clustering around 20 and 40

Intermediate alleles (also termed "gray zone" or “borderline”).
Approximately 45-54 repeats

Intermediate alleles do not cause fragile X syndrome. However, about
14% of intermediate alleles are unstable and may expand into the
premutation range when transmitted by the mother [Nolin et al 2011].
They are not known to expand to full mutations; therefore, offspring
are not at increased risk for fragile X syndrome.


Historically, the largest repeat included in the intermediate range has
been 54; the use of 54 as the upper limit for normal alleles is a
conservative estimate reflecting observations that transmission of
alleles with 54 repeats or fewer from mothers to their offspring has not
resulted in an affected individual to date. The conservative nature of
the estimate also reflects potential imprecision (usually stated as ±2-3
repeats) in laboratory measurement of repeat number during
diagnostic testing; however, to date no transmission of alleles with 56
or fewer repeats is known to have resulted in an affected individual
[Fernandez-Carvajal et al 2009].
Note: Clinical laboratories performing FMR1 analysis typically state
their estimated precision range when measuring intermediate alleles
and usually report their estimates as ±2-3 repeats. Thus, it may be
prudent to consider reported test results with 55 repeats as potential
premutations. If the repeat precision estimate is not on the laboratory
report, the laboratory should be contacted in order to determine if a
result should be considered as a potential premutation.

Premutation alleles. Approximately 55-200 repeats

Alleles of this size are not associated with fragile X syndrome, but do
convey increased risk for FXTAS and POI (Table 4). Because of potential
repeat instability upon transmission of premutation alleles, women
with alleles in this range are considered to be at risk of having children
affected with fragile X syndrome.


Fernandez-Carvajal et al [2009] reported maternal transmission of a
56-repeat allele resulting in an offspring with a full mutation; thus, 56
is the smallest repeat known to expand to full mutation in a single

the need for Southern blot analysis of every patient may decrease [Chen et al 2010. As a result. Hawkins et al [2011] on the availability of reference materials for clinical laboratories. Hantash et al 2010. Note: Although Southern blot analysis provides a low-resolution estimation of repeat number. More than 200 CGG repeats. Lyon et al 2010. See Published Guidelines/Consensus Statements. and full mutations and in addition determines methylation status of the FMR1 promoter region. As newer and more sensitive PCR methods gain acceptance in diagnostic testing. traditional PCR plus Southern blot analysis has been the “gold standard” for FMR1 molecular diagnosis.  Full-mutation alleles. Almost always. varies by testing laboratory). Chen et al 2011. Both numbers (200 and 230) are estimates derived from Southern blot analysis. traditional FMR1-specific PCR is less sensitive to larger premutations and fails to amplify full mutations. larger-sized premutations.transmission. o Southern blot analysis detects all FMR1 alleles including normal. AGG genotyping is offered as a separate test to determine the number and location of AGG trinucleotide interruptions within the tract of CGG repeats of FMR1. Filipovic-Sadic et al 2010. Note: The upper limit of the premutation range is sometimes noted as approximately 230. in which repeat size can only be roughly estimated. Recent results have linked the length of the uninterrupted . o AGG trinucleotide repeat genotyping. extensive somatic variation of repeat number is observed in a peripheral blood specimen of a patient with a full mutation. Abnormal hypermethylation of FMR1 is the cause of transcriptional silencing and is critical to assess for premutation and full mutation alleles. see Amos Wilson et al [2008]. Nahhas et al 2011]. Clinical testing  Targeted mutation analysis o Polymerase chain reaction (PCR) specific for the CGG trinucleotide repeat region of FMR1 has high sensitivity for FMR1 repeats in the normal and lower premutation range (typically ≤100 to 120 repeats. However. Newer methods promise to overcome these limitations (see Molecular Genetic Pathogenesis). The number and position of AGG trinucleotide repeats are known to be important in the overall stability of the CGG repeat sequence [Eichler et al 1994]. with several hundred to several thousand repeats being typical and associated with aberrant hypermethylation of the FMR1 promoter. clinical laboratories may report this somatic variation as a range of several hundred repeats.

FISH. Information on test sensitivity. and other test characteristics can be found at www. both small deletions near the repeat region in exon 1 and large-scale deletions that completely remove FMR1 continue to be reported in the literature. However.3’ CGG repeat length with expansion and suggest a minimum threshold for expansion risk [Nolin et al 2011]. footnote 4). are under ascertained. CGG expansion in FMR1 analysis (allele sizes in the normal and lower premutation range) 2.eurogentest. Deletions are typically detected in FMR1 as a secondary finding when the trinucleotide repeat region is being interrogated by Southern blot [Jacquemont et al 2011. see full text]. Table 2. Fewer than 1% of individuals with fragile X syndrome have a partial or full deletion of FMR1 (reviewed in Hammond et al [1997]).  Methylation status can be assessed by PCR-based methods independent of measuring the number of CGG repeats  Sequence analysis. as well as other gene rearrangements. methylation status 2. CGG expansion in FMR1 (all repeat ranges). Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males. Therefore. it is likely that FMR1 deletions downstream of the repeat region. Summary of Molecular Genetic Testing Used in FMR1-Related Disorders Gene Symb Test Method ol FMR1 Mutations Detected Targeted mutation PCR. specificity. confirmation may require additional testing by deletion/duplication analysis. 3 Southern blot. 4 Mutation Test Detection Availabili Frequency by ty Test Method 1 Clinical >99% AGG trinucleotide repeat 100% of alleles genotyping. The clinical usefulness of such testing awaits publication of the full study. or other method (see Table 2. Number and of this position of AGG trinucleotide structure 5 repeats that may interrupt the . Nevertheless. Test characteristics. Very few individuals with fragile X syndrome have been identified with an intragenic FMR1 mutation.  Deletion/duplication analysis. This test is offered for female carriers of intermediate and small premutation alleles. deletions not located in the repeat region of the gene may be missed in males on routine clinical testing by PCR for the trinucleotide repeat expansion.

confirmation may require additional testing by deletion/duplication analysis. the latter may offer a more rapid test turnaround time [Das et al 1997. . the need for Southern blot analysis may decrease [Chen et al 2010. and chromosomal microarray (CMA) that includes this gene/chromosome segment. Filipovic-Sadic et al 2010. As newer and more sensitive PCR methods gain acceptance in diagnostic testing. Chen et al 2011]. Hantash et al 2010. long-range PCR. 3. 4.CGG repeats of FMR1 5 Methylation analysis 100% of alleles Methylation of FMR1 promoter with this region 6 modification FISH Large (partial. and in some instances Southern blot analysis cannot detect an exonic or whole-gene deletion on the X chromosome in carrier females. Nahhas et al 2011]. This test is offered for female carriers of intermediate and small premutation alleles to assess risk of expansion upon transmission. Nygren et al 2008. Chen et al 2011. targeted mutation analysis by PCR. The clinical usefulness of such testing awaits publication of the full study. multiplex ligation-dependent probe amplification (MLPA). Lyon et al 2010.or whole-gene) <1% FMR1 deletions Deletion/duplicati Large (partial. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. See Molecular Genetic Pathogenesis. Weinhausel & Haas 2001. Lack of amplification by PCR prior to sequence analysis can suggest a putative partial or whole-gene deletion on the X chromosome in affected males. 7. 3. Methylation status can be determined by either Southern blot or methylation-specific PCR. The ability of the test method used to detect a mutation that is present in the indicated gene 2. 5. Sequence analysis. 6. included in the variety of methods that may be used are: quantitative PCR. 8 <1% 1.or whole-gene) <1% on analysis 7 FMR1 deletions / duplications Sequence analysis FMR1 sequence variants 2. Coffee 2009.

Interpretation of test results  For issues to consider in interpretation of sequence analysis results.. including:  Those who have a strong clinical indication (including risk of being a carrier) and who have had a normal or ambiguous cytogenetic fragile X test result. especially if they have any of the following:  Any physical or behavioral characteristics of fragile X syndrome  A family history of fragile X syndrome  Male or female relatives with undiagnosed intellectual disability Individuals who have a cytogenetic fragile X test result that is discordant with their phenotype. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense.e.. and  Those with an atypical phenotype who have had a positive cytogenetic fragile X test result Note: Chromosome analysis using modified culture techniques to induce fragile sites (i. developmental delay.g. o Males and females older than age 50 years who have progressive cerebellar ataxia and intention tremor with a positive family history of FMR1-related disorders in whom other common causes of ataxia have been excluded (see Ataxia Overview) . typically. and splice site mutations. molecular genetic testing of a second tissue type (e. Testing algorithm): o o Individuals of either sex with intellectual disability. skin fibroblasts) should be considered [MacKenzie et al 2006].8. cytogenetic fragile X test) is no longer used for diagnosis of fragile X syndrome because it is less sensitive and more costly than molecular genetic testing. exonic or whole-gene deletions/duplications are not detected.  If the clinical phenotype is consistent with fragile X syndrome and molecular genetic testing of DNA extracted from leukocytes is normal. Testing Strategy Confirming/establishing the diagnosis  Molecular genetic testing is appropriate for the following (see Figure 1. click here. or autism. nonsense.

e.) Clarification of the genetic status of women seeking reproductive counseling who have a family history of FMR1-related disorders requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family or the presence of undiagnosed intellectual disability.. Southern blot. When PCR detects one normal allele in a male or two in a female. o Sequence analysis is very rarely needed.o  Women with unexplained POI [Corrigan et al 2005] Molecular genetic laboratory testing o Molecular genetic testing for fragile X syndrome must include method(s) to detect all types of FMR1 allele expansions. typically. Southern blot analysis detects these complex alterations in most cases. Note: (1) Female carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. or another method to detect hypermethylation. Schmucker & Seidel 1999]. See Testing Strategy. i. The boxes marked with asterisks (*) identify individuals to be considered for FMR1 molecular testing. fragile Xassociated tremor ataxia syndrome and primary ovarian insufficiency (POI) in premutation . Very few affected individuals have been identified with a mutation outside of the CGG repeats. in individuals who have cellular mosaicism for the FMR1 repeat PCR may give a false negative result because it cannot detect mosaicism for larger premutation and full mutation alleles [Orrico et al 1998. should be performed for premutations and full mutations detected by PCR.  Rarely.  For intermediate and small premutation alleles in carrier females.. o FISH or deletion/duplication analysis should be used if PCR fails to detect the CGG repeats in a male or in female relatives of a proband known to have an FMR1 deletion. Southern blot analysis may not always be indicated. Figure Figure 1.. AGG trinucleotide genotyping may be useful to assess risk of allele expansion upon transmission. these are PCR and Southern blot analysis. Testing algorithm for FMR1-related disorders. intellectual disability in full-mutation carriers. Confirming/establishing the diagnosis in a proband for further discussion (more.

FXTAS. and POI are known to be associated with mutations in FMR1.carriers. premutation. hence. CVS. The phenotypic features of males with a full mutation and. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls. and deletion) with only learning disability [Han et al 2006] also raises issues concerning gene and protein expression in FMR1-related phenotypes. vary in relation to puberty (see Clinical features in males with fragile X syndrome). while a standard technique for prenatal diagnosis. may lead to a situation in which follow-up amniocentesis is necessary to resolve an ambiguous result. Hagerman et al 2009]. Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family. Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family. However. providing more evidence for such an association [Chonchaiya et al 2010]. the fragile X syndrome. Delayed attainment of . and recurrent otitis media are problems in infancy that require medical attention [Hagerman & Hagerman 2002]. Note: Results from chorionic villus sampling (CVS) testing must be interpreted with caution because often the methylation status of FMR1 is not yet established in chorionic villi at the time of sampling. preliminary studies of the correlation of FMR1 allele size variations in the normal and premutation range suggest a possible relationship to mild intellectual disability in females [Allen et al 2005] and males [Loat et al 2006. Genetically Related (Allelic) Disorders No phenotypes other than fragile X syndrome. Hypotonia. A male with complex FMR1 mosaicism (full mutation. Prepubertal males tend to have normal growth but large occipitofrontal head circumference (>50th percentile). gastroesophageal reflux. Predictive testing for at-risk asymptomatic adult family members (male relatives at risk for FXTAS and female relatives at risk for POI) requires prior identification of an expanded (or altered) FMR1 allele in the family. Go to: Clinical Description Natural History Males with full-mutation alleles (fragile X syndrome). (2) Identification of female carriers requires appropriate molecular genetic testing to identify their status.

Behaviors in postpubertal males with fragile X syndrome often include tactile defensiveness. cardiac (mitral valve prolapse). prominent jaw Postpubertal features . The comorbid diagnosis of autism occurs in nearly 25% of affected individuals [Hatton et al 2006]. and prominent jaw) and genitalia (macro-orchidism). orthopedic (joint laxity). autism o Intellectual disability: IQ 30-50 o Abnormal craniofacies: long face. Other physical features not readily recognizable in the preschool-age child become more obvious with age. and cutaneous (excess softness and smoothness) abnormalities have also been noted. hand flapping. Clinical features in males with fragile X syndrome (adapted from Tarleton & Saul [1993])    Delayed developmental milestones (usual age of attainment in boys) o Sit alone (10 months) o Walk (20. these issues typically do not require significant intervention. prominent forehead. Except for the strabismus. hyperactivity. and occasionally autism). and abnormal temperament (hyperactivity. Hagerman et al 2009]. hand biting. especially speech o Abnormal temperament: tantrums. large ears. and distractibility. Ophthalmologic (strabismus).6 months) o First clear words (20 months) Prepubertal features o Developmental delay. Note: Recent evidence suggests an increased risk for autism spectrum disorder and/or attention deficit disorder in premutation carriers as well [Farzin et al 2006. These involve the craniofacies (long face. temper tantrums. large ears. The behaviors tend to become more obvious over time. perseverative speech. poor eye contact. prominent forehead.motor milestones and speech is apparent in the first several years of life. problems in impulse control. Periventricular heterotopia and other neuroradiologic abnormalities [Moro et al 2006] are consistent with abnormal neuronal migration and development suggested by the metabotropic glutamate receptor (mGluR) theory of fragile X intellectual disability (see Molecular Genetics).

Hunter et al 2009]. executive function deficits. aortic root dilatation o Dermatologic: usually soft and smooth skin Females heterozygous for full-mutation alleles (fragile X syndrome). The physical and behavioral features seen in males with fragile X syndrome have been reported in females heterozygous for the full mutation. and autonomic dysfunction [Loesch et al 2005. dementia. Both males and females with a premutation are at increased risk for FXTAS. Fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an FMR1 premutation [Jacquemont et al 2004. Jacquemont et al 2006]. Kogan et al 2008. lower-limb proximal muscle weakness. o Macro-orchidism o Abnormal behavior: shyness. Other neurologic findings include short-term memory loss. McConkie-Rosell et al 2007. Louis et al 2006.5%) than in males (45. Rodriguez-Revenga et al 2009]. The prevalence of FXTAS is estimated at approximately 40% to 45% overall for males with premutations who are older than age 50 years [Grigsby et al 2005. Jacquemont et al 2006. cognitive decline. but with lower frequency and milder involvement. Grigsby et al 2006. pes planus Other features o Cardiac: mitral valve prolapse. gaze aversion o Ophthalmologic: strabismus o Orthopedic: joint hyperextensibility. FXTAS occurs in both males and female premutation carriers. Bacalman et al 2006. Table 3. parkinsonism. Penetrance in males is age related (see Table 3).5%) [Rodriguez-Revenga et al 2009]. but the penetrance in individuals older than age 50 years is lower in females (16. Risk for FXTAS by Age in Males with an FMR1 Premutation Age in Years Risk 50-59 17% 60-69 38% 70-79 47% ≥80 75% Adapted from Grigsby et al [2005] . peripheral neuropathy.

) Sullivan et al [2005] suggest that variation in the age at menopause in the general population may be related to FMR1 CGG repeat size below 80. Increasing premutation repeat lengths are correlated to increasing likelihood of developing FXTAS [Tassone et al 2007. A significant increase of alleles in the 35 to 54 range was found in women with POI [Bretherick et al 2005]. increased ventricular volume. A retrospective longitudinal review of 55 males with premutations provides early natural history information of FXTAS [Leehey et al 2007]. defined as cessation of menses before age 40 years. and increased white matter hyperdensity) appear to correlate with premutation CGG repeat length [Cohen et al 2006].5 was estimated for intermediate repeat sizes of 41-58 [Wittenberger et al 2007]. prevalence estimates range from approximately 8% to 16. . Ovarian failure has occurred as early as age 11 years. A premutation carrier woman had a child with fragile X syndrome after her diagnosis with POI [Corrigan et al 2005. compared to a 1% background risk. Hunter et al [2008] suggested that other factors in addition to CGG repeat size affect the age at menopause. Life expectancy after onset of symptoms ranged from five to 25 years. Currently.5% of female premutation carriers [Coffey et al 2008.While FXTAS is more difficult to ascertain in females because of milder clinical presentation. The first sign to appear is usually tremor at approximately age 60 years. Nelson et al 2005]. McConkieRosell et al 2007]. Uzielli et al 1999. Premutation for additional risk estimates. (See Genotype-Phenotype Correlations. a finding further supported by data from Ennis et al [2006]. larger premutations (>80 CGG repeats) carried lower risk for POI. Rodriguez-Revenga et al 2009]. FMR1-related primary ovarian insufficiency (POI). In this review an odds ratio of 2. In all three studies. See Sullivan et al [2011] for a review. It is estimated that 5%-10% of women may conceive after the diagnosis of POI is established [Nelson et al 2005]. Ataxia tends to develop two years later. Sherman [2005] concluded that the risk for POI was 21% (estimates ranged from 15% to 27% in various studies) in premutation carriers. leading to increased tendency to fall and subsequent dependence on walking aids. Machado-Ferreira Mdo et al 2004. has been observed in carriers of premutation alleles [Murray et al 1999. an additional study with over 360 women failed to demonstrate an increased risk for POI for women with alleles in the high normal and intermediate range (35-58 repeats) [Bennett et al 2010]. The earlier findings that alleles in the high normal and intermediate range conferred an increased risk for FMR1-related POI [Bretherick et al 2005. no consensus exists for estimating an absolute risk for POI when a woman has high normal or intermediate repeat alleles. Hundscheid et al 2000. Bussani et al 2004. Leehey et al 2008]. The diagnosis of POI does not eliminate the possibility of subsequent conception. Bodega et al 2006] were not supported by a recent more robust study [Bennett et al 2010]. Neuroradiologic signs (decreased cerebellar volume.

Women with full mutation alleles are not at increased risk for POI. methylated in affected with ID. Chonchaiya et al 2010]. ~50% normal intellect Partial: unmethylated in the premutation cell Nearly 100% line. Types of FMR1 Repeat Expansion Mutations Mutation Type Number of CGG Methylation Trinucleotide Status of FMR1 Repeats Premutatio ~55-200 n Unmethylated Full mutation Completely methylated >200 Varies between premutation and Repeat size full mutation in mosaicism different cell lines Methylation >200 mosaicism Unmethylat ed full >200 mutation Clinical Status Male At risk for FXTAS 100% with MR Female 1 At risk for POI and FXTAS 1 ~50% with ID. Genotype-Phenotype Correlations The phenotype of males with an FMR1 mutation depends almost entirely on the nature of the mutation. the phenotype of females with an FMR1 mutation depends on both the nature of the FMR1 mutation and random X-chromosome inactivation (see Table 4). Table 4. Bourgeois et al 2009. Hunter et al 2009. This . the full-mutation may be higher cell line functioning 2 than Highly variable: Partial: mixture of males with full ranges from mutation methylated and normal unmethylated cell intellect to lines affected Nearly all have ID but often have Unmethylated high-functioning MR to low-normal intellect ID=intellectual disability 1. 2. FMR1 mutations are complex alterations involving non-classic gene inactivating mutations (trinucleotide repeat expansion) and abnormal gene methylation. Both males and females with premutations and manifestations of some symptoms of fragile X syndrome have been reported [Riddle et al 1998.

Males who have a full FMR1 mutation generally have moderate to severe intellectual disability and may or may not have a distinctive appearance. The difficulties are usually not socially debilitating. however. in which full mutations have varying degrees of methylation. and these individuals may still marry and have children. approximately 50% of females who are heterozygous for the full mutation are intellectually normal.9 80-99 25. Odds Ratios for POI by Premutation Size Premutation Size in CGG Repeats Odds Ratio for POI 59-79 6. Premutation. As noted in Table 4. It is estimated that 21% of premutation carriers develop POI [Sherman 2005]. such individuals are usually intellectually disabled.4 Sherman [2005] Full mutation. Mosaicism is present in approximately 15%-20% of individuals with FMR1 mutations. Mosaicism. Although some data suggest that individuals with repeat size mosaicism or methylation mosaicism perform at a higher intellectual level than those with completely methylated full mutations. the traditional demarcation denoting intellectual disability (previously referred to as mental retardation). Table 5. Such mosaicism may be (1) "repeat size mosaicism. The variability among females is believed to result from the ratio in the brain of active X chromosomes with the FMR1 full mutation to inactive X chromosomes with the normal FMR1 allele. Conversely. or (2) methylation mosaicism. other studies confirm that these increased risks tend to plateau above 80-100 repeats [Bodega et al 2006. . Males and females who have a fragile X premutation have normal intellect and appearance. they are usually less severely affected than males with a full mutation.complexity at the gene level affects production of the FMR1 protein and may result in an atypical presentation in which affected individuals occasionally have an IQ above 70. Approximately 50% of females who have a full FMR1 mutation are intellectually disabled." in which both full mutations and premutations are present (also termed "full-mutation / premutation mosaicism"). Although the numbers vary slightly. The odds ratios for POI in premutation carrier females increase with increasing repeat sizes [Sherman 2005] (see Table 5).1 >100 16. a few individuals with a premutation have subtle intellectual or behavioral symptoms including learning difficulties or social anxiety. Ennis et al 2006]. footnote 1.

Unaffected female FMR1 premutation carriers.000 males affected with the syndrome (often still quoted in the fragile X literature) were based on the cytogenetic detection of the fragile site FRAXA for confirmation of the diagnosis of fragile X syndrome in males with intellectual disability.) More recent studies using molecular genetic testing of FMR1 have estimated a prevalence of 16 to 25:100.. Prevalence Fragile X syndrome. although confidence intervals overlap those estimated for whites from this and other studies (27:100. Typically. In an analysis of 36. myotonic dystrophy type 1. Many families transmit premutation FMR1 alleles for generations with little or no presentation of clinical symptoms until a full mutation is produced. The prevalence of females who are unaffected FMR1 premutation carriers is high: .000) [Crawford et al 2002].000. and FRAXF) were likely included in the initial estimates.Rarely. anticipation occurs when less severely affected premutation or mosaic mutation carriers transmit unstable FMR1 alleles to their offspring (e. A blinded study of 10.g. (Cytogenetic differentiation of these fragile sites is difficult because they are located in close proximity in the Xq27-q28 region.000) than reported previously for whites. Prevalence estimates of males with fragile X syndrome have been revised downward since the isolation of FMR1 in 1991. However. Individuals with intellectual disability coincidentally having other chromosomal fragile sites near FRAXA (e. resulting in an affected individual. 95% CI. transmission from a grandfather who carries a premutation to his daughter. Coffee et al [2009] determined that the incidence of a full mutation (and hence. The milder phenotype appears to be related to FMRP production arising from transcription of unmethylated alleles [Tassone et al 1999].046 newborn males in Taiwan yielded one male with a full mutation and estimated prevalence of 1:1. A population-based prevalence study of affected African American males revealed a higher estimate (39:100. for example..000 males affected with the fragile X syndrome (using intellectual disability as the hallmark clinical finding) [de Vries et al 1997]. the anticipation found in families with members affected with fragile X syndrome is not classic. who has intellectual disability as a result). FRAXD. these individuals produce at least some FMRP because FMR1 is unmethylated.g. FRAXE. Presumably.000. as is that found in. whose premutation expands into a full mutation when she transmits it to her son. The existence of these exceptional individuals suggests that repeat expansion and methylation of the gene are not absolutely coupled. 95% CI. fragile X syndrome) was 1:5164. Original estimates of 80:100. 19-78:100. The prevalence of females affected with fragile X syndrome is presumed to be approximately one half the male prevalence. individuals with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported. Anticipation Fragile X syndrome is a trinucleotide repeat disorder that may demonstrate anticipation in some families. 13-54:100.674 for males with a premutation and 1:143 for intermediate (45-54) alleles [Tzeng et al 2005].124 newborn males.

000) and of intermediate alleles. Any child (male or female) with delay of speech. Go to: Differential Diagnosis Developmental delay/ intellectual disability. representing a prevalence of 1:113 (885:100. Rauch et al [2006] found the yield to be 1.000. In 10. Moeschler & Shevell 2006].XX POI [reviewed in Sullivan et al 2011].  In nearly 2. language.  In the largest study to date from a laboratory database of more than 59. a single occurrence in a family) have a premutation in FMR1 [Brussino et al 2005. 41 were found to have an FMR1 premutation. chromosome analysis should be performed as a part of their laboratory evaluation [Moeschler & Shevell 2006].000) [ToledanoAlhadef et al 2001]. the prevalence of premutations was 1:382 (262:100. especially in the presence of a family history of intellectual disability and a consistent physical and behavioral phenotype.3% (0. Females with FMR1-related POI. When fragile X molecular genetic testing is used regularly in this large and loosely defined group of unselected males with intellectual disability.334 Israeli women of child-bearing age.2%. Males with FXTAS.e.300 women from the United States.7% for a premutation) [Strom et al 2007].000 tests. the yield of positive test results is relatively low (~3%-6%) [Curry et al 1997. 1:143 (699:100. and the absence of structural abnormalities of the brain or other birth defects [Curry et al 1997. Cellini et al 2006]. Conditions to be considered in the differential diagnosis include the following: .. Shevell et al 2003]. The signs of fragile X syndrome in early childhood are nonspecific. 1. In a more recent study. 1:373-1:198 (268-505:100. or motor development of unknown etiology should be considered for fragile X testing. including three asymptomatic women with full mutations. representing a prevalence of 1:259 [386:100. 127 were found to have CGG repeats greater than 54.000) [Cronister et al 2005]. the overall female carrier frequency was 1. An estimated 2%-4% of men with adult-onset cerebellar ataxia who represent simplex cases (i. The FMR1 premutation accounts for 4%-6% of all cases of 46.000)] [Rousseau et al 1995].  In 14. Because cytogenetic abnormalities have been identified as frequently or more frequently than FMR1 mutations in developmentally disabled or intellectually impaired individuals referred for fragile X testing.61% for full mutation. 95% CI.624 French-Canadian women. with developmental delay being an almost universal manifestation among affected individuals.

The differential diagnosis for FXTAS is broad. Cellini et al 2006]. dementia. a single occurrence in a family) have a premutation in FMR1 [Brussino et al 2005. incomplete puberty. It is associated with behavioral problems.  Attention deficit-hyperactivity disorder (ADHD). and characteristic facial appearance are common. Mild intellectual disability (not as severe as that typically seen in fragile X syndrome) without consistent physical features has been described in males with expanded CCG repeats in FMR2 at the FRAXE fragile site. One group of 56 individuals had 98 different diagnoses prior to the diagnosis of FXTAS. FRAXA and FRAXE are distinct fragile sites. seizures. and obsessive-compulsive characteristics are common. stubbornness. tremor. Hypogonadism (genital hypoplasia.  Fragile XE syndrome (FRAXE). However. followed by early childhood onset of excessive eating and development of morbid obesity unless controlled. All individuals have developmental delay and cognitive impairment. Most of these were in the following categories: parkinsonism. Diagnosis is by DNA-based methylation testing to detect abnormal parentspecific imprinting within the Prader-Willi critical region on chromosome 15. autonomic dysfunction. A small subset of people with fragile X syndrome have the hyperphagia and obesity characteristic of PWS.  Adult-onset neurologic disorders. congenital cardiac anomalies. The genes spanning the two fragile sites are designated FMR1 (FRAXA) and FMR2 (FRAXE). Sotos syndrome is characterized by typical facial appearance. and stroke [Biancalana et al 2005. Temper tantrums. PWS is characterized by severe infantile hypotonia and feeding difficulties. short stature.  Autism.  Prader-Willi syndrome (PWS). Go to: . overgrowth. infertility). neonatal jaundice. Sotos syndrome. in most. Hyperactivity is frequently seen in individuals with fragile X syndrome.. and a slightly increased risk for sacrococcygeal teratoma and neuroblastoma. It is estimated that 2%-4% of men with adult-onset cerebellar ataxia who represent as simplex cases (i. Approximately 80%-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. the genes do not have any detectable similarity at the DNA level and the associated clinical entities are discrete. ataxia. manipulative behavior. and learning disability ranging from mild to severe. albeit in close proximity on the X chromosome. scoliosis. Hall et al 2005]. renal anomalies. Autistic-like behavior is frequently found in individuals with fragile X syndrome. and.e.

gynecologic evaluation including hormonal and/or ultrasonographic assessment is appropriate. primarily joint hyperextensibility and pes planus  Cardiac auscultation for mitral valve prolapse. the following are recommended:  Neurologic examination  Behavioral and psychological assessment  Neuroradiologic evaluation POI.  Assessment for hypertension  History for possible seizure activity  Ophthalmologic evaluation for possible strabismus  In young children. anxiety. history and physical examination for evidence of recurrent otitis media FXTAS. the following evaluations are recommended:  Complete developmental and educational assessments (including speech and language evaluation and occupational/physical therapy evaluation) for educational planning  Behavioral and psychological assessment to determine the presence of concentration/attention problems. feeding assessment (including attention to possible gastroesophageal reflux)  Physical examination to evaluate for hypotonia and/or connective tissue findings. To establish the extent of disease in an individual diagnosed with FXTAS. To establish the extent of disease in an individual diagnosed with fragile X syndrome. To establish the extent of disease in a woman diagnosed with POI.Management Evaluations Following Initial Diagnosis Fragile X syndrome. and depression  In infants. consider echocardiography (usually in adulthood). If indicated by a murmur or click. Note: The diagnosis of POI does not eliminate the possibility of subsequent conception. A premutation carrier woman had a child with fragile X syndrome after being diagnosed with POI . obsessive-compulsive disorder. aggression.

[Corrigan et al 2005. Agents/Circumstances to Avoid Folic acid should be avoided in individuals with poorly controlled seizures [Hagerman 2002].  Pharmacologic management of behavioral issues that significantly affect social interaction is appropriate. . No particular pharmacologic treatment has been shown to be uniquely beneficial.  Early educational intervention. Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Treatment of Manifestations Fragile X syndrome. More specific guidelines are available through education resources (see Resources). FXTAS. Supportive therapy for children and adults with fragile X syndrome currently consists of the following [Hagerman et al 2009. and the avoidance of sudden change. A closely monitored and integrated program of behavioral management and pharmacologic treatment with an experienced developmental team may prove to be beneficial. and vocational training should be aimed specifically at the known impediments to learning.  Routine medical management of strabismus. for access to information on clinical studies for a wide range of diseases and conditions. gastroesophageal reflux. Parents and teachers of children with fragile X syndrome have recognized the need for individual attention. No specific treatment is available. therapy must be individualized and closely monitored. mitral valve prolapse. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive options. special education. Supportive care for problems with gait and/or cognitive deficits may require assistance with activities of daily living. It is estimated that 5%-10% of women with POI may conceive after the diagnosis [Nelson et al 2005]. Nelson et al 2005]. small class size. Note: There may not be clinical trials for this disorder. No specific treatment is available. Utari et al 2010]:  Recognition of the need for special education and anticipatory management such as the avoidance of excessive stimulation whenever possible may ameliorate some of the behavioral difficulties. otitis media. POI. and hypertension is appropriate. No specific treatment is available. Therapies Under Investigation Search ClinicalTrials.

Offspring of an individual with a full mutation  Males with a full mutation have intellectual disability and generally do not reproduce. cultural. inheritance.  Men with premutations are at risk for FXTAS..  Women with normal alleles with greater than 54 repeats may be at increased risk for POI. hypermethylated allele of >200 trinucleotide repeats) is a carrier of a premutation or full mutation and may be affected.. —ED.e. The risk to sibs depends on their gender.Go to: Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature. This section is not meant to address all personal. Whether or not a female has phenotypic manifestations. Offspring of an individual with a premutation . The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members.  The mother of a male with a premutation has a premutation allele or an intermediate allele. and implications of genetic disorders to help them make informed medical and personal decisions. Risk to Family Members Parents of a proband  The mother of an individual with an FMR1 full mutation (i. Sibs of a proband. or ethical issues that individuals may face or to substitute for consultation with a genetics professional. a "transmitting male") or a mother who is a premutation carrier or an intermediate allele carrier. the gender of the carrier parent. and the size of the expanded allele in the carrier parent. Mode of Inheritance FMR1-related disorders are inherited in an X-linked dominant manner.  Females who inherit the full mutation are at an approximately 50% risk for intellectual disability.  An unaffected female premutation carrier may have a father who is a premutation carrier (i.  Women with premutations are at risk for POI and FXTAS.e. her offspring are at a 50% risk of inheriting the full mutation.

offspring are at negligible risk of being affected.. contraction of trinucleotide repeat number. In some categories. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender and family relationship). the risk of a maternal premutation becoming a full mutation on transmission to her offspring is correlated with the number of CGG trinucleotide repeats in the premutation. the risk to offspring of an individual with a larger intermediate allele of inheriting a premutation allele is low but greater than that of the general population. Other family members of a proband. For example. Offspring of an individual with an intermediate allele. When premutations are transmitted by the father. risks were significantly different if the premutation was carried by women with a family history of fragile X. o In general. Very rarely. risk assessment for expansion of a maternal premutation to a full mutation on transmission to offspring is nearly always based on the number of CGG trinucleotide repeats in the premutation. Intermediate alleles ranging from 50 to 54 repeats may be somewhat more unstable than those with fewer than 50 repeats.  Females who are premutation carriers have a 50% risk of transmitting an abnormal (premutation or full mutation) allele in each pregnancy. maternal premutation alleles with 70-79 CGG repeats had a 54% risk for expansion if there was a family history of fragile X versus an 18% risk in the absence of a family history." The premutation is inherited by all of their daughters and none of their sons. the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion (see Molecular Genetic Testing and Molecular Genetics). Nolin et al [2011] recently compared the risk of expanding to a full mutation relative to the size of the premutation allele (N=95). Thus. has been reported [Vits et al 1994]. (In actuality.) All daughters of transmitting males are unaffected premutation carriers. About 16% of maternal transmissions of an intermediate allele may occasionally have a minor variation in repeat size (i. small increases in trinucleotide repeat number may occur but do not result in full mutations. o For small premutations. Males who are premutation carriers are considered "transmitting males. premutations transmitted from father to daughter may often regress slightly in repeat number. Intermediate alleles may infrequently contract by a few repeats. Note: Because most clinical laboratories do not examine the AGG repeat status and its clinical utility remains to be fully explored. such as contraction of a premutation of 110 repeats in a mother to 44 repeats in her daughter. and rarely by sufficiently large number of repeats to be in the normal range [Nolin et al 2011]. and potentially may become premutation size (>55 repeats) [Nolin et al 2011]. .e. a change of 1 or 2 repeats).

Primary ovarian insufficiency (POI) in females with premutation alleles. Fewer than 8% of women elected such testing. Related Genetic Counseling Issues Family history. Half of the surveyed families reported having subsequent pregnancies before diagnosis of the first affected child. See Sullivan et al [2011] for a review. The presence of premutation carriers within families leads to pedigrees with generation-skipping or seemingly spontaneous occurrences of fragile X syndrome with no previous family history of the disorder. The first indication of fragile X syndrome within a family is usually the diagnosis in an affected child. These findings emphasize the importance of increased opportunities for early diagnosis so that children and families can receive all possible benefits. Nelson et al 2005]. A survey to assess the timing of a diagnosis in an affected child and genetic counseling for the family indicated that in approximately half of the families surveyed.e. Fragile X tremor ataxia syndrome (FXTAS) in males with premutation alleles. age at menopause <40 years) in female premutation carriers should be taken into account when providing genetic counseling. When a child is diagnosed with fragile X syndrome and his mother is found to have a premutation allele. Grandchildren of transmitting males. their offspring are at risk for fragile X syndrome. For additional information regarding population-based testing see McConkie-Rosell et al [2007]. The increased risk for POI (i. The daughters of transmitting males are premutation carriers.. thus. Premutation carrier females are also at increased risk for neurologic and psychiatric problems [Chonchaiya et al 2010]. It is estimated that 5%-10% of women with POI may conceive after the diagnosis [Nelson et al 2005].Carrier Detection Carrier testing of at-risk females is possible and involves determination of the trinucleotide repeat number and the FMR1 methylation status (see Molecular Genetics). Note: The diagnosis of POI does not eliminate the possibility of subsequent conception. Early diagnosis of fragile X syndrome. Fragile X syndrome carrier screening has been offered to women not known to be at risk in the prenatal genetic counseling setting [Cronister et al 2005]. including genetic counseling and intervention services [Centers for Disease Control and Prevention 2002]. A premutation carrier woman had a child with fragile X syndrome after being given the diagnosis POI [Corrigan et al 2005. Anido et al [2005] analyzed women's attitudes toward carrier testing and suggest that non-carrier women from the general population would be unprepared to learn that they are carriers. the diagnosis was made more than a year after the child's development or behavior first raised concerns. . Population-based carrier testing. his maternal grandfather is then known to be at risk of developing FXTAS.

however. Implantation of embryos detected with normal alleles led to unaffected offspring. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified. . Gamete donation. differences in FMR1 methylation patterns may occur in DNA derived from cells obtained by CVS. clarification of carrier status. making the distinction between large premutations and small full mutations difficult. and discussion of the availability of prenatal testing is before pregnancy. Transmission of a fragile X premutation has occurred via sperm donation [Wirojanan et al 2008] prompting the suggestion that all egg and sperm donors have FMR1 molecular genetic testing. Family planning  The optimal time for determination of genetic risk. consideration should be given to banking DNA of affected individuals. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Malcov et al 2007].  It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Technical improvements enabling better testing of FMR1 in single embryonic cells produced for PGD have recently been reported [Burlet et al 2006. and diseases will improve in the future. The FMR1 Southern blot patterns for DNA derived from amniocytes are identical to those found in adult tissues. for pregnancies evaluated by CVS. or are at risk of being carriers.For additional information regarding genetic counseling and cascade testing see McConkieRosell et al [2007]. Thus. mutations. are carriers. follow-up amniocentesis or testing using PCR may be necessary to determine the size of the FMR1 alleles in a methylation-independent manner [McConkieRosell et al 2005]. Because it is likely that testing methodology and our understanding of genes. Prenatal Testing Prenatal testing for fetuses at increased risk for FMR1 full mutations can be performed using DNA extracted from cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation (see Molecular Genetic Testing and Published Guidelines/Consensus Statements).

FXTAS and POI resulting from FMR1 premutations may be manifestations of RNA-mediated toxicity [Galloway & Nelson 2009]. The mGluR theory of fragile X intellectual disability is based on the observation that activated group 1 metabotropic glutamate receptors (mGluRs) mediate long-term depression of transmission at hippocampal synapses. FXTAS 300624 FRAGILE X MENTAL RETARDATION SYNDROME 309550 FMR1 GENE. FMR1 Molecular Genetic Pathogenesis Nearly all FMR1 mutations (>99%) resulting in fragile X syndrome occur as trinucleotide repeat (CGG) expansions accompanied by aberrant hypermethylation of the gene. Kenneson et al [2001] found a decrease in FMRP and an increase in transcription of FMR1 in premutation carriers. locus name. Table B. These findings suggest that mRNA over-production from FMR1 premutations may exert an effect on intracellular transport of mRNAs produced by FMR1 and other genes. —ED. Methylation of the CGG expansion results in decrease or silencing of FMR1 transcription and loss of the protein encoded by the gene (see Abnormal gene product).Molecular Genetics Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. critical region. FMR1-Related Disorders: Genes and Databases Gene Symbol FMR1 Chromosomal Locus Xq27. click here. Hagerman et al [2001] and Jacquemont et al [2004] review evidence of dysregulation of FMR1 in the premutation range.3 Protein Name Fragile X mental retardation 1 protein Locus Specific FMR1 @ LOVD HGM D FMR1 Data are compiled from the following standard references: gene symbol from HGNC. Thus. chromosomal locus. a process that requires translation of preexisting mRNA . OMIM Entries for FMR1-Related Disorders (View All in OMIM) 300623 FRAGILE X TREMOR/ATAXIA SYNDROME. Deletions and point mutations in FMR1 account for the remaining mutations found in individuals with the syndrome. Table A. which may explain many of the clinical observations. For a description of databases (Locus Specific. protein name from UniProt. Paradoxically. Repeat expansion to the disease-causing range occurs only when a premutation or full mutation is transmitted by females to their offspring. HGMD) to which links are provided. complementation group from OMIM.

Sequences of uninterrupted CGG repeats beyond the last AGG repeat ("pure CGG trinucleotide repeats") greater than approximately 33-39 triplets appear to increase the instability of maternal alleles and increase the risk for expansion of the number of trinucleotide repeats on transmission to offspring [Eichler et al 1994. Recent results have linked the length of the uninterrupted 3’ CGG repeat length with expansion of intermediate and small . composed primarily of CGG.. Bodega et al 2006] but a recent study was unable to replicate this finding [Bennett et al 2010]. An important predictor of repeat instability in large intermediate alleles (>50 repeats) is the number of "pure" CGG repeats without interrupting AGG repeats.near synapses. probably by disruption of DNA secondary structures that may form during DNA replication. Large increases in the number of the CGG trinucleotide repeats contained in FMR1 occur exclusively during transmission from female carriers (see Genetic Counseling). are more likely to become unstable [Eichler et al 1994]. Kunst & Warren 1994]. These AGG repeats appear to "anchor" the segment against repeat expansion. some uncertainty exists regarding alleles with fewer than 55 repeats. Kunst & Warren 1994]. The risk for increase in the size of the expansion of maternal premutation alleles depends on the number of CGG repeats and the presence of AGG triplets embedded in the CGG repeat segment [Eichler et al 1994. is contained in the untranslated portion of exon 1 ending 69 bp upstream of the translational start. FMR1 occupies 38 kb of genomic DNA and has 17 exons contained in a messenger RNA of approximately 4 kb. near the 5' end of the gene. See Molecular Genetic Testing). Alternative splicing of FMR1 occurs toward the 3' end of the mRNA. mGluR-dependent protein synthesis may be exaggerated and result in the fragile X syndrome phenotype [Bear et al 2004]. Normal allelic variants.  AGG repeats. CGG repeat lengths in the high normal (35-44) and intermediate (45-54) ranges have been reported to be associated with POI [Bretherick et al 2005. especially those with more than 35 uninterrupted CGG repeats. The mGluR theory of fragile X syndrome hypothesizes that in the absence of the FMRP. Increasingly longer pure repeats. Variation of the repeat copy number in normal (i. Loss of FMRP increases long-term depression of transmission at hippocampal synapses in the fmr-1 mouse model and likely has the same effect in individuals with the fragile X syndrome.e.  Intermediate alleles. stable) alleles ranges from five to 44 CGG repeats. In most FMR1 alleles the sequence of CGG trinucleotide repeats is interrupted by an AGG at repeat 9 or 10 and 19 or 20 (and occasionally repeat 30) [Eichler et al 1994]. Evidence strongly indicates that the FMRP represses translation of specific mRNAs. with a trimodal distribution consisting of a major peak at around 30 repeats and minor peaks at around 20 and 40 repeats. A trinucleotide repeat. Variation of the repeat number in intermediate alleles is approximately 45-54 repeats. while premutation alleles clearly have an increased risk for POI. Thus.

It is the loss of FMRP that results in the fragile X syndrome phenotype. FMRP contains both a nuclear localization signal and a nuclear export signal. The product of FMR1. see Table A. the number and structure of AGG trinucleotide interrupts may also affect the risk of expansion [Nolin et al 2011]. risk of expansion is dependent upon the number of CCG repeats in the mother's premutation allele. Expansion of the CGG repeat number beyond approximately 200. an individual will appear to have no cells in which the abnormal promoter methylation events have occurred even when more than 200 CGG repeats are found. accompanied by hypermethylation of the deoxycytosine residues in the FMR1 promoter. FRAXA. suggesting . inhibits or reduces FMR1 transcription. Newer methods promise to overcome the limitations of Southern blot analysis and greatly increase the sensitivity of PCR-based diagnosis for the full range of FMR1 mutations [Chen et al 2010. The protein contains two KH-binding domains found in other proteins with RNA-binding properties and appears to function as an RNA-binding protein that interacts with a subset of mRNAs containing G-quartet motifs. Wang et al 1997] have been reported but account for far fewer than 1% of those with fragile X syndrome. there is a surprising paucity of reports of individuals with point mutations or other small alterations in FMR1 resulting in fragile X syndrome. Nahhas et al 2011]. also occurs in some individuals. Expansion can result in an FMR1 full mutation that causes fragile X syndrome in offspring. in which both premutation and full-mutation cell lines are present. Although FMR1 would be expected to have a mutation rate similar to other genes. Pathologic allelic variants.  Premutation FMR1 alleles.) Normal gene product. Lyon et al 2010. Rare individuals with deletions of all or part of FMR1 (reviewed in Hammond et al [1997]) or point mutations in FMR1 [De Boulle et al 1993. Cellular mosaicism. Chen et al 2011. Lugenbeel et al 1995.premutation alleles and suggest a minimum threshold for expansion risk [Nolin et al 2011]. is found in the cytoplasm of many cell types but is most abundant in neurons. The existence of affected individuals with deletions has confirmed that the syndrome is caused by the lack of FMR1 transcription.  Full FMR1 expansion mutation. Hantash et al 2010. fragile X mental retardation 1 protein (FMRP). (For more information. Premutation alleles often expand upon maternal transmission. Occasionally. Filipovic-Sadic et al 2010. The clinical usefulness of such testing awaits publication of the full study. Premutation alleles have 55-200 CGG repeats and are not hypermethylated.  Rare FMR1 mutations: deletion or point mutation. For smaller maternal premutation alleles." Individuals having partial methylation of full mutations ("methylation mosaics") are also observed. They do not cause fragile X syndrome in males or females. resulting in the loss of the protein product (FMRP) and giving rise to the expression of the cytogenetic fragile site. Such individuals are usually described as having "unmethylated full mutations.

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