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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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FMR1-Related Disorders

, MD, FACMG and , PhD, FACMG.

Author Information
, MD, FACMG
Greenwood Genetic Center
Greenwood, South Carolina
, PhD, FACMG
Fullerton Genetics Center
Asheville, North Carolina

Initial Posting: ; Last Revision: April 26, 2012.

Summary

Disease characteristics. FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related primary ovarian insufficiency (POI).

Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function mutation and is nearly always characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. 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 (previously referred to as mental retardation). Males with an FMR1 full mutation accompanied by aberrant methylation may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities, sometimes including autism spectrum disorder, are common.

FXTAS occurs in males (and some females) who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor.

FMR1-related POI (age at cessation of menses <40 years) occurs in approximately 20% of females who have an FMR1 premutation.

Diagnosis/testing. The diagnosis of FMR1-related disorders rests on the detection of an alteration in FMR1. More than 99% of individuals with fragile X syndrome have a loss-of-function mutation in FMR1 caused by an increased number of CGG trinucleotide repeats (typically >200) accompanied by aberrant methylation of FMR1. Other mutations within FMR1 that cause fragile X syndrome include deletions and point mutations. All individuals with FXTAS and FMR1-related POI have FMR1 premutation trinucleotide repeats ranging from 55 to approximately 200. Both increased trinucleotide repeats and methylation changes in FMR1 can be detected by molecular genetic testing.

Management. Treatment of manifestations: Fragile X syndrome: early developmental intervention, special education (individual attention, small class size, and avoiding sudden change and excessive stimulation), and vocational training; individualized pharmacologic management of behavioral issues that significantly affect social interaction; routine treatment of medical problems. FXTAS: supportive care for gait disturbance and/or cognitive deficits. POI: reproductive endocrine evaluation for treatment and counseling for reproductive options.

Agents/circumstances to avoid: Folic acid in individuals with poorly controlled seizures.

Genetic counseling. All mothers of individuals with an FMR1 full mutation (expansion >200 CGG trinucleotide repeats and abnormal methylation) are carriers of an FMR1 mutation. Mothers and their female relatives who are premutation carriers are at increased risk for FXTAS and POI; those with a full mutation may have findings of fragile X syndrome. All are at increased risk of having offspring with fragile X syndrome, FXTAS, and POI. Males with premutations are at increased risk for FXTAS. Males with FXTAS will transmit their FMR1 premutation expansion to none of their sons and to all of their daughters, who will be premutation carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diagnosis of an FMR1-related disorder has been confirmed in a family member.

GeneReview Scope

FMR1-Related Disorders: Included Disorders
  • Fragile X syndrome
  • Fragile X-associated tremor/ataxia syndrome (FXTAS)
  • FMR1-related primary ovarian insufficiency

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Fragile X syndrome. A definite diagnosis of fragile X syndrome requires the presence of a loss-of-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 SignsClinical Signs
Major
  • Premutation in FMR1
  • White matter lesions on MRI in the middle cerebellar peduncles and/or brain stem
  • Intention tremor
  • Gait ataxia
Minor
  • MRI white matter lesions in the cerebral white matter
  • 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].

Testing

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 repeats.
  • 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 transmission.

      Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
  • Full-mutation alleles. More than 200 CGG repeats, with several hundred to several thousand repeats being typical and associated with aberrant hypermethylation of the FMR1 promoter. Almost always, extensive somatic variation of repeat number is observed in a peripheral blood specimen of a patient with a full mutation. As a result, clinical laboratories may report this somatic variation as a range of several hundred repeats.

See Published Guidelines/Consensus Statements; see Amos Wilson et al [2008], Hawkins et al [2011] on the availability of reference materials for clinical laboratories.

Clinical testing

    • 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; varies by testing laboratory). However, traditional FMR1-specific PCR is less sensitive to larger premutations and fails to amplify full mutations. Newer methods promise to overcome these limitations (see Molecular Genetic Pathogenesis).
    • Southern blot analysis detects all FMR1 alleles including normal, larger-sized premutations, and full mutations and in addition determines methylation status of the FMR1 promoter region. Abnormal hypermethylation of FMR1 is the cause of transcriptional silencing and is critical to assess for premutation and full mutation alleles.

      Note: Although Southern blot analysis provides a low-resolution estimation of repeat number, traditional PCR plus Southern blot analysis has been the “gold standard” for FMR1 molecular diagnosis. As newer and more sensitive PCR methods gain acceptance in diagnostic testing, the need for Southern blot analysis of every patient may decrease [Chen et al 2010, Filipovic-Sadic et al 2010, Hantash et al 2010, Lyon et al 2010, Chen et al 2011, Nahhas et al 2011].
    • AGG trinucleotide repeat genotyping. 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. 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]. Recent results have linked the length of the uninterrupted 3’ CGG repeat length with expansion and suggest a minimum threshold for expansion risk [Nolin et al 2011]. The clinical usefulness of such testing awaits publication of the full study. This test is offered for female carriers of intermediate and small premutation alleles.
  • Methylation status can be assessed by PCR-based methods independent of measuring the number of CGG repeats
  • Sequence analysis. Very few individuals with fragile X syndrome have been identified with an intragenic FMR1 mutation.
  • Deletion/duplication analysis. Fewer than 1% of individuals with fragile X syndrome have a partial or full deletion of FMR1 (reviewed in Hammond et al [1997]). 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; confirmation may require additional testing by deletion/duplication analysis. However, 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. Deletions are typically detected in FMR1 as a secondary finding when the trinucleotide repeat region is being interrogated by Southern blot analysis, FISH, or other method (see Table 2, footnote 4). Therefore, it is likely that FMR1 deletions downstream of the repeat region, as well as other gene rearrangements, are under ascertained. Nevertheless, 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.

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Jacquemont et al 2011; see full text].

Table 2. Summary of Molecular Genetic Testing Used in FMR1-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FMR1Targeted mutation analysisPCR. CGG expansion in FMR1 (allele sizes in the normal and lower premutation range) 4, 5>99%
Southern blot. CGG expansion in FMR1 (all repeat ranges); methylation status 4, 6
AGG trinucleotide repeat genotyping. Number and position of AGG trinucleotide repeats that may interrupt the CGG repeats of FMR1 7100% of alleles of this structure 7
Methylation analysisMethylation of FMR1 promoter region 8100% of alleles with this modification
FISHLarge (partial- or whole-gene) FMR1 deletions<1%
Deletion/duplication analysis 9Large (partial- or whole-gene) FMR1 deletions/duplications <1%
Sequence analysisFMR1 sequence variants 4, 5, 10<1%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Sequence analysis, targeted mutation analysis by PCR, and in some instances Southern blot analysis cannot detect an exonic or whole-gene deletion on the X chromosome in carrier females.

5. 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; confirmation may require additional testing by deletion/duplication analysis.

6. As newer and more sensitive PCR methods gain acceptance in diagnostic testing, the need for Southern blot analysis may decrease [Chen et al 2010, Filipovic-Sadic et al 2010, Hantash et al 2010, Lyon et al 2010, Chen et al 2011, Nahhas et al 2011].

7. This test is offered for female carriers of intermediate and small premutation alleles to assess risk of expansion upon transmission. The clinical usefulness of such testing awaits publication of the full study. See Molecular Genetic Pathogenesis.

8. Methylation status can be determined by either Southern blot or methylation-specific PCR; the latter may offer a more rapid test turnaround time [Das et al 1997, Weinhausel & Haas 2001, Nygren et al 2008, Coffee 2009, Chen et al 2011].

9. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Interpretation of test results. If the clinical phenotype is consistent with fragile X syndrome and molecular genetic testing of DNA extracted from leukocytes is normal, molecular genetic testing of a second tissue type (e.g., skin fibroblasts) should be considered [MacKenzie et al 2006].

Testing Strategy

Confirming/establishing the diagnosis

  • Molecular genetic testing is appropriate for the following (see Figure 1. Testing algorithm):
    • Individuals of either sex with intellectual disability, developmental delay, or autism, 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, 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; 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.e., 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.
    • 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)
    • Women with unexplained POI [Corrigan et al 2005]
  • Molecular genetic laboratory testing
    • Molecular genetic testing for fragile X syndrome must include method(s) to detect all types of FMR1 allele expansions; typically, these are PCR and Southern blot analysis. When PCR detects one normal allele in a male or two in a female, Southern blot analysis may not always be indicated. Southern blot, or another method to detect hypermethylation, should be performed for premutations and full mutations detected by PCR.
    • 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.
    • Sequence analysis is very rarely needed. Very few affected individuals have been identified with a mutation outside of the CGG repeats.
Figure 1

Figure

Figure 1. Testing algorithm for FMR1-related disorders. The boxes marked with asterisks (*) identify individuals to be considered for FMR1 molecular testing. See Testing Strategy, Confirming/establishing the diagnosis in a proband for further discussion (more...)

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.

Note: (1) Female carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder; i.e., intellectual disability in full-mutation carriers, fragile X-associated tremor ataxia syndrome and primary ovarian insufficiency (POI) in premutation carriers. (2) Identification of female carriers requires appropriate molecular genetic testing to identify their status.

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.

Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family.

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. CVS, while a standard technique for prenatal diagnosis, may lead to a situation in which follow-up amniocentesis is necessary to resolve an ambiguous result.

Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family.

Clinical Description

Natural History

Males with full-mutation alleles (fragile X syndrome). The phenotypic features of males with a full mutation and, hence, the fragile X syndrome, vary in relation to puberty (see Clinical features in males with fragile X syndrome).

Prepubertal males tend to have normal growth but large occipitofrontal head circumference (>50th percentile). Hypotonia, gastroesophageal reflux, and recurrent otitis media are problems in infancy that require medical attention [Hagerman & Hagerman 2002]. Delayed attainment of motor milestones and speech is apparent in the first several years of life. Other physical features not readily recognizable in the preschool-age child become more obvious with age. These involve the craniofacies (long face, prominent forehead, large ears, and prominent jaw) and genitalia (macro-orchidism), and abnormal temperament (hyperactivity, hand flapping, hand biting, temper tantrums, and occasionally autism).

Behaviors in postpubertal males with fragile X syndrome often include tactile defensiveness, poor eye contact, perseverative speech, problems in impulse control, and distractibility. The behaviors tend to become more obvious over time. The comorbid diagnosis of autism occurs in nearly 25% of affected individuals [Hatton et al 2006].

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, Hagerman et al 2009].

Ophthalmologic (strabismus), orthopedic (joint laxity), cardiac (mitral valve prolapse), and cutaneous (excess softness and smoothness) abnormalities have also been noted. Except for the strabismus, these issues typically do not require significant intervention.

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).

Clinical features in males with fragile X syndrome (adapted from Tarleton & Saul [1993])

  • Delayed developmental milestones (usual age of attainment in boys)
    • Sit alone (10 months)
    • Walk (20.6 months)
    • First clear words (20 months)
  • Prepubertal features
    • Developmental delay, especially speech
    • Abnormal temperament: tantrums, hyperactivity, autism
    • Intellectual disability: IQ 30-50
    • Abnormal craniofacies: long face, prominent forehead, large ears, prominent jaw
  • Postpubertal features
    • Macro-orchidism
    • Abnormal behavior: shyness, gaze aversion
    • Ophthalmologic: strabismus
    • Orthopedic: joint hyperextensibility, pes planus
  • Other features
    • Cardiac: mitral valve prolapse, aortic root dilatation
    • 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, but with lower frequency and milder involvement.

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]. Other neurologic findings include short-term memory loss, executive function deficits, cognitive decline, dementia, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction [Loesch et al 2005, Bacalman et al 2006, Grigsby et al 2006, Louis et al 2006, McConkie-Rosell et al 2007, Kogan et al 2008, Hunter et al 2009].

Both males and females with a premutation are at increased risk for FXTAS. 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, Rodriguez-Revenga et al 2009]. Penetrance in males is age related (see Table 3). FXTAS occurs in both males and female premutation carriers, but the penetrance in individuals older than age 50 years is lower in females (16.5%) than in males (45.5%) [Rodriguez-Revenga et al 2009].

Table 3. Risk for FXTAS by Age in Males with an FMR1 Premutation

Age in YearsRisk
50-5917%
60-6938%
70-7947%
≥8075%

While FXTAS is more difficult to ascertain in females because of milder clinical presentation, prevalence estimates range from approximately 8% to 16.5% of female premutation carriers [Coffey et al 2008, Rodriguez-Revenga et al 2009].

Increasing premutation repeat lengths are correlated to increasing likelihood of developing FXTAS [Tassone et al 2007, Leehey et al 2008].

A retrospective longitudinal review of 55 males with premutations provides early natural history information of FXTAS [Leehey et al 2007]. The first sign to appear is usually tremor at approximately age 60 years. Ataxia tends to develop two years later, leading to increased tendency to fall and subsequent dependence on walking aids. Life expectancy after onset of symptoms ranged from five to 25 years.

Neuroradiologic signs (decreased cerebellar volume, increased ventricular volume, and increased white matter hyperdensity) appear to correlate with premutation CGG repeat length [Cohen et al 2006].

FMR1-related primary ovarian insufficiency (POI), defined as cessation of menses before age 40 years, has been observed in carriers of premutation alleles [Murray et al 1999, Uzielli et al 1999, Hundscheid et al 2000, Bussani et al 2004, Machado-Ferreira Mdo et al 2004, McConkie-Rosell et al 2007]. Ovarian failure has occurred as early as age 11 years. The diagnosis of POI does not eliminate the possibility of subsequent conception. A premutation carrier woman had a child with fragile X syndrome after her diagnosis with POI [Corrigan et al 2005, Nelson et al 2005]. It is estimated that 5%-10% of women may conceive after the diagnosis of POI is established [Nelson et al 2005]. See Sullivan et al [2011] for a review.

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]. Currently, no consensus exists for estimating an absolute risk for POI when a woman has high normal or intermediate repeat alleles. Sherman [2005] concluded that the risk for POI was 21% (estimates ranged from 15% to 27% in various studies) in premutation carriers, compared to a 1% background risk. In this review an odds ratio of 2.5 was estimated for intermediate repeat sizes of 41-58 [Wittenberger et al 2007]. (See Genotype-Phenotype Correlations, Premutation for additional risk estimates.)

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, a finding further supported by data from Ennis et al [2006]. A significant increase of alleles in the 35 to 54 range was found in women with POI [Bretherick et al 2005]. In all three studies, larger premutations (>80 CGG repeats) carried lower risk for POI. Hunter et al [2008] suggested that other factors in addition to CGG repeat size affect the age at menopause; 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].

Women with full mutation alleles are not at increased risk for POI.

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. Types of FMR1 Repeat Expansion Mutations

Mutation Type Number of CGG Trinucleotide Repeats Methylation Status of FMR1 Clinical Status
MaleFemale
Premutation ~55-200 UnmethylatedAt risk for FXTAS 1 At risk for POI and FXTAS 1
Full mutation >200 Completely methylated100% with MR ~50% with ID, ~50% normal intellect
Repeat size mosaicism Varies between premutation and full mutation in different cell linesPartial: unmethylated in the premutation cell line; methylated in the full-mutation cell line Nearly 100% affected with ID; may be higher functioning 2 than males with full mutationHighly variable: ranges from normal intellect to affected
Methylation mosaicism >200Partial: mixture of methylated and unmethylated cell lines
Unmethylated full mutation >200 UnmethylatedNearly all have ID but often have high-functioning MR to low-normal intellect

ID=intellectual disability

1. Both males and females with premutations and manifestations of some symptoms of fragile X syndrome have been reported [Riddle et al 1998, Bourgeois et al 2009, Hunter et al 2009, Chonchaiya et al 2010].

2. FMR1 mutations are complex alterations involving non-classic gene inactivating mutations (trinucleotide repeat expansion) and abnormal gene methylation. This 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, the traditional demarcation denoting intellectual disability (previously referred to as mental retardation).

Premutation. Males and females who have a fragile X premutation have normal intellect and appearance. As noted in Table 4, footnote 1, a few individuals with a premutation have subtle intellectual or behavioral symptoms including learning difficulties or social anxiety. The difficulties are usually not socially debilitating, and these individuals may still marry and have children.

It is estimated that 21% of premutation carriers develop POI [Sherman 2005]. The odds ratios for POI in premutation carrier females increase with increasing repeat sizes [Sherman 2005] (see Table 5). Although the numbers vary slightly, other studies confirm that these increased risks tend to plateau above 80-100 repeats [Bodega et al 2006, Ennis et al 2006].

Table 5. Odds Ratios for POI by Premutation Size

Premutation Size in CGG RepeatsOdds Ratio for POI
59-796.9
80-9925.1
>10016.4

Full mutation. Males who have a full FMR1 mutation generally have moderate to severe intellectual disability and may or may not have a distinctive appearance.

Approximately 50% of females who have a full FMR1 mutation are intellectually disabled; however, they are usually less severely affected than males with a full mutation. Conversely, approximately 50% of females who are heterozygous for the full mutation are intellectually normal. 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.

Mosaicism. Mosaicism is present in approximately 15%-20% of individuals with FMR1 mutations. Such mosaicism may be (1) "repeat size mosaicism," in which both full mutations and premutations are present (also termed "full-mutation / premutation mosaicism"), or (2) methylation mosaicism, in which full mutations have varying degrees of methylation.

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, such individuals are usually intellectually disabled.

Rarely, individuals with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported. The milder phenotype appears to be related to FMRP production arising from transcription of unmethylated alleles [Tassone et al 1999]. Presumably, these individuals produce at least some FMRP because FMR1 is unmethylated. The existence of these exceptional individuals suggests that repeat expansion and methylation of the gene are not absolutely coupled.

Anticipation

Fragile X syndrome is a trinucleotide repeat disorder that may demonstrate anticipation in some families. Typically, anticipation occurs when less severely affected premutation or mosaic mutation carriers transmit unstable FMR1 alleles to their offspring (e.g., transmission from a grandfather who carries a premutation to his daughter, whose premutation expands into a full mutation when she transmits it to her son, who has intellectual disability as a result). However, the anticipation found in families with members affected with fragile X syndrome is not classic, as is that found in, for example, 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, resulting in an affected individual.

Nomenclature

FMR1-related primary ovarian insufficiency is also referred to as FMR1-related premature ovarian failure.

Fragile X syndrome is also refrerred to as FXS, fragile X mental retardation, marker X syndrome, or Martin-Bell syndrome.

Prevalence

Fragile X syndrome. Prevalence estimates of males with fragile X syndrome have been revised downward since the isolation of FMR1 in 1991. Original estimates of 80:100,000 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. Individuals with intellectual disability coincidentally having other chromosomal fragile sites near FRAXA (e.g., FRAXD, FRAXE, and FRAXF) were likely included in the initial estimates. (Cytogenetic differentiation of these fragile sites is difficult because they are located in close proximity in the Xq27-q28 region.) More recent studies using molecular genetic testing of FMR1 have estimated a prevalence of 16 to 25:100,000 males affected with the fragile X syndrome (using intellectual disability as the hallmark clinical finding) [de Vries et al 1997].

A blinded study of 10,046 newborn males in Taiwan yielded one male with a full mutation and estimated prevalence of 1:1,674 for males with a premutation and 1:143 for intermediate (45-54) alleles [Tzeng et al 2005]. In an analysis of 36,124 newborn males, Coffee et al [2009] determined that the incidence of a full mutation (and hence, fragile X syndrome) was 1:5164.

The prevalence of females affected with fragile X syndrome is presumed to be approximately one half the male prevalence. A population-based prevalence study of affected African American males revealed a higher estimate (39:100,000; 95% CI, 19-78:100,000) than reported previously for whites, although confidence intervals overlap those estimated for whites from this and other studies (27:100,000; 95% CI, 13-54:100,000) [Crawford et al 2002].

Unaffected female FMR1 premutation carriers. The prevalence of females who are unaffected FMR1 premutation carriers is high:

  • In 10,624 French-Canadian women, 41 were found to have an FMR1 premutation, representing a prevalence of 1:259 [386:100,000; 95% CI, 1:373-1:198 (268-505:100,000)] [Rousseau et al 1995].
  • In 14,334 Israeli women of child-bearing age, 127 were found to have CGG repeats greater than 54, including three asymptomatic women with full mutations, representing a prevalence of 1:113 (885:100,000) [Toledano-Alhadef et al 2001].
  • In nearly 2,300 women from the United States, the prevalence of premutations was 1:382 (262:100,000) and of intermediate alleles, 1:143 (699:100,000) [Cronister et al 2005].
  • In the largest study to date from a laboratory database of more than 59,000 tests, the overall female carrier frequency was 1.3% (0.61% for full mutation, 1.7% for a premutation) [Strom et al 2007].

Females with FMR1-related POI. The FMR1 premutation accounts for 4%-6% of all cases of 46,XX POI [reviewed in Sullivan et al 2011].

Males with FXTAS. An estimated 2%-4% of men with adult-onset cerebellar ataxia who represent simplex cases (i.e., a single occurrence in a family) have a premutation in FMR1 [Brussino et al 2005, Cellini et al 2006].

Differential Diagnosis

Developmental delay/ intellectual disability. The signs of fragile X syndrome in early childhood are nonspecific, with developmental delay being an almost universal manifestation among affected individuals. Any child (male or female) with delay of speech, language, or motor development of unknown etiology should be considered for fragile X testing, especially in the presence of a family history of intellectual disability and a consistent physical and behavioral phenotype, and the absence of structural abnormalities of the brain or other birth defects [Curry et al 1997, Moeschler & Shevell 2006]. When fragile X molecular genetic testing is used regularly in this large and loosely defined group of unselected males with intellectual disability, the yield of positive test results is relatively low (~3%-6%) [Curry et al 1997, Shevell et al 2003]. In a more recent study, Rauch et al [2006] found the yield to be 1.2%.

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, chromosome analysis should be performed as a part of their laboratory evaluation [Moeschler & Shevell 2006].

Conditions to be considered in the differential diagnosis include the following:

  • Sotos syndrome. Sotos syndrome is characterized by typical facial appearance, overgrowth, and learning disability ranging from mild to severe. It is associated with behavioral problems, congenital cardiac anomalies, neonatal jaundice, renal anomalies, scoliosis, seizures, and a slightly increased risk for sacrococcygeal teratoma and neuroblastoma. Approximately 80%-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1.
  • Prader-Willi syndrome (PWS). A small subset of people with fragile X syndrome have the hyperphagia and obesity characteristic of PWS. PWS is characterized by severe infantile hypotonia and feeding difficulties, followed by early childhood onset of excessive eating and development of morbid obesity unless controlled. All individuals have developmental delay and cognitive impairment. Temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics are common. Hypogonadism (genital hypoplasia, incomplete puberty, and, in most, infertility), short stature, and characteristic facial appearance are common. Diagnosis is by DNA-based methylation testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region on chromosome 15.
  • Autism. Autistic-like behavior is frequently found in individuals with fragile X syndrome.
  • Attention deficit-hyperactivity disorder (ADHD). Hyperactivity is frequently seen in individuals with fragile X syndrome.
  • Fragile XE syndrome (FRAXE). 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. FRAXA and FRAXE are distinct fragile sites, albeit in close proximity on the X chromosome. The genes spanning the two fragile sites are designated FMR1 (FRAXA) and FMR2 (FRAXE). However, the genes do not have any detectable similarity at the DNA level and the associated clinical entities are discrete.
  • Adult-onset neurologic disorders. The differential diagnosis for FXTAS is broad. One group of 56 individuals had 98 different diagnoses prior to the diagnosis of FXTAS. Most of these were in the following categories: parkinsonism, tremor, ataxia, dementia, autonomic dysfunction, and stroke [Biancalana et al 2005, Hall et al 2005].

    It is estimated that 2%-4% of men with adult-onset cerebellar ataxia who represent as simplex cases (i.e., a single occurrence in a family) have a premutation in FMR1 [Brussino et al 2005, Cellini et al 2006]. See Hereditary Ataxia Overview.

Management

Evaluations Following Initial Diagnosis

Fragile X syndrome. To establish the extent of disease in an individual diagnosed with fragile X syndrome, 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, anxiety, obsessive-compulsive disorder, aggression, and depression
  • In infants, feeding assessment (including attention to possible gastroesophageal reflux)
  • Physical examination to evaluate for hypotonia and/or connective tissue findings, primarily joint hyperextensibility and pes planus
  • Cardiac auscultation for mitral valve prolapse. If indicated by a murmur or click, consider echocardiography (usually in adulthood).
  • Assessment for hypertension
  • History for possible seizure activity
  • Ophthalmologic evaluation for possible strabismus
  • In young children, history and physical examination for evidence of recurrent otitis media

FXTAS. To establish the extent of disease in an individual diagnosed with FXTAS, the following are recommended:

  • Neurologic examination
  • Behavioral and psychological assessment
  • Neuroradiologic evaluation

POI. To establish the extent of disease in a woman diagnosed with POI, gynecologic evaluation including hormonal and/or ultrasonographic assessment is appropriate.

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 [Corrigan et al 2005, Nelson et al 2005]. It is estimated that 5%-10% of women with POI may conceive after the diagnosis [Nelson et al 2005].

Treatment of Manifestations

Fragile X syndrome. No specific treatment is available. Supportive therapy for children and adults with fragile X syndrome currently consists of the following [Hagerman et al 2009, 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.
  • Early educational intervention, special education, and vocational training should be aimed specifically at the known impediments to learning. Parents and teachers of children with fragile X syndrome have recognized the need for individual attention, small class size, and the avoidance of sudden change. More specific guidelines are available through education resources (see Resources).
  • Pharmacologic management of behavioral issues that significantly affect social interaction is appropriate. No particular pharmacologic treatment has been shown to be uniquely beneficial; therapy must be individualized and closely monitored. A closely monitored and integrated program of behavioral management and pharmacologic treatment with an experienced developmental team may prove to be beneficial.
  • Routine medical management of strabismus, otitis media, gastroesophageal reflux, seizures, mitral valve prolapse, and hypertension is appropriate.

FXTAS. No specific treatment is available. Supportive care for problems with gait and/or cognitive deficits may require assistance with activities of daily living.

POI. No specific treatment is available. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive options.

Agents/Circumstances to Avoid

Folic acid should be avoided in individuals with poorly controlled seizures [Hagerman 2002].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FMR1-related disorders are inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a proband

  • The mother of an individual with an FMR1 full mutation (i.e., hypermethylated allele of >200 trinucleotide repeats) is a carrier of a premutation or full mutation and may be affected.
  • An unaffected female premutation carrier may have a father who is a premutation carrier (i.e., a "transmitting male") or a mother who is a premutation carrier or an intermediate allele carrier.
  • The mother of a male with a premutation has a premutation allele or an intermediate allele.
  • Women with premutations are at risk for POI and FXTAS.
  • Women with normal alleles with greater than 54 repeats may be at increased risk for POI.
  • Men with premutations are at risk for FXTAS.

Sibs of a proband. The risk to sibs depends on their gender, the gender of the carrier parent, and the size of the expanded allele in the carrier parent.

Offspring of an individual with a full mutation

  • Males with a full mutation have intellectual disability and generally do not reproduce.
  • Females who inherit the full mutation are at an approximately 50% risk for intellectual disability. Whether or not a female has phenotypic manifestations, her offspring are at a 50% risk of inheriting the full mutation.

Offspring of an individual with a premutation

  • Males who are premutation carriers are considered "transmitting males." The premutation is inherited by all of their daughters and none of their sons. When premutations are transmitted by the father, small increases in trinucleotide repeat number may occur but do not result in full mutations. (In actuality, premutations transmitted from father to daughter may often regress slightly in repeat number.) All daughters of transmitting males are unaffected premutation carriers.
  • Females who are premutation carriers have a 50% risk of transmitting an abnormal (premutation or full mutation) allele in each pregnancy.

    Very rarely, contraction of trinucleotide repeat number, such as contraction of a premutation of 110 repeats in a mother to 44 repeats in her daughter, has been reported [Vits et al 1994].
    • In general, 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.
    • For small premutations, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion (see Molecular Genetic Testing and Molecular Genetics).

Note: Because most clinical laboratories do not examine the AGG repeat status and its clinical utility remains to be fully explored, 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. Nolin et al [2011] recently compared the risk of expanding to a full mutation relative to the size of the premutation allele (N=95). In some categories, risks were significantly different if the premutation was carried by women with a family history of fragile X. For example, 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.

Offspring of an individual with an intermediate allele. About 16% of maternal transmissions of an intermediate allele may occasionally have a minor variation in repeat size (i.e., a change of 1 or 2 repeats); offspring are at negligible risk of being affected. Intermediate alleles ranging from 50 to 54 repeats may be somewhat more unstable than those with fewer than 50 repeats, and potentially may become premutation size (>55 repeats) [Nolin et al 2011]. Thus, 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. Intermediate alleles may infrequently contract by a few repeats, and rarely by sufficiently large number of repeats to be in the normal range [Nolin et al 2011].

Other family members of a proband. 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).

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).

Population-based carrier testing. 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]. Fewer than 8% of women elected such testing. 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.

For additional information regarding population-based testing see McConkie-Rosell et al [2007].

Related Genetic Counseling Issues

Family history. 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.

Grandchildren of transmitting males. The daughters of transmitting males are premutation carriers; thus, their offspring are at risk for fragile X syndrome.

Early diagnosis of fragile X syndrome. The first indication of fragile X syndrome within a family is usually the diagnosis in an affected child. 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, the diagnosis was made more than a year after the child's development or behavior first raised concerns. Half of the surveyed families reported having subsequent pregnancies before diagnosis of the first affected child. These findings emphasize the importance of increased opportunities for early diagnosis so that children and families can receive all possible benefits, including genetic counseling and intervention services [Centers for Disease Control and Prevention 2002].

Fragile X tremor ataxia syndrome (FXTAS) in males with premutation alleles. When a child is diagnosed with fragile X syndrome and his mother is found to have a premutation allele, his maternal grandfather is then known to be at risk of developing FXTAS. Premutation carrier females are also at increased risk for neurologic and psychiatric problems [Chonchaiya et al 2010].

Primary ovarian insufficiency (POI) in females with premutation alleles. The increased risk for POI (i.e., age at menopause <40 years) in female premutation carriers should be taken into account when providing genetic counseling.

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 given the diagnosis POI [Corrigan et al 2005, Nelson et al 2005]. It is estimated that 5%-10% of women with POI may conceive after the diagnosis [Nelson et al 2005]. See Sullivan et al [2011] for a review.

For additional information regarding genetic counseling and cascade testing see McConkie-Rosell et al [2007].

Gamete donation. 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, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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). The FMR1 Southern blot patterns for DNA derived from amniocytes are identical to those found in adult tissues; however, differences in FMR1 methylation patterns may occur in DNA derived from cells obtained by CVS, making the distinction between large premutations and small full mutations difficult. Thus, for pregnancies evaluated by CVS, follow-up amniocentesis or testing using PCR may be necessary to determine the size of the FMR1 alleles in a methylation-independent manner [McConkie-Rosell et al 2005].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutation has been identified. Technical improvements enabling better testing of FMR1 in single embryonic cells produced for PGD have recently been reported [Burlet et al 2006, Malcov et al 2007]. Implantation of embryos detected with normal alleles led to unaffected offspring.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • FRAXA Research Foundation
    45 Pleasant Street
    Newburyport MA 01950
    Phone: 978-462-1866
    Fax: 978-463-9985
    Email: info@fraxa.org
  • National Fragile X Foundation
    Journal: The Foundation Quarterly. Subscriptions through National Fragile X Foundation
    PO Box 190488
    San Francisco CA 94119-0488
    Phone: 800-688-8765; 925-938-9300
    Fax: 925-938-9315
    Email: NATLFX@FragileX.org
  • National Fragile X Foundation
    PO Box 190488
    San Francisco CA 94119-0488
    Phone: 800-688-8765; 925-938-9300
    Fax: 925-938-9315
    Email: NATLFX@FragileX.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Fragile X Research Registry
    University of North Carolina at Chapel Hill
    Campus Box 3366
    Chapel Hill NC 27599
    Phone: 866-744-7879 (toll-free)
    Fax: 919-966-7080
    Email: info@fragilexregistry.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. FMR1-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FMR1Xq27​.3Fragile X mental retardation 1 proteinFMR1 @ LOVDFMR1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for FMR1-Related Disorders (View All in OMIM)

300623FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS
300624FRAGILE X MENTAL RETARDATION SYNDROME
309550FMR1 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. Deletions and point mutations in FMR1 account for the remaining mutations found in individuals with the syndrome. Repeat expansion to the disease-causing range occurs only when a premutation or full mutation is transmitted by females to their offspring. 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).

Hagerman et al [2001] and Jacquemont et al [2004] review evidence of dysregulation of FMR1 in the premutation range, which may explain many of the clinical observations. Paradoxically, Kenneson et al [2001] found a decrease in FMRP and an increase in transcription of FMR1 in premutation carriers. 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. Thus, 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, a process that requires translation of preexisting mRNA near synapses. Evidence strongly indicates that the FMRP represses translation of specific mRNAs. 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. The mGluR theory of fragile X syndrome hypothesizes that in the absence of the FMRP, mGluR-dependent protein synthesis may be exaggerated and result in the fragile X syndrome phenotype [Bear et al 2004].

Normal allelic variants. FMR1 occupies 38 kb of genomic DNA and has 17 exons contained in a messenger RNA of approximately 4 kb. A trinucleotide repeat, composed primarily of CGG, is contained in the untranslated portion of exon 1 ending 69 bp upstream of the translational start, near the 5' end of the gene. Variation of the repeat copy number in normal (i.e., stable) alleles ranges from five to 44 CGG repeats, with a trimodal distribution consisting of a major peak at around 30 repeats and minor peaks at around 20 and 40 repeats. Alternative splicing of FMR1 occurs toward the 3' end of the mRNA.

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]. These AGG repeats appear to "anchor" the segment against repeat expansion, probably by disruption of DNA secondary structures that may form during DNA replication.

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, Bodega et al 2006] but a recent study was unable to replicate this finding [Bennett et al 2010]. Thus, while premutation alleles clearly have an increased risk for POI, some uncertainty exists regarding alleles with fewer than 55 repeats.

  • Intermediate alleles. Variation of the repeat number in intermediate alleles is approximately 45-54 repeats. See Molecular Genetic Testing). An important predictor of repeat instability in large intermediate alleles (>50 repeats) is the number of "pure" CGG repeats without interrupting AGG repeats. Increasingly longer pure repeats, especially those with more than 35 uninterrupted CGG repeats, are more likely to become unstable [Eichler et al 1994].
  • AGG repeats. Large increases in the number of the CGG trinucleotide repeats contained in FMR1 occur exclusively during transmission from female carriers (see Genetic Counseling). 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, Kunst & Warren 1994]. 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, Kunst & Warren 1994]. Recent results have linked the length of the uninterrupted 3’ CGG repeat length with expansion of intermediate and small premutation alleles and suggest a minimum threshold for expansion risk [Nolin et al 2011]. The clinical usefulness of such testing awaits publication of the full study.

Pathogenic allelic variants. 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, Filipovic-Sadic et al 2010, Hantash et al 2010, Lyon et al 2010, Chen et al 2011, Nahhas et al 2011].

  • Premutation FMR1 alleles. Premutation alleles have 55-200 CGG repeats and are not hypermethylated. They do not cause fragile X syndrome in males or females. Premutation alleles often expand upon maternal transmission. Expansion can result in an FMR1 full mutation that causes fragile X syndrome in offspring; risk of expansion is dependent upon the number of CCG repeats in the mother's premutation allele. For smaller maternal premutation alleles, the number and structure of AGG trinucleotide interrupts may also affect the risk of expansion [Nolin et al 2011].
  • Full FMR1 expansion mutation. Expansion of the CGG repeat number beyond approximately 200, accompanied by hypermethylation of the deoxycytosine residues in the FMR1 promoter, inhibits or reduces FMR1 transcription, resulting in the loss of the protein product (FMRP) and giving rise to the expression of the cytogenetic fragile site, FRAXA. It is the loss of FMRP that results in the fragile X syndrome phenotype.
  • Rare FMR1 mutations: deletion or point mutation. Although FMR1 would be expected to have a mutation rate similar to other genes, there is a surprising paucity of reports of individuals with point mutations or other small alterations in FMR1 resulting in fragile X syndrome.

    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, Lugenbeel et al 1995, Wang et al 1997] have been reported but account for far fewer than 1% of those with fragile X syndrome. The existence of affected individuals with deletions has confirmed that the syndrome is caused by the lack of FMR1 transcription. Occasionally, 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. Such individuals are usually described as having "unmethylated full mutations." Individuals having partial methylation of full mutations ("methylation mosaics") are also observed. Cellular mosaicism, in which both premutation and full-mutation cell lines are present, also occurs in some individuals. (For more information, see Table A.)

Normal gene product. The product of FMR1, fragile X mental retardation 1 protein (FMRP), is found in the cytoplasm of many cell types but is most abundant in neurons. 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. FMRP contains both a nuclear localization signal and a nuclear export signal, suggesting that it functions as a nucleocytoplasmic shuttling protein that binds several mRNAs, including its own mRNA, forms messenger ribonucleoprotein complexes, and associates with translating ribosomes [Ceman et al 1999]. FMRP is expressed in many tissues; it also appears to play a role in structural and functional maturation of synapses by serving as a translational suppressor in postsynaptic spaces [Weiler & Greenough 1999]. Absence of FMRP appears to disrupt neurotransmission mediated by the metabotropic glutamate receptor (mGluR) [Bear et al 2004]. Thus, FMRP likely regulates long-term depression and potentiation at neuronal synapses.

Abnormal gene product. It is evident from affected individuals with deletions in FMR1 that gene loss and the consequent lack of FMRP causes fragile X syndrome. The pathogenic mechanism whereby premutation, intermediate, or high-normal alleles result in POI is not well understood. However, in contrast to the loss-of-function mutations producing fragile X syndrome, mounting evidence indicates that FXTAS results from RNA toxicity related to overexpression of premutations [Galloway & Nelson 2009]

References

Published Guidelines/Consensus Statements

  1. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG), Chitayat D, Wyatt PR, Wilson RD, Johnson JA, Audibert F, Allen V, Gagnon A, Langlois S, Blight C, Brock JA, Désilets V, Farell SA, Geraghty M, Nelson T, Nikkel SM, Skidmore D, Shugar A. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837–46. [PubMed: 18845054]
  2. Kronquist KE, Sherman SL, Spector EB. Clinical significance of tri-nucleotide repeats in Fragile X testing: a clarification of American College of Medical Genetics guidelines. Genet Med. 2008;10:845–7. [PMC free article: PMC3111547] [PubMed: 18941415]
  3. Maddalena A, Richards CS, McGinniss MJ, Brothman A, Desnick RJ, Grier RE, Hirsch B, Jacky P, McDowell GA, Popovich B, Watson M, Wolff DJ (Quality Assurance Subcommittee of the Laboratory Practice Committee). Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. 2001. Available online. Accessed 3-17-14. [PMC free article: PMC3110344] [PubMed: 11388762]
  4. McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett RL, Pettersen BJ. Genetic counseling for fragile X syndrome: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2005;14:249–70. [PubMed: 16047089]
  5. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584–7. [PMC free article: PMC3110946] [PubMed: 16247297]
  6. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189–94. [PubMed: 11449487]
  7. Spector EB, Kronquist KE. Technical standards and guidelines for fragile X testing. ACMG Standards and Guidelines for Clinical Genetics Laboratories. 2006. Available online. Accessed 3-17-14.

Literature Cited

  1. Allen EG, Sherman S, Abramowitz A, Leslie M, Novak G, Rusin M, Scott E, Letz R. Examination of the effect of the polymorphic CGG repeat in the FMR1 gene on cognitive performance. Behav Genet. 2005;35:435–45. [PubMed: 15971024]
  2. Amos Wilson J, Pratt VM, Phansalkar A, Muralidharan K, Highsmith WE, Beck JC, Bridgeman S, Courtney EM, Epp L, Ferreira-Gonzalez A, Hjelm NL, Holtegaard LM, Jama MA, Jakupciak JP, Johnson MA, Labrousse P, Lyon E, Prior TW, Richards CS, Richie KL, Roa BB, Rohlfs EM, Sellers T, Sherman SL, Siegrist KA, Silverman LM, Wiszniewska J, Kalman LV. Fragile Xperts Working Group of the Association for Molecular Pathology Clinical Practice Committee; Consensus characterization of 16 FMR1 reference materials: a consortium study. J Mol Diagn. 2008;10:2–12. [PMC free article: PMC2175538] [PubMed: 18165276]
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  101. Wirojanan J, Angkustsiri K, Tassone F, Gane LW, Hagerman RJ. A girl with fragile X premutation from sperm donation. Am J Med Genet A. 2008;146:888–92. [PubMed: 18286596]
  102. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, Corrigan EC, Simpson JL, Nelson LM. The FMR1 premutation and reproduction. Fertil Steril. 2007;87:456–65. [PubMed: 17074338]

Suggested Reading

  1. Chonchaiya W, Schneider A, Hagerman RJ. Fragile X: a family of disorders. Adv Pediatr. 2009;56:165–86. [PMC free article: PMC2921504] [PubMed: 19968948]
  2. D'Hulst C, Kooy RF. Fragile X syndrome: from molecular genetics to therapy. J Med Genet. 2009;46:577–84. [PubMed: 19724010]
  3. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol. 2007;6:45–55. [PubMed: 17166801]
  4. Koukoui SD, Chaudhuri A. Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome. Brain Res Rev. 2007;53:27–38. [PubMed: 16844227]
  5. Maddalena A, Richards CS, McGinniss MJ, Brothman A, Desnick RJ, Grier RE, Hirsch B, Jacky P, McDowell GA, Popovich B, Watson M, Wolff DJ. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality Assurance Subcommittee of the Laboratory Practice Committee. Genet Med. 2001;3:200–5. [PMC free article: PMC3110344] [PubMed: 11388762]
  6. Ribeiro FM, Paquet M, Cregan SP, Ferguson SS. Group I Metabotropic Glutamate Receptor Signalling and Its Implication in Neurological Disease. CNS Neurol Disord Drug Targets. 2010;9:574–9. [PubMed: 20632969]
  7. Tejada MI, García-Alegría E, Bilbao A, Martínez-Bouzas C, Beristain E, Poch M, Ramos-Arroyo MA, López B, Fernandez Carvajal I, Ribate MP, Ramos F. Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome. Menopause. 2008;15:945–9. [PubMed: 18427356]
  8. Warren ST, Sherman SL. The fragile X syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 64. Available online. Accessed 3-17-14.

Chapter Notes

Revision History

  • 26 April 2012 (rs/jt) Revision: clarification in Clinical Diagnosis and Natural History sections
  • 26 January 2012 (cd) Revision: AGG genotyping as a discrete test to determine number and location of AGG interruptions with CGG repeats in FMR1 listed in GeneTests™ Laboratory Directory; findings re POI reported in 16 June 2011 revision confirmed; new data on risk for intermediate and premutation allele expansion when a family history of fragile X syndrome is present
  • 16 June 2011 (cd) Revision: repeats in the high-normal range found not to predispose to POI [Bennett et al 2010]
  • 28 October 2010 (me) Comprehensive update posted live
  • 5 August 2008 (cd) Revision: deletion/duplication testing available clinically
  • 7 March 2008 (cd) Revision: FISH analysis available clinically
  • 20 December 2007 (me) Comprehensive update posted to live Web site
  • 15 March 2007 (cd) Revision: correction of the wording and the discrepancy associated with only using premutation when gray zone (AKA intermediate) FMR1 alleles also present increased risk
  • 25 April 2006 (bp) Revision: Table 4 updated according to Nolin et al (2003)
  • 1 March 2006 (cd) Revision: updated ACMG practice guideline
  • 2 December 2005 (jt) Revision: sequence analysis of FMR1 clinically available; updated genetic counseling recommendations
  • 24 May 2005 (rs/jt) Comprehensive update: change in scope of GeneReview from fragile X syndrome to FMR1-related disorders
  • 13 September 2004 (me) Comprehensive update posted to live Web site
  • 20 April 2004 (jt) Revisions: Testing Algorithm; FXTAS
  • 22 November 2002 (me) Comprehensive update posted to live Web site
  • 26 May 2000 (me) Comprehensive update posted to live Web site
  • 16 June 1998 (pb) Review posted to live Web site
  • May 1996 (jt) Original submission
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