FX 1: Introduction
FX 2: Background On Fragile X Syndrome
FX 2.1: Gene Symbol/Chromosome Locus
FX 2.2: Omim Number
FX 2.3: Brief clinical description
- Berry-Kravis E.
- et al.
|Disorder||OMIM||Main clinical features||Associated FMR1 variant|
|Fragile X syndrome (FXS)||300624||Cognitive deficit, seizures, macro-orchidism, large ears, autism spectrum disorder||Full-mutation allele (99%), FMR1 sequence variants, FMR1 gene deletion|
|Fragile X primary ovarian insufficiency (FXPOI)||311360||Premature ovarian insufficiency, amenorrhea||Premutation|
|Fragile X tremor ataxia syndrome (FXTAS)||300623||Tremor, cerebellar gait ataxia, MRI white matter lesions||Premutation|
|Fragile X–associated neuropsychiatric disorders (FXAND)||None||Anxiety, depression, ADHD, addictive behavior||Premutation|
FX 2.4: Mode of inheritance
FX 2.5: Gene product and mutational mechanism
- O’Donnell W.T.
- Warren S.T.
FX 2.6: Non-CGG repeat expansion variants in the FMR1 gene
FX 2.7: Prevalence and ethnic association of common variants
FX 2.7.1: Full mutations
- Hunter J.
- et al.
FX 2.7.2: Premutations
- Cronister A.
- DiMaio M.
- Mahoney M.J.
- Donnenfeld A.E.
- Hallam S.
- Berkenstadt M.
- Ries-Levavi L.
- Cuckle H.
- Peleg L.
- Barkai G.
- Tzeng C.C.
- et al.
- Cellini E.
- et al.
- Sullivan S.D.
- Welt C.
- Sherman S.
FX 2.8: Special testing considerations
FX 2.8.1: Sensitivity and specificity
FX 2.8.2: Indications for testing
- Borch L.A.
- Parboosingh J.
- Thomas M.A.
- Veale P.
FX 2.8.3: Prenatal testing
- Methylation associated with lyonization is usually not present, and methylation associated with full mutations may or may not be present.69.In the past, the hypomethylated status of this locus in this tissue had been thought of as a limitation or possible source of confusion. However, because it is unwarranted to use methylation status or X-inactivation for phenotypic prediction of a full mutation, the possible hypomethylation of this tissue is no disadvantage, provided that the tissue-specific basis of the hypomethylation is understood.70.,
- The degree of somatic variation in a full-mutation “smear” has a wider range of possibilities than is typically seen in blood specimens, from very limited to extraordinarily diffuse.
- Mosaicism between trophoblasts and somatic cells is theoretically possible. For this reason, when CVS results indicate a premutation, a follow-up amniocentesis has been suggested to rule out mosaicism for a full mutation. However, there are currently no known occurrences of this type of mosaicism.
FX 2.9: Nomenclature
FX 3: Guidelines
FX 3.1: Definition of normal and variant categories
|# CGG repeats||Category||Clinical significance|
|≤44||Normal||No disease association. Rare cases with FMR1 deletion or base change may cause fragile X. Very low risk of CGG repeat expansion to next generation.|
|45–54||Intermediate or gray zone||No disease association. Very low risk of CGG expansion to full mutation within one generation.|
|55–200||Premutation||Males and females: fragile X–associated tremor ataxia syndrome (FXTAS). Females only: fragile X–associated primary ovarian insufficiency (FXPOI). Risk of expansion to full mutation in the next generation when maternally inherited.|
|>200||Full mutation||Fragile X syndrome: clinical severity influenced by sex, degree of methylation, and level of mosaicism.|
FX 3.1.1: Normal alleles
FX 3.1.2: Intermediate (gray zone, inconclusive, borderline)
FX 3.1.3: Premutation
|Variant||Interpretation||Clinical Significance for the Patient||Clinical Significance for the Patient’s Family||Recommendations|
|Full mutation, heterozygote female||(1) This patient possesses a full fragile X expansion mutation with greater than 200 CGG repeats on one FMR1 allele as determined by triple repeat–primed PCR. (2) This patient possesses a full fragile X expansion mutation with approximately [***] CGG repeats on one FMR1 allele. Southern blot analysis identified a pattern consistent with hypermethylation in the FMR1 gene. The second FMR1 allele contains [**] CGG repeats, which falls within the normal range (≥5–≤44 CGG repeats).||These results indicate that this patient possesses the common trinucleotide repeat expansion variant observed in the majority of patients affected with fragile X syndrome. Females with full mutations have variable clinical presentations, ranging from no detectable deficits to clinical symptoms as severe as affected males.||Mothers of children with full mutations carry a premutation or a full mutation in one of their FMR1 genes and are at risk to have other affected children. With each pregnancy, female carriers of full mutations have a 50% chance of passing the mutation on to their child (daughters and sons).||Genetic counseling and FMR1 DNA testing are recommended for at-risk family members to determine the size of their FMR1 allele(s). Prenatal diagnosis in future pregnancies should be considered.|
|Full mutation, male||(1) This patient possesses a full fragile X expansion mutation with greater than 200 CGG repeats on one FMR1 allele as determined by triple repeat–primed PCR. (2) This patient possesses a full fragile X mutation with approximately [***] CGG repeats. Southern blot analysis identified a pattern consistent with hypermethylation in the FMR1 gene.||This result is consistent with a clinical diagnosis of fragile X syndrome.||Mothers of children with full mutations carry a premutation or a full mutation in one of their FMR1 genes and are at risk to have other affected children.||Genetic counseling and FMR1 DNA testing are recommended for at-risk family members to determine the size of their FMR1 allele(s). Prenatal diagnosis in future pregnancies should be considered.|
|Premutation heterozygote, female||One allele of this patient’s FMR1 gene contains [**] CGG repeats, which falls within the premutation range (≥55–≤200 CGG repeats). The second FMR1 allele contains [**] CGG repeats, which falls within the normal range (≥5–≤44 CGG repeats).||Females carrying a premutation allele do not have fragile X syndrome, but they are at an increased risk for fragile X–associated primary ovarian insufficiency (FXPOI), which is defined as menopause prior to the age of 40. Approximately 20% of female premutation heterozygotes have FXPOI, although the rate varies with expanded repeat length; the greatest prevalence of FXPOI is between 80 and 100 CGG repeats. Women are also at risk for fragile X–associated tremor ataxia syndrome (FXTAS), an adult-onset neurodegenerative disorder that occurs in approximately 16% of women who are premutation heterozygotes. Premutation heterozygotes are also at increased risk for fragile X–associated neuropsychiatric disorders (FXAND).||The premutation allele may have been inherited from either parent. Males can pass a premutation allele to female children, however, in male transmission the size of the premutation allele remains stable. When premutation alleles are transmitted from females to their children, expansion of the premutation allele into the full-mutation range can occur. Recent studies have demonstrated that premutation alleles with no AGGs are at risk for expansion to full mutations in the next generation while alleles that include AGG interruptions are associated with greater intergenerational stability of the repeat.||Genetic counseling and FMR1 DNA testing are recommended for at-risk family members to determine the size of their FMR1 allele(s). Females with premutations may be referred for determination of AGG interruptions. Prenatal diagnosis in future pregnancies should be considered.|
|Premutation, male||This patient’s FMR1 gene contains [**] CGG repeats, which falls within the premutation range (≥55–≤200 CGG repeats).||Males with premutation alleles do not have fragile X syndrome but they are at risk for fragile X–associated tremor ataxia syndrome (FXTAS), an adult-onset neurodegenerative disorder that occurs in approximately 40% of men with a premutation. Premutation heterozygotes are also at increased risk for fragile X–associated neuropsychiatric disorders (FXAND).||In males, fragile X premutations are maternally inherited. When premutation alleles are transmitted from females to their children, expansion of the premutation allele into the full-mutation range can occur. Recent studies have demonstrated that premutation alleles with no AGGs are at risk for expansion to full mutations in the next generation while alleles that include AGG interruptions are associated with greater intergenerational stability of the repeat. In the next generation, all daughters of males carrying fragile X premutations will inherit the premutation allele and will be at risk for having sons with fragile X syndrome and fragile X heterozygote daughters.||Genetic counseling and FMR1 DNA testing are recommended for at-risk family members to determine the size of their FMR1 allele(s). Prenatal diagnosis in future pregnancies should be considered.|
|Intermediate range, female heterozygote||One allele of this patient’s FMR1 gene contains [**] CGG repeats, which falls within the intermediate range (≥45–≤54 CGG repeats). The second FMR1 allele contains [**] CGG repeats, which falls within the normal range (≥5–≤44 CGG repeats).||No FMR1-related disorders are associated with patients possessing an intermediate range allele.||Studies have shown that 7.7% of parents with FMR1 alleles in the 40–49 range and 25% of parents with FMR1 alleles in the 50–60 CGG repeat range are likely to pass a changed FMR1 allele to their children.|
|Intermediate range, male||This patient’s FMR1 gene contains [**] CGG repeats, which falls within the intermediate range (≥45–≤54 CGG repeats).||No FMR1-related disorders are associated with patients possessing an intermediate range allele.||Studies have shown that 7.7% of parents with FMR1 allele in the 40–49 range and 25% of parents with FMR1 alleles in the 50–60 CGG repeat range are likely to pass a changed FMR1 allele to their children.|
|Normal range, female||This patient’s FMR1 alleles contain [**] and [**] CGG repeats, both of which fall within the normal range (≥5–≤44 CGG repeats).||No FMR1-related disorders are associated with patients possessing normal range alleles.||Genetic counseling is recommended.|
|Normal range, male||This patient’s FMR1 allele contains [**] CGG repeats, which falls within the normal range (≥5–≤44 CGG repeats).||No FMR1-related disorders are associated with patients possessing normal range alleles.||Genetic counseling is recommended. If clinically indicated, FMR1 sequencing and/or deletion analysis may be considered.|
FX 3.1.4: Full mutations
FX 3.1.5: Mosaicism
FX 188.8.131.52: Size mosaics
FX 184.108.40.206: Methylation mosaics
FX 3.1.6: AGG interruptions
FX 3.2: Methodological considerations
- Monaghan K.G.
- et al.
FX 3.2.1: Southern blot analysis
FX 220.127.116.11: Probe and restriction site combinations
- Help discriminate between premutations and full mutations for the rare alleles that fall near the boundary (i.e., around 200 repeats).
- Detect rare individuals who are methylation mosaics.
FX 3.2.2: PCR methods
FX 18.104.22.168: Triplet repeat–primed PCR
- Hantash F.M.
- et al.
- Hantash F.M.
- et al.
FX 3.2.3: Non–Southern blot methods for methylation detection
FX 22.214.171.124: Methylation-specific PCR
FX 126.96.36.199: Multiplexed ligation probe amplification (MLPA)
FX 188.8.131.52: Real-time PCR
FX 3.3: Interpretations
FX 3.3.2: The following descriptive elements may appear, with caution:
FX 3.3.3: Helpful points on alternative diagnoses may be included
FX 4: Alternative Testing Methods
FX 4.1: Next-generation sequencing (NGS)
FX 4.2: Cytogenetic evaluation
FX 4.3: Protein analysis
FX 5: Policy statements
- Maddalena A.
- et al.
- Monaghan K.G.
- et al.
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