Table 3 Suggested comments for the reporting of fragile X results.

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.⁷⁵ Both expansion and contraction of the CGG repeat size were observed in the next generation.

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, 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.⁷⁵ Both expansion and contraction of the CGG repeat size were observed in the next generation.

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.

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.