Table 14.

Risk for an FMR1 Disorder in Sibs Who Inherit an FMR1 CGG Expansion

Transmitting
Parent		Risk to Sibs Who Inherit an FMR1 CGG ExpansionComment
Hemizygous maleHeterozygous female
Mother w/
intermediate
allele (~45-
54 CGG
repeats)		If allele remains < ~55 repeats:
not at risk for an FMR1 disorder
  • ~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size. 1
  • Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats. 2
If allele expands into premutation range:
At risk for FXTASAt risk for FXPOI, FXTAS, & psychiatric disorders
Mother w/
premutation
allele (~55-
200 CGG
repeats)		If allele remains in premutation range:
  • In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation. 3, 4
  • For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
At risk for FXTASAt risk for FXPOI, FXTAS, & psychiatric disorders
If allele expands into full mutation range: 5
Affected w/FXS~50% risk of ID & ~50% likelihood of normal intellect
Mother w/
full-mutation
allele (>200
CGG repeats)		Affected w/FXS~50% risk of ID & ~50% likelihood of normal intellect 5
Father w/
premutation
allele
("transmitting
male"; ~55-
200 CGG
repeats)		NAAt risk for FXPOI, FXTAS, & psychiatric disorders
  • Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
  • Premutations transmitted from father to daughter may often regress slightly in repeat number.

FXPOI = fragile X-associated primary ovarian insufficiency; FXS = fragile X syndrome; FXTAS = fragile X-associated tremor/ataxia syndrome; ID = intellectual disability

1.

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].

2.
3.

Rarely, contraction of trinucleotide repeat number occurs, though this appears to be more frequent in paternal transmissions than maternal transmissions, with the highest frequency of contractions in the 70-90 repeat range [Nolin et al 2015].

4.

Nolin et al [2011] 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 vs an 18% risk in the absence of a family history. Risk of expansion is also increased with fewer AGG trinucleotide repeat interruptions [Nolin et al 2015].

5.

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.

From: FMR1 Disorders

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