Objective: To describe the role of X-inactivation in clinically discordant phenotypes in sisters with a fragile X mental retardation 1 (FMR1) gene premutation but varying X-inactivation rates.

Background: X chromosome inactivation is the transcriptional silencing of one X chromosome in the somatic cells of women. For FMR1 premutation carrier women, this means that a percentage of their cells contain an active normal FMR1 allele and the remaining cells will contain an active abnormal FMR1 allele. Skewed X-inactivation may be responsible for mediating some of the phenotypic variability seen in FMR1 premutation carrier women, including the presence of the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a progressive neurodegenerative disorder characterized by tremor, ataxia, and cognitive decline in FMR1 premutation carriers.

Methods: Four sisters with premutation size FMR1 repeats underwent detailed clinical characterization, including the FXTAS Motor Rating Scale. Diagnostic criteria for FXTAS were performed. CGG repeat length was determined by PCR and AR was determined using a newly developed commercial mPCR assay (Asuragen) and confirmed with results from Southern blot with densitometric image analysis.

Results: Sister 1 had the largest CGG expansion (90) and the lowest AR (10%), with the most severe clinical presentation. She met criteria for definite FXTAS and died six years after neurological symptom onset. Sister 2 had a lower CGG expansion (70) and an AR of 10%. She had milder neurological symptoms and met criteria for possible FXTAS. Sister 3 had a CGG expansion of 79, but a slightly higher AR of 15%. She had less neurological involvement and also met criteria for possible FXTAS. Sister 4 had a similar CGG expansion (80), but had the largest AR (40%) and was the only sister not to be affected by FXTAS or show any abnormal neurological signs.

Conclusions: Women in the same family who have higher AR or lower CGG repeat sizes than their sisters may be less likely to show manifestations of FXTAS. In prior studies, severity of motor impairment in FMR1 premutation carrier women has been shown to relate to CGG length only when accounting for AR. Thus, using AR data could be beneficial to supplement CGG repeat size when counseling premutation carrier women for their risk for FXTAS.

Paper is in press in Neurology Genetics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/repeat-size-and-x-inactivation-in-the-clinical-phenotype-of-fragile-x-premutation-carrier-sisters-a-familial-case-series/