X-inactivation in the clinical phenotype of fragile X premutation carrier sisters.
X-inactivation in the clinical phenotype of fragile X premutation carrier sisters.
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DOI：
10.1212/nxg.0000000000000045
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Berry-Kravis E
中科院分区：
文献类型：
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作者：
Hall DA;Robertson-Dick EE;O'Keefe JA;Hadd AG;Zhou L;Berry-Kravis E
本研究的目的是描述一个病例系列的4姐妹篇与不一致的临床表型与脆性X相关震颤/共济失调综合征（FXTAS），这可能是由不同的CGG重复序列大小和激活率（AR）（细胞携带正常的脆性X智力低下1 [FMR 1]等位基因的活性X染色体的比例）解释。四个姐妹篇与前突变大小FMR 1基因重复进行了详细的临床特征。PCR法测定CGG重复序列长度，甲基化PCR法测定AR，并与Southern印迹法结合光密度图像分析的结果进行比较。姐妹1的CGG扩张最大（82），AR最低（12%），临床表现最严重。姐妹2的CGG扩张较低（70），AR为10%，但临床表现较轻。姐妹3的CGG扩张相似（79），但AR略高（15%），神经系统受累较少。姐妹4具有相似的CGG扩张尺寸80，但具有最大的AR（40%），并且是唯一未受FXTAS影响或在检查时具有任何神经学体征的姐妹。这些结果表明，具有较高AR的前突变携带者女性可能不太可能表现出FXTAS的表现。如果更大规模的研究显示类似的模式，AR数据可能是有益的，以补充CGG重复的大小时，咨询前突变携带妇女在诊所。
The purpose of this study is to describe a case series of 4 sisters with discordant clinical phenotypes associated with fragile X–associated tremor/ataxia syndrome (FXTAS) that may be explained by varying CGG repeat sizes and activation ratios (ARs) (the ratio of cells carrying the normal fragile X mental retardation 1 [FMR1] allele on the active X chromosome). Four sisters with premutation size FMR1 gene repeats underwent detailed clinical characterization. CGG repeat length was determined by PCR, and AR was determined using a newly developed commercial methylation PCR assay and was compared with the results from Southern blot with densitometric image analysis. Sister 1 had the largest CGG expansion (82) and the lowest AR (12%), with the most severe clinical presentation. Sister 2 had a lower CGG expansion (70) and an AR of 10% but had a milder clinical presentation.Sister 3 had a similar CGG expansion (79) but a slightly higher AR of 15% and less neurologic involvement. Sister 4 had a similar CGG expansion size of 80 but had the largest AR (40%) and was the only sister not to be affected by FXTAS or have any neurologic signs on examination. These results suggest that premutation carrier women who have higher ARs may be less likely to show manifestations of FXTAS. If larger studies show similar patterns, AR data could potentially be beneficial to supplement CGG repeat size when counseling premutation carrier women in the clinic.