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Lack of MECP2 gene transcription on the duplicated alleles of two MECP2 duplication females with opposite skewed X chromosome inactivation
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  • Yixi Sun,
  • Yali Yang,
  • Yuqin Luo,
  • Min Chen ,
  • Liya Wang,
  • Yingzhi Huang ,
  • Yanmei Yang,
  • Mingyue Dong
Yixi Sun
Zhejiang University
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Yali Yang
Zhejiang University
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Yuqin Luo
Zhejiang University
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Min Chen
Zhejiang University
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Liya Wang
Zhejiang University
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Yingzhi Huang
Zhejiang University
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Yanmei Yang
Zhejiang University
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Mingyue Dong
Zhejiang University
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Abstract

Xq28 (involving MECP2) duplication syndrome is a severe neurodevelopmental disorder in males, most females are asymptomatic carriers, but there are phenotypic heterogeneities in the females. Skewed X-chromosome inactivation (XCI) seems to prevent duplicated region activation in asymptomatic females, but it remains controversial. Herein we reported two asymptomatic females (daughter and mother) with interstitial Xq28 duplication. HUMARA and RP2 assays showed that both had complete skewed XCI, the Xq28 duplicated chromosome was inactivated in the daughter, but surprisingly, it was activated in her mother. Interestingly, by combining RNA sequencing and whole-exome sequencing, we confirmed that XIST only expressed in the Xq28 duplication chromosomes of the two females, indicating that the Xq28 duplication chromosomes were inactive. Meanwhile, MECP2 and most XCI genes in the duplicated X-chromosomes were not transcriptionally expressed or upregulated, precluding major clinical phenotypes in the two females, especially the mother. We showed that XCI status detected by RNA sequencing was more relevant for establishing the clinical phenotype of MECP2 duplication females. It suggested there were other factors maintaining the XCI status in addition to DNA methylation, a possible additional inhibition mechanism occured at the transcriptional level in the unmethylated X-chromosome, counter balancing the MECP2 duplication’s detrimental phenotype effects

Peer review status:IN REVISION

12 Mar 2021Submitted to Human Mutation
16 Mar 2021Assigned to Editor
16 Mar 2021Submission Checks Completed
05 Apr 2021Reviewer(s) Assigned
15 Apr 2021Review(s) Completed, Editorial Evaluation Pending
21 Apr 2021Editorial Decision: Revise Major