Lack of MECP2 gene transcription on the duplicated alleles of two MECP2
duplication females with opposite skewed X chromosome inactivation
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